Compositions and methods of use thereof for treatment and modulation of acute and chronic symptoms of mitochondrial disease and dysfunction

Abstract

Compositions and methods for treatment and amelioration of mitochondrial dysfunction and disease are disclosed.

Description

[0001] COMPOSITIONS AND METHODS OF USE THEREOF FOR TREATMENT AND MODULATION OF ACUTE AND CHRONIC SYMPTOMS OF MITOCHONDRIAL DISEASE AND DYSFUNCTION By Marni J. Falk, MD Neal Matthew, PhD Eiko Nakamaru-Ogiso, PhD CROSS REFERENCE TO RELATED APPLICATION This application claims priority to US Provisional Application No. 63 / 538,063 filed September 12, 2023, the entire disclosure being incorporated herein by reference as though set forth in full. GRANT SUPPORT STATEMENT This invention was made with government support under grant numbers GM134863 and GM120762 awarded by the National Institutes of Health. The government has certain rights in the invention. FIELD OF THE INVENTION This invention relates to the fields of physiology, pharmacology, and mitochondrial disease. More specifically, the invention provides compositions comprising tartrate, bitartrate, derivatives thereof and other therapeutic agents, for use alone and in combination for amelioration of symptoms of mitochondrial disease and dysfunction in human subjects. Also provided are methods for combining potent therapeutic agents for use in synergistic combinations for the treatment of mitochondrial disease. BACKGROUND OF THE INVENTION Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated herein by reference as though set forth in full. Mitochondrial diseases are a group of clinically and genetically heterogeneous yet collectively common group of energy deficiency disorders driven by oxidative phosphorylation dysfunction of the mitochondrial respiratory chain caused by pathogenic mutations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). The treatment of mitochondrial diseases is largely symptomatic currently with empiric therapies that do not significantly change the course of the disease. There are no FDA approved treatments or cures. Intensive genomic research has identified more than 350 genes in nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) that are known to cause mitochondrial diseases. Symptoms are varied but can include seizures, stroke, fatigue, exercise intolerance, weakness, heart muscle and rhythm problems, vision and hearing loss, cognitive disabilities, respiratory problems, hormonal deficiencies, immune deficiencies, gastrointestinal dysmotility, or poor growth, among others. Patients on average have 16 major medical problems, which often progressively develop over time. The disease can adversely affect any of the body's organs and systems and is sometimes fatal. In addition, it is difficult to diagnose mitochondrial disease or dysfunction because its symptoms may be non-specific or resemble those of other illnesses. Recent figures estimate that there is a minimal prevalence of 1 in 4,300 people of all ages affected with primary (e.g., genetic alteration-based) mitochondrial disease. Secondary mitochondrial dysfunction occurs in a much bigger population as well as in a diversity of common complex disorders (such as neurogenerative diseases including Alzheimer’s disease, Parkinson’s Disease, Amyotrophic Lateral Sclerosis; metabolic diseases including diabetes mellitus and metabolic syndrome; and cancer) and is as likely to benefit from similar therapies as primary mitochondrial disease. Secondary mitochondrial dysfunction also occurs from many toxic environmental exposures including medications and poisons, as well as aging (e.g., frailty syndrome, organ dysfunction with age) and immobilization (disuse atrophy). There is a clear, urgent need for new and effective treatments for mitochondrial disease and dysfunction. In the last 5 years, more than 50 biopharma companies have entered this space to develop novel and effective therapies for mitochondrial disease. However, to date, only very few efficacious agents have been identified. SUMMARY OF THE INVENTION In accordance with the present invention, a composition which modulates at least one of primary, secondary, acute and chronic, mitochondrial disease or dysfunction for the treatment of mitochondrial disease or dysfunction comprising an effective amount of at least one of bitartrate or tartrate in a pharmaceutically acceptable formulation is disclosed. In certain embodiments, the one or more agents include those listed in Table 1, Figure 9, or modified derivatives thereof. In other embodiments, the composition includes one or more of N-acetylcysteine, nicotinic acid (niacin), niacinamide, nicotinamide riboside, nicotinamide mononucleotide, probucol, glucose, 2-deoxyglucose, lipoic acid, resveratrol, thiamine, riboflavin, leucine, uridine, 3-methyladenine, hemin, trypterin, (+) epicatechin, (-) epicatechin, 11-hydroxyprogesterone, 11- hydroxypregnenolone, cycloheximide, rapamycin, lithium chloride, creatine, dichloroacetate, omaveloxolone, elamipretide, dimethylfumarate, a deubiquitalase (DUB) modulating agent, a PPAR alpha modulating agent, a PPAR gamma modulating agent, a PPAR delta modulating agent, an AMPK modulating agent, a sirtuin modulating agent, a mTORC1 modulating agent, a MAPK modulating agent, a PGC1-α modulating agent, a HIF1-alpha modulating agent, a mitochondrial biogenesis modulating agent, an antioxidant, a phosphodiesterase modulator, sildenafil, doxycycline, tetracycline, trapidil, a calcium channel modulator, flunarizine, folinic acid, metformin, a nucleoside, valproic acid, dexamethasone, etoposide, vorinostat, quercitin, hydralazine, pfithrin-α, ginsenoside, sulfonsuccinimidyl oleate, carnitine, levocarnitine, AICAR, GSK2578215A, bezafibrate, vatiquinone, coenzyme Q10, alpha-tocopherolquinone, a coenzyme Q10 analog, ubiquinone, ubiquinol, cytochrome C, 5 I-2-(4-hydroxyphenyl)-ethenyl] benzene- 1,3 diol, flavin mononucleotide, urolithin A, idebenone, latrepirdine, 2′,3′,5′-tri-O-acetyluridine, olesoxime, thiamine diphosphate, vitamin C, vitamin D, vitamin E, delta-aminolevulinic acid, magnesium, calcium, phosphate, membrane phospholipid, unsaturated fatty acid, pyruvate, nicotinamide adenine dinucleotide, cysteamine bitartrate, acipimox, glutathione, a redox- modulating agent, curcumin, schisandrin, triheptanoin, an inhibitory nucleic acid targeting an upregulated gene associated with mitochondrial dysfunction, an activating genetic construct for increasing expression of a mitochondrial disease modulator protein, a nucleic acid / protein complex for genetic and / or base editing suitable for replacement therapies for primary mitochondrial diseases, a viral or non-viral vector gene therapy targeting a mitochondrial disease mutation, or a combination of any 2, 3, 4, 5 or 6 of the agents listed above. In a preferred embodiment, the compositions of the invention correct a deficiency in oxidative phosphorylation (OXPHOS), wherein said deficiency is associated with mitochondrial respiratory chain complex I, complex II, complex III, complex IV, and / or complex V dysfunction alone or in combination. The respiratory chain complex dysfunction can be caused by a genetic mutation or exposure to a toxic agent. In preferred embodiments, the composition reduces or inhibits one or more of acute stressor induced decompensation, neurologic and / or neuromuscular dysfunction, cell death, whole animal death, brain death, impairment of tricarboxylic acid cycle anaplerosis, impairment of intermediary metabolism, impairment of NADH:NAD+redox state, aberrant alteration in glutathione (GSH:GSSG) redox metabolic stroke, aberrant mitophagy, or aberrant mitochondrial energy production. In other embodiments, the composition provides protective effects selected from one or more of improvement in cell viability, cell proliferation, ATP production, mitochondrial stress, mitochondrial unfolded protein response, mitochondrial integrated stress response, mitochondrial membrane potential, mitochondrial oxygen consumption capacity, mitochondrial coupling of oxidation to phosphorylation, mitochondrial electron transport chain enzyme activities, mitochondrial metabolite levels, mitochondrial mass or content, mitochondrial oxidant levels, cellular or mitochondrial oxidant scavenging capacity, mitochondrial DNA mutation, reduced oxidative stress, improvement in total cellular oxidant levels, increases in cellular antioxidant defense enzymes, improved glutathione metabolism, improved cellular pH, improved anaplerosis, improved pyruvate dehydrogenase capacity, and improved cellular oxygen capacity consumption. The composition can comprise at least two agents, at least three agents or at least four agents and can be administered together or separately and sequentially. In certain embodiments the combination of agents acts synergistically. In another embodiment, the composition excludes at least two, at least three, or at least 4 of agents selected from N- acetylcysteine, nicotinic acid, niacinamide, nicotinamide riboside, nicotinamide mononucleotide, glucose, trypterin, hemin, (+) epicatechin, (-) epicatechin, 11-hydroxyprogesterone, 11- hydroxypregnenolone, dichloroacetate, and probucol. The invention also provides a method for treatment or amelioration of symptoms of a mitochondrial disease in a patient in need thereof comprising administration of an effective amount of the compositions described above, thereby treating said mitochondrial disease in said patient. The mitochondrial disease can be caused by a genetic alteration in a gene selected from at least one listed in one or all of Mitochondrial Disease Genes Compendium - 1st Edition on the world wide web at elsevier.com; McCormick EM, et al. Expert Panel Curation of 113 Primary Mitochondrial Disease Genes for the Leigh Syndrome Spectrum. Ann Neurol. 2023 May 31. doi: 10.1002 / ana.26716; ClinGen gene curation expert panel on the world wide web at clinicalgenome.org; the Clin Gene Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel - ClinGen | Clinical Genome Resource and the annotated locus-specific database of pathogenic variants for mitochondrial diseases on the world wide web at mseqdr.org / mb.php?url=genes.php. In certain approaches, at least two agents, at least three or at least four agents are administered simultaneously in a one or more pharmaceutically acceptable formulations. In other approaches, the at least three agents are administered sequentially in separate pharmaceutically acceptable formulations. The compositions can be screened for efficacy prior to said treatment in at least one model of mitochondrial disease selected from a C. elegans model, a D. rerio model, a mouse model, and a H. sapiens cell line model. The methods are useful for treatment of a mitochondrial disease selected from one or more of ADOA: Autosomal Dominant Optic Atrophy; AD: Alzheimer's Disease; ADPD: Alzheimer's Disease and Parkinson's Disease; AMDF: Ataxia, Myoclonus and Deafness CIPO: Chronic Intestinal Pseudo-obstruction with myopathy and Ophthalmoplegia; CPEO: Chronic Progressive External Ophthalmoplegia; CPEO plus including multi-systemic symptoms; MID: Maternally inherited deafness or aminoglycoside-induced Deafness; DEMCHO: Dementia and Chorea; DMDF: Diabetes Mellitus & Deafness; Exercise Intolerance; ESOC: Epilepsy, Strokes, Optic atrophy, & Cognitive decline; FBSN: Familial Bilateral Striatal Necrosis; FICP: Fatal Infantile Cardiomyopathy Plus, a MELAS-associated cardiomyopathy; GER: Gastrointestinal Reflux; KSS: Kearns Sayre Syndrome; LDYT: Leber's hereditary optic neuropathy and Dystonia; LHON: Leber Hereditary Optic Neuropathy; LIMM: Lethal Infantile Mitochondrial Myopathy; LSS: Leigh syndrome spectrum; MDM: Myopathy and Diabetes Mellitus; MELAS: Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes; MEPR: Myoclonic Epilepsy and Psychomotor Regression; MERME: MERRF / MELAS overlap disease; MERRF: Myoclonic Epilepsy and Ragged Red Muscle Fibers; MHCM: Maternally Inherited Hypertrophic Cardiomyopathy; MICM: Maternally Inherited Cardiomyopathy; MILS: Maternally Inherited Leigh Syndrome; Mitochondrial Encephalocardiomyopathy; Mitochondrial Encephalomyopathy; MM: Mitochondrial Myopathy; MMC: Maternal Myopathy and Cardiomyopathy; Multisystem Mitochondrial Disorder (myopathy, encephalopathy, blindness, hearing loss, peripheral neuropathy); NARP: Neurogenic muscle weakness, Ataxia, and Retinitis Pigmentosa; alternate phenotype at this locus is reported as Leigh Disease; NIDDM: Non-Insulin Dependent Diabetes Mellitus; PEM: Progressive Encephalopathy; PME: Progressive Myoclonus Epilepsy; PS: Pearson syndrome; RTT: Rett Syndrome; SIDS: Sudden Infant Death Syndrome, SLSMDs, single large-scale mtDNA deletion syndrome; Multiple large-scale deletion disorders; and pathogenic mitochondrial cytopathies caused by point mutations or deletions / duplications in the mitochondrial DNA genome, said composition alleviating one or more symptoms of said mitochondrial disease. In other embodiments, the disease is Leigh syndrome or Leigh syndrome spectrum. Before or after treatment, the patient is assessed using one or more assessment tests selected from Motor Function Measure, Dynamometry Measures, Cardiopulmonary exercise Test (CPET), Creatine-CEST MRI measures of post-exercise creatine and phosphocreatine levels recovery in muscle, Twelve Minute Walk Test, Six Minute Walk Test Total Distance Walked, Six Minute Walk Distance Per Minute Distance Walked, Two Minute Walk Test, Modified Fatigue Impact Scale, MM-COAST Mitochondrial Myopathy Composite Assessment Tool, Finger Dexterity Score (9-hole peg test), Barry Albright Dystonia Scale (BADS), Friedreich's Ataxia Rating Scale (FARS), Scale for the Rating and Assessment of Ataxia (SARA), Movement Disorders Childhood Rating Scale (CRS), Patient-Reported Outcomes Measurement Information System Gastrointestinal Symptom Scales, 30-Second Sit to Stand Test, Muscle Strength by Myometry Test, Newcastle Mitochondrial Disease Adult Scale, Newcastle Mitochondrial Disease Pediatric Scale, 36-Item Short Form Survey, PediCAT score of function, Peds-QL Quality of Life Score, Karnofsky-Lansky Scale, Caregiver Burden Scale, Observer Reported Outcome (ObsRO) scale, Clinical Global Impression of Change, Patient's Global Impression of Change, Patient-Reported Initial Mitochondrial Personalized Composite Scale (MitoPC) Symptoms, Patient-Reported MitoPC Symptom Changes, Columbia Suicide Severity Rating Scale, Neuropathy Impairment Score, Migraine Disability Assessment Test, Quick Inventory of Depressive Symptomatology—Self-Report, Montreal Cognitive Assessment, NY Heart Association Functional Classification, Diabetes Health Profile, Hemoglobin A1C measure, Lactate measure, Pyruvate measure, Lactate:Pyruvate ratio measure, Alanine measure, Alanine- linked amino acid ratios measure, ketone body levels and ratio of acetoacetate: β- hydroxybutyrate, 2-hydroxy-butyrate level, glutathione GSH (reduced) and GSSG (oxidized) levels and ratio, CoQ10 level, creatine level, creatinine level, transaminase (ALT and AST) levels, urine organic acid levels, carnitine and acylcarnitine levels, N-lactoyl-amino acids, β- hydroxy acylcarnitines, β-hydroxy fatty acids, Ocular Motility Assessments, Marginal Reflex Distance, Ocular Motility & Fixation in 8 Gaze Directions, Degree of Ocular Saccades, Visual Function Test, Logarithm of Minimum Angle of Resolution, Pelli-Robson Score, Humphrey Visual Field mean deviation, or a combination thereof. In certain embodiments, the patient is assessed using 1, 2, 3, 4, 5, 6, or 7 of tests selected from MM-COAST, Motor Function Measure, Six Minute Walk Test, Modified Fatigue Impact Scale, Friedreich's Ataxia Rating Scale, and the Patient-Reported Outcomes Measurement Information System Gastrointestinal Symptom Scales. In yet another embodiment, a method for identifying compositions having efficacy for the treatment of mitochondrial disease symptoms is provided. An exemplary method comprises determining levels of one or more of parameters associated with mitochondrial dysfunction in a biological sample from the subject, comparing the measurement of said one or more parameters to levels observed i) prior to administration of the composition, or ii) after administration of the composition; and identifying agents which alter levels of one or more of cellular OXPHOS function, blood pH, levels of cellular redox molecules selected from NADH, NAD+, NADH / NAD+, glutathione, GSH:GSSG ratio, reduced GSH, oxidized GSSG, ketone body, beta- hydroxybutyrate:acetoacetate, citrate, lactate, succinate, fumarate, alanine, 2-hydroxy-butyrate, 4-hydroxy-butyrate, methylglutaconic acid, ethylmalonic acid in plasma or urine, hemoglobin A1C, lactate , pyruvate, lactate:pyruvate ratios, alanine-linked amino acids, acetoacetate: β- hydroxybutyrate ratio, CoQ10 level, creatine, creatinine, transaminase ALT, transaminase AST, urine organic acid, carnitine, acylcarnitine, a N-lactoyl-amino acid, a β-hydroxy acylcarnitine, a β-hydroxy fatty acid, ATP in whole blood or platelets, agents altering said parameter levels while reducing mitochondrial dysfunction, having efficacy for the treatment of mitochondrial disease. In certain approaches, OXPHOS function is determined in platelets, whole blood, cells, or tissues. The disease to be treated can comprise one or more of the mitochondrial diseases listed above. In preferred embodiments, the composition alters a parameter resulting in amelioration of symptoms associated with mitochondrial dysfunction, selected from improved cell viability, improved cell proliferation, increased ATP production, reduction in mitochondrial stress, improved mitochondrial unfolded protein response, mitochondrial integrated stress response, improved mitochondrial membrane potential, increased mitochondrial oxygen consumption capacity, increased mitochondrial coupling of oxidation to phosphorylation, improved mitochondrial electron transport chain enzyme activities, increased mitochondrial metabolite levels, improved mitochondrial mass or content, improved mitochondrial oxidant levels, cellular or mitochondrial oxidant scavenging capacity, corrects a mitochondrial DNA mutation, reduces oxidative stress, improves total cellular oxidant levels, increases in cellular antioxidant defense enzyme levels, improved glutathione metabolism, improved cellular pH, improved anaplerosis, improved pyruvate dehydrogenase capacity, and improved cellular oxygen capacity consumption. As noted above, the mitochondrial disease to be treated is associated with an underlying genetic alteration. In certain aspects, the genetic alteration is in mitochondrial DNA in one or more genes selected from MT-ND1, MT-ND2, MT-ND3, MT- ND4, MT-ND4L, MT-ND5, MT-ND6, MT-CYB, MT-CO1, MT-CO2, MT-CO3, MT-RNR1, MT- RNR2, MT-TA, MT-TC, MT-TE, MT-TF, MT-TH, MT-TI, MT-TK, MT-TL1, MT-TL2, MT-TM, MT-TN, MT-7-Q, MT-TS1, MT-TS2, MT-TV, MT-TW, MT-ATP6, and MT-ATP8. In other aspects, the genetic alteration is in nuclear DNA in one or more genes selected from AARS2, ABCB7, ABCC8, ACAD8, ACAD9, ACADM, ACADS, ACADSB, ACADVL, ACAT1, ACO2, ADCK3, ADRB2, ADRB3, AFG3L2, AGK, AGRP, AlFM1, AK2, AKAP10, AKT2, ALAS2, ALDH2, ALDH4A1, ALDH6A1, AMACR, AMT, APOPT1, APTX, ARMS2, ATP5A1, ATP5E, ATP5F1A, APT5F1D, ATP5F1E, ATPAF2, AUH, BAX, BCAT2, BCKDHA, BCKDHB, BCL2, BCS1L, BOLA3, C8orf38, C10orf2, C12orf62, C12orf65, C19orf12, C20orf7, C1QBP, CAPN10, CARS2, CARTPT, CDH23, CDKAL1, CHCHD10, CHKB, CISD2, CLRN1,C0A5, COA7, COA10, COQ2, COQ4, COQ6, COQ7, COQ8A, COQ9, COX10, COX14, COX15, COX20, C0X412, COX6B1, COX8A, CPS1, CPT1A, CPT2, CRAT, CYB5R3, CYC1, CYC5, CYCS, CYP11A1, CYP1161, CYP1162, CYP24A1, CYP27A1, CYP2761, D2HGDH, DARS2, DBT, DECR1, DFNB31, DGUOK, DHODH, DIABLO, DLD, DLAT, DMGDH, DNA2, DNAJC19, DNM1L, EARS2, ECHS1, ELAC2, ENPP1, ETFA, ETFB, ETFDH, ETHE1, FARS2, FASTKD2, FBXL4, FOXRED1, FH, FXN, GA TM, GCDH, GCGR, GCK, GCSH, GDAP1, GFER, GFM1, GHRL, GJB2, GJB3, GJB6, GK, GLDC, GLRX5, GLUD1, GPD2, GPR98, GTPBP3, HADH, HADHA, HADHB, HARS2, HCCS, HIBCH, HK1, HLCS, HMGA1, HMGCS2, HMGCL, HNF1A, HNF1B, HNF4A, HOGA1, HSD17610, HSPD1, HTRA1, HTRA2, IBA57, IDH2, IDH3B, IGF2BP2, IL6, INSR, IRS1, IRS2, ISCA1, ISCA2, ISCU, IVD, KANK1, KARS, KCNJ11, KIF1B, L2HGDH, LARS2, LEPR, LIAS, LIPC, LRPPRC, LRRK2, LYRM4, LYRM7, MAOA, MAPK8IP1, MAR52, MC4R, MCCC1, MCCC2, MCEE, ME2, MFF, MFN2, MGME1, MIPEP, MLYCD, MMAA, MMAB, MMADHC, MPC1, MPV17, MRAP2, MRPL3, MRPL44, MRPS2, MRPS7, MRPS16, MRPS22, MRPS34, MST01, MTFMT, MT01, MTPAP, MUT, MY07A, NAGS, NARS2, NDUFA1, NDUFA2, NDUFA6, NDUFA9, NDUFA10, NDUFA11, NDUFA12, NDUFA13, NDUFAF1, NDUFAF2, NDUFAF3, NDUFAF4, NDUFAF5, NDUFAF6, NDUFB3, NDUFB8, NDUFB9, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS5, NDUFS6, NDUFS7, NDUFS8, NDUFV1, NDUFV2, NEUROD1, NF2, NFU1, NGLY1, NROB2, NUBPL, NUP62, OAT, OGDH, OPA1, OPA3, OTC, OXCT1, PANK2, PARK2, PARK7, PAX4, PC, PCCA, PCCB, PCDH15, PCK2, PDHA1, PDHB, PDHX, PDP1, PDSS1, PDSS2, PDX1, PET100, PINK1, PNKD, PNPT1, POLG, POLG2, POMC, PPARG, PPARGC1B, PPDX, PPP1R3A, PUS1, PYCR1, PYY, RARS2, REEP1, RMRP, RMND1, RNASEH1, RRM2B, SACS, SARDH, SARS2, SC01, SCO2, SC03, SDHA, SDHAF1, SDHAF2, SDHB, SDHC, SDHD, SERAC1, SFXN4, SIM1, SLC2A2, SLC2A4, SLC22A5, 5LC25A1, 5LC25A3, 5LC25A4, 5LC25Al2, 5LC25A13, 5LC25A15, 5LC25A19, 5LC25A20, 5LC25A22, 5LC25A26, 5LC25A38, SLC30A8, 50D2, SPG7, SPG20, STAR, SUCLA2, SUCLG1, SURF1, TAC01, TARS2, TAZ, TDF7L2, TFAM, TIMM8A, TIMMDC1, TK2, TMEM70, TMEM126, TMEM126B, TOP3A, TRIT1, TRMT10C, TRMT5, TRMU, TRNT1, TSFM, TTC19, TUFM, TWNK, UCP1, UCP2, UCP3, UNG, UQCC2, UQCC3, UQCRB, UQCRC2, UQCRQ, USMG5, USH1C, USH1G, USG2A, VARS2, WARS2, WFS1, WWOX, XPNPEP3, YARS2. In other aspects the genetic alteration or loss of function is in NDUFS2 or SURF1. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1: Schematic of genetic and pharmacologic inhibition of Complex I (CI) and Complex IV (CIV) of the mitochondrial electron transport chain. Pharmacologic inhibitors rotenone and azide (purple) inhibit mitochondrial CI and CIV activities, respectively. Genetic mutants were generated for study in zebrafish by CRISPR / Cas9 editing of Ndufs2 and Surf1 (red) to inhibit CI activity and CIV activity, respectively. A ndufs2- / -missense mutant C. elegans strain with reduced complex I activity was also studied. Figures 2A – 2B: Sodium bitartrate rescues impaired swimming activity in mitochondrial complex I deficient Ndufs2- / -zebrafish larvae. Fig. 2A: Ndufs2- / -zebrafish larvae were treated with either 500 µM cysteamine bitartrate, 500 µM cysteamine hydrochloride, 500 µM sodium bitartrate, or 10 mM of glucose (positive treatment control) and compared relative to wild-type (Ndufs2-+ / +and Ndufs2+ / -) and untreated mutant (N4dufs2- / -) zebrafish larvae. Fig. 2B: NDUFS2- / -zebrafish larvae were treated with 2 mM sodium bitartrate and compared relative to wild-type (Ndufs2-+ / +and Ndufs2+ / -) and untreated mutant (Ndufs2- / -) zebrafish larvae. In all conditions, zebrafish larvae treatment with different compounds was initiated on 5 days post fertilization (dpf). On 7 dpf, zebrafish swimming activity was collected by ZebraBox (Viewpoint Life Sciences), where larvae were exposed to repetitive light cycles of 60% light for 20 min followed by 0% light for 20 min. Swimming activity was calculated as the average of the first 5 minutes of three sequential dark periods in one experiment averaged across three biological replicate experiments. Data were normalized as percent of wild-type buffer-only exposed control animals for each independent biological replicate. n = 32-36 animals across all biological replicates for each condition. Data is shown as scatter plot, where each dot indicates swim activity of a single animal and horizontal lines convey mean as well as 25thand 75thpercentiles. Statistical significance between experimental conditions was assessed by Student’s t-test in GraphPad Prism v7.04.#, P ≤ 0.1,∗, P < 0.05,∗∗, P < 0.01, and∗∗∗, P < 0.001. Figures 3A – 3E: Sodium bitartrate rescues neuromuscular function and swimming activity in mitochondrial complex IV deficient Surf1- / -zebrafish larvae. (Fig. 3A) Sodium bitartrate effects on Surf1- / -zebrafish larvae brain health and neuromuscular function with low-dose azide stress. Larvae were pre-treated from 5 dpf with sodium bitartrate at 100 µM, 200 µM, and 500 µM concentrations and on 6-dpf were co-exposed to sodium bitartrate and 35 µM sodium azide (complex IV inhibitor). Zebrafish larval brain clarity (where gray brain indicates brain death), startle response, touch response, and survival (presence or absence of heartbeat) were measured as previously described (Haroon, 2023, supra). Data shown represent combined results across three biological replicate experiments. Fig. 3B: Sodium bitartrate effects on Surf1- / -zebrafish larvae swimming activity with low-dose and high-dose azide stress. Swimming activity was measured as described in Figure 2. Specifically, zebrafish larvae were exposed on 5 dpf to 500 µM sodium bitartrate, and on 6 dpf were co-exposed to sodium bitartrate and either 35 µM or 40 µM sodium azide (complex IV inhibitor). Zebrafish swimming activity was measured on 7 dpf activity. Data is shown as scatter plot, where each dot indicates swim activity of a single animal and horizontal lines convey mean as well as 25thand 75thpercentiles. Statistical significance between experimental conditions was assessed by Student’s t- test in GraphPad Prism v7.04. ***, P < 0.001. Fig. 3C: Sodium bitartrate effects on Surf1- / - zebrafish larvae brain health and neuromuscular function with low-dose and high-dose azide stress. Larvae were pre-treated from 5 dpf with sodium bitartrate at 500 µM concentrations and on 6-dpf were co-exposed to sodium bitartrate and either low-dose (35 µM) or high-dose (40 µM) sodium azide (complex IV inhibitor). Zebrafish larval brain clarity (where gray brain indicates brain death), startle response, touch response, and survival (presence or absence of heartbeat) were measured as previously described (Haroon, 2023, supra) (. Data shown represent combined results across five biological replicate experiments. Fig. 3D: Sodium bitartrate and sodium tartrate effects on Surf1- / -zebrafish larvae brain health and neuromuscular function with high-dose azide stress. Larvae were pre-treated from 5 dpf with 500 µM sodium bitartrate or 500 µM sodium tartrate. On 6-dpf zebrafish larvae were co-exposed to sodium bitartrate or sodium tartrate together with 40 µM sodium azide. As comparison, Surf1- / - zebrafish larvae were treated only with buffer (first column) or sodium bitartrate pre-treated and then only exposed to sodium azide (without sodium bitartrate treatment) on 6-dpf (last column). Zebrafish larval brain clarity (where gray brain indicates brain death), startle response, touch response, and survival (presence or absence of heartbeat) were measured as previously described. Data shown represent combined results across three biological replicate experiments. Fig. 3E: Sodium bitartrate and sodium tartrate effects on Surf1- / -zebrafish larvae swimming activity with high-dose azide stress. Larvae were pre-treated from 5 dpf with 500 µM sodium bitartrate or 500 µM sodium tartrate. On 6-dpf zebrafish larvae were co-exposed to sodium bitartrate or sodium tartrate together with 40 µM sodium azide. As comparison, Surf1- / -zebrafish larvae were treated only with buffer (first column) or sodium bitartrate pre-treated on 5 dpf and then only exposed to sodium azide (without sodium bitartrate treatment) on 6-dpf (last column). Data shown represent results of one biological replicate experiment. Data is shown as scatter plot, where each dot indicates swim activity of a single animal and horizontal lines convey mean as well as 25thand 75thpercentiles. Statistical significance between experimental conditions was assessed by Student’s t-test in GraphPad Prism v7.04. *, P < 0.05. ***, P < 0.001. Figures 4A – 4E: Bitartrate treatment rescued biochemical alterations of mitochondrial complex I deficient Ndufs2- / -zebrafish. Zebrafish larvae were pre-treated on 5 dpf with 500 µM sodium bitartrate (Figs. 4A and 4B) or 2 mM sodium bitartrate (Figs. 4C to 4E) in E3 buffer with 10 mm Tris–HCl (pH 7.2). In some cases (Figs. 4D and 4E), at 7 dpf, the zebrafish larvae were further co-exposed to sodium bitartrate and the complex I inhibitor, rotenone, at 35 nM for 1-2h before sample collections. At 7 dpf, 20 embryos were collected per tube and washed two times with E3 buffer. After buffer removal, embryos were flash frozen in liquid nitrogen, then stored at −80◦C until ready for biochemical analyses. Zebrafish samples were prepared separately depending on each biochemical analysis. Fig. 4A: 500 µM sodium bitartrate effects on ATP, NAD+, and lactate levels were measured in Ndufs2- / -zebrafish larvae. Whole animal population tissue samples were extracted using perchloric acid (PCA) extraction. Tissue ATP and lactate levels were significantly increased by 86.5% and 179% in Ndufs2- / -, respectively, as compared to wild-type (WT) healthy control sibling animals, but upon sodium bitartrate treatment these levels were normalized to wild-type control level for ATP (p < 0.01) and by 80% for lactate (p = 0.09). Fig. 4B: 500 µM sodium bitartrate effects on reduced glutathione (GSH) levels, oxidized glutathione (GSSG) levels, and GSH / GSSG redox ratio were measured in zebrafish larvae. GSH and GSH / GSSG were increased in Ndufs2- / -zebrafish relative to controls. Upon bitartrate treatment a trend was seen of decreased GSSG (oxidized glutathione) levels and GSH / GSSG ratio, as well as significantly decreased GSH (reduced glutathione) levels. Fig. 4C: 2 mM bitartrate effects were measured in Ndufs2- / -zebrafish at baseline. Lactate and pyruvate levels, as well as lactate / pyruvate ratio were significantly increased in Ndufs2- / -. 2 mM sodium bitartrate treatment showed a trend toward decreased lactate levels and lactate / pyruvate ratio. While NAD+levels (performed with acetonitrile extraction) were unchanged, NADH and NADH / NAD ratio were increased in Ndufs2- / -zebrafish relative to WT controls. 2 mM sodium bitartrate treatment significantly normalized their NADH level and showed a trend in reducing NAD+level and NADH / NAD ratio. Finally, while hydrogen peroxide (H2O2) levels, measured by amplex red assay as an indicator of ROS production levels, were significantly low in Ndufs2- / -zebrafish tissue homogenate as compared to WT sibling animals, 2 mM bitartrate did not alter the ROS production levels in Ndufs2- / -zebrafish. Fig. 4D: 2 mM bitartrate effects were measured in complex I inhibitor (rotenone)-exposed Ndufs2- / -zebrafish. ATP levels in rotenone-treated Ndufs2- / -zebrafish larvae were significantly decreased by 56% compared to WT sibling animals, but co-treatment with 2 mM sodium bitartrate minimized rotenone effects and increased ATP levels by 42.4%. NAD+levels in rotenone-treated NDUFS2- / -zebrafish larvae were significantly decreased by 68.2% compared to WT sibling animals, but co-treatment with 2 mM bitartrate showed no effects. NDUFS2- / -zebrafish co- treatment of 2 mM sodium bitartrate with rotenone exposure had no effect on lactate and pyruvate levels, although 2 mM bitartrate showed a trend of decreasing the extremely high pyruvate levels (and increased the Lactate / Pyruvate tissue ratio) in Ndufs2- / -zebrafish larvae. Fig. 4E:2 mM bitartrate effects on whole animal protein levels were measured in Ndufs2- / -zebrafish. Extracted protein levels were significantly lower in Ndufs2- / -zebrafish larvae by 26.2% as compared to WT sibling animals, consistent with their smaller body sizes at 7 dpf. 2 mM sodium bitartrate treatment increased protein levels by 22% in the Ndufs2- / -zebrafish, reflecting improved animal growth. A similar trend was seen in rotenone-exposed Ndufs2- / -zebrafish. All graphs are shown with mean and standard error of the mean for the indicated number of biological replicates (n = 3-6), where∗P < 0.05,∗∗P < 0.01 by Student’s t-test. Figure 5: Principal Component Analysis (PCA) of GC / MS metabolite data for comparing each condition with and without sodium bitartrate in zebrafish larvae. PCA is a dimensionality reduction method that is often used to reduce the dimensionality of large data sets, by transforming a large set of variables into a smaller one that still contains most of the information in the large set. Upon PCA analysis, each zebrafish mutant condition was found to be distinct, showing that the primary mitochondrial disease and treatment conditions could be distinguished from their whole animal metabolite profiles as measured by gas chromatography / mass spectrometry (GC / MS). Importantly, sodium bitartrate (NaBit) rescues the Surf1- / -and AB treated with sodium azide (AB+Az) complex IV deficient zebrafish condition populations towards the AB wild-type control zebrafish population, which could suggest partial rescue of intermediary metabolism defects. The complex I deficient population of Ndufs2- / -is also moved by treatment with NaBit, highlighting its clear biological effect on mitochondrial disease zebrafish metabolism. The gray arrows depict the effect of NaBit on the different conditions. n=6 biological replicate experiments performed for all conditions except Surf1- / -+ NaBit for which n=4. Each biological replicate was comprised of 100 pooled 7 days post fertilization (dpf) zebrafish larvae, which are each represented by a single point. 40 µM sodium azide exposure occurred for 24 h prior to freezing the animal populations. 500 µM NaBit treatment occurred for 48 h prior to freezing the animal populations. ‘Ndufs2 Mix’ indicates a mixture of Ndufs2+ / +and Ndufs2+ / -genotypes and collectively are considered as wild-type siblings. Figures 6A -6H: Sodium bitartrate induced significant metabolic changes in intermediary metabolism as measured by GC / MC in Ndufs2- / -complex I deficient larvae and in azide- treated AB complex IV deficient zebrafish larvae. The metabolites shown in this figure are a subset of all of the organic acid and amino acid metabolites measured by GC / MS, where each biological replicate was comprised of 100 pooled 7 days post fertilization (dpf) zebrafish larvae (as described in Fig 5 legend). Graphs show organic acid levels in different biologic conditions (as described in Fig 5 legend), including Fig. 6A: Citrate. Citrate levels were significantly increased upon sodium bitartrate (NaBit) supplementation in Ndufs2- / -larvae, suggesting a possible anaplerotic (providing carbon into the tricarboxylic acid cycle) mechanism of action. All other mitochondrial disease conditions also trended towards an increase in citrate levels upon NaBit supplementation. Fig. 6B: Succinate. Succinate levels were significantly decreased in AB (wild-type) larvae exposed to sodium azide (AB+ Az) and trended towards a decrease in Surf1- / -larvae upon NaBit supplementation that indicates a possible reduction in the NADH / NAD+reduction-oxidation (redox) ratio. Fig. 6C: 4-OH-butyrate (with undetected points indicated as zero), Fig. 6AD: 4-OH-butyrate (with undetected points removed), Fig. 6E: 2-OH-butyrate (with undetected points indicated as zero), and Fig. 6F: 2-OH-butyrate (with undetected points removed). AB + Az larvae showed significantly decreased 2-OH-butyrate and 4-OH-butyrate with NaBit. Ndufs2- / -larvae trended towards decreased 2-OH-butyrate with NaBit. The reactions for butyrate biosynthesis also produce NAD+, which may represent a cellular mechanism to restore the NADH / NAD+ratio that is increased in primary mitochondrial disease. Therefore, a reduction in both hydroxy butyrate species suggest NaBit treatment restores redox balance toward wild-type levels. Fig. 6G: lactate and Fig. 6H: alanine levels in all conditions. There is also a trend in lactate decreasing in Ndufs2- / -and Surf1- / -upon NaBit supplementation and alanine decreasing in Surf1- / -upon NaBit supplementation. Lactate biosynthesis also produces NAD+. Each point is a biological replicate. All conditions have n=6 biological replicate, except Surf1- / -+ NaBit for which n=4. Figure 7: Sodium bitartrate reduced mitochondrial stress in C. elegans in complex I deficient gas-1(fc21) ndufs2- / -worms. A significant reduction in mitochondrial stress occurred with 2 mM sodium bitartrate, as well as with positive treatment control (N-acetylcysteine). A trend toward reduced stress was also seen with 1 mM and 4 mM sodium bitartrate treatments. In all conditions, mitochondrial stress was measured as a read out of induction of the mitochondrial unfolded stress response pathway (UPRmt) as quantified by analysis of green (stress) to red (number of worms) normalized fluorescence in a triple transgenic hsp-6p::gfp C. elegans complex I deficient gas-1(fc21) strain stably crossed to a myo-2p::mCherry reporter that quantifies animal number. Approximately 50 larval L4 stage worms were sorted into each well of a 384-well plate with a BioTek’s MultiFlo FX with a final volume of 50 µL, in liquid nematode growth media (OD6000.7). Compound was added each well, and after 24 hours fluorescence intensity was measured using a Cellinsight CX5 (Thermo Scientific). Each point represents an individual well. Figures 8A – 8C: Sodium bitartrate rescued survival in human fibroblasts from mitochondrial complex IV disease SURF1- / -patients. Cell viability assay was performed under buthionine sulfoximine (BSO) + sodium azide (NaAzide) induced stress. BSO is a glutathione synthesis inhibitor that causes the depletion of cellular glutathione (GSH) and increased reactive oxygen species (ROS) production, thereby inducing apoptosis. NaAzide is a mitochondrial complex IV inhibitor. The concentration of BSO and NaAzide was optimized at 50 μM and 50 μM, respectively, to obtain a 10% to 15% survival rate of human mitochondrial disease patient fibroblasts. Fibroblasts from 3 healthy control subjects and 3 complex IV deficient SURF1- / -Leigh Syndrome patients were cultured in 1.0 g / L low-glucose DMEM with 10% FBS at 37°C in 5% CO2until they reached semi-confluence and then seeded at 5,000 cells per well in a 96-well plate. After 24 h incubation, each cell line was divided into 5 different conditions with 6 technical replicates in 10 mM galactose media, including: BSO + NaAzide; BSO + NaAzide + NaBitartrate 500 μM; NaAzide, BSO + NaAzide + NaBitartrate 2 mM; BSO + NaAzide + NaBitartrate 10 mM. After 72 h incubation, cell survival rates were quantified using CellTiter- Glo ® viability assay. Fig. 8A: 500 μM NaBitartrate and 2 mM NaBitartrate increased cell survival by 60-80%. However, 10 mM NaBitartrate did not improve cell survival in early passage number cells. Values represent means ± standard error for 4 independent biological replicate experiments.****P< 0.0001 Fig. 8B: Cell survival was tested at passage 12 cells, where NaBitartrate 10 mM cell survival by up to 80% in SURF1- / -patient cells. Fig. 8C: Cell survival was tested at passage 16 cells, where NaBitartrate improved cell survival up to 60% in SURF1- / -patient cells. Figure 9: Sodium bitartrate and sodium tartrate structure-activity relationship (SAR) assays. Assays for design of new of active compounds and derivatives thereof to further elucidate chemical structure similar to sodium bitartrate and sodium tartrate, structural-related properties, biological activity, and target directed properties of compounds showing desirable effects ameliorating phenotypes, symptoms, and / or biochemical abnormalities associated with mitochondrial disease. Figures 10A -10B. Assessing synergism of sodium bitartrate drug combinations in complex I deficient gas-1(fc21) ndufs2- / - worms. A significant reduction in mitochondrial unfolded protein response (UPRmt) stress was observed for treatment with 2 mM sodium bitartrate (NaBit) and a positive treatment control compound (2.5 mM N-acetylcysteine). In addition, treatment with 25 mM sodium dichloroacetate (DCA), 1 mM nicotinic acid (NA) and 20 mM lithium chloride (LiCl) significantly decreased mitochondrial stress. A trend toward reduced UPRmtstress was observed for treatment with 10 nM epicatechin (p= 0.0781), which was further reduced by treatment with pair-wise combination of 10 nM epicatechin and 2 mM sodium bitartrate, implying a synergistic effect. In all conditions, mitochondrial stress was determined by normalizing the green fluorescence (UPRmtstress induction) to number of red heads (number of animals) in a triple transgenic hsp-6p::gfp C. elegans complex I deficient gas-1(fc21) strain stably crossed to a myo-2p::mCherry reporter. L4 larval stage worms were resuspended in S. Media (OD6000.7) to a concentration of 1 worm per microliter, and 50 µL was dispensed into each well of a 384-well plate. Drugs were individually added into each well, and fluorescence was measured after 24h, using a Cellinsight CX5 (Thermo Scientific). Each point represents an individual well. Figure 10B. Sodium bitartrate and epicatechin show a synergistic effect in complex I deficient gas-1(fc21) ndufs2- / -worms. Treatment with 2 mM sodium bitartrate (NaBit) and a positive treatment control compound (2.5 mM N-acetylcysteine) showed significantly decreased mitochondrial stress in ndufs2- / -complex I deficient gas-1(fc21) worms. A trend toward reduced UPRmtstress was observed upon treatment with 10 nM epicatechin (p= 0.0781). Treatment with a combination of 10 nM epicatechin and 2 mM NaBit significantly improved mitochondrial stress, suggesting a synergistic effect. In all conditions, mitochondrial stress was determined by normalizing the green fluorescence (UPRmtstress induction) to number of red heads (number of animals) in a triple transgenic hsp-6p::gfp C. elegans complex I deficient gas-1(fc21) strain stably crossed to a myo-2p::mCherry reporter. L4 larval stage worms were resuspended in S. Media (OD6000.7) to a concentration of 1 worm per microliter, and 50 µL was dispensed into each well of a 384-well plate. Drugs were individually added into each well, and fluorescence was measured after 24h, using a Cellinsight CX5 (Thermo Scientific). Each point represents an individual well. Figures 11A - 11B: Sodium bitartrate, N-acetylcysteine (NAC), and Glucose rescued survival in human fibroblasts from SURF1- / -patients with mitochondrial complex IV disease. Cell viability was performed under 10 buthionine sulfoximine (BSO) + sodium azide (Na Azide) induced stress. The concentration of BSO and Na Azide was optimized at 50 µM and 50 µM, respectively. Fibroblasts from 1 healthy control subject and 1 Complex IV deficient SURF1- / -subject were cultured in DMEM low glucose (1.0 g / L) with 10% FBS at 37°C in 5% CO2 until the cells reached semi-confluence and then seeded at 5,000 cells per well in a 96-well plate. After 24 hours, each cell line was divided into 16 different conditions with 3 technical replicates in 10 mM Galactose media, including: BSO + Na Azide; 500 µM Sodium bitartrate + BSO + Na Azide; 1 mM Nicotinic acid + BSO + Na Azide; 2.5 mM N-acetylcysteine (NAC) + BSO + Na Azide; 10 mM Glucose + BSO + Na Azide; 500 µM Thiamine + BSO + Na Azide; 20 mM Lithium Chloride + BSO + Na Azide; 10 µM Lipoic acid + BSO + Na Azide; 1 mM Nicotinic acid + 500 µM Sodium bitartrate + BSO + Na Azide; 2.5 mM NAC + 500 µM Sodium bitartrate + BSO + Na Azide; 10 mM Glucose + 500 µM Sodium bitartrate + BSO + Na Azide; 1 mM Nicotinic acid + 2.5 mM NAC + 10 mM Glucose + BSO + Na Azide; 1 mM Nicotinic acid + 2.5 mM NAC + 10 mM Glucose + 500 µM Sodium bitartrate + BSO + Na Azide; 500 µM Thiamine + 500 µM Sodium bitartrate + BSO + Na Azide; 10 µM Lipoic acid + + 500 µM Sodium bitartrate + BSO + Na Azide. After 72-hour incubation, cell survival rates were quantified using CellTiter-Glo viability assay. Values represent 1 independent biologic experiment with 3 technical replicates performed per condition, **** P<0.0001. Cell survival was tested at passage 7 from the healthy control fibroblast line and passage 6 from the SURF1- / -Complex IV deficient fibroblast line. DETAILED DESCRIPTION OF THE INVENTION The prevalence of mitochondrial diseases is estimated to be 11.5:100,000 (Chinnery 2014). Childhood-onset (<16 years of age) mitochondrial diseases are estimated to range from five to 15 cases per 100,000 individuals, two-thirds of which are caused by mutations in nuclear DNA (nDNA). In adults (>16 years of age), the prevalence of mitochondrial diseases caused by mutations in mtDNA and nDNA is estimated at 9.6 and 2.9 cases per 100,000 individuals, respectively, in northeast England (Gorman et al. 2016). A recent systematic review of the natural history of mitochondrial disorders reported that 59% of disorders had an onset before 18 months and 81% before 18 years (Keshavan and Rahman 2018). The minimum prevalence rate for mtDNA mutations was 1 in 5,000 (20 per 100,000), comparable with previously published prevalence rates. In this population, nuclear mutations were responsible for clinically overt adult mitochondrial disease in 2.9 per 100,000 adults. Data confirm that the total prevalence of adult mitochondrial disease, including pathogenic mutations of both the mitochondrial and nuclear genomes (1 in 4,300), is among the most common adult forms of inherited neurological disorders. Cysteamine bitartrate is a US Food and Drug Administration-approved therapy for nephropathic cystinosis and is also reported to enhance glutathione biosynthesis. We hypothesized this antioxidant effect may reduce oxidative stress in primary mitochondrial respiratory chain (RC) disease, improving cellular viability and organismal health. In an earlier study, the therapeutic potential of cysteamine bitartrate in RC disease models spanning three evolutionarily distinct species was evaluated (Guha et al. (2019). These pre-clinical studies demonstrated the very narrow therapeutic window even in healthy control cells and animal models of cysteamine bitartrate, with undesirable toxicity at millimolar levels that directly correlated with marked induction of hydrogen peroxide production (Guha et al., supra). DEFINITIONS: The terms "patient" or "individual" are used interchangeably herein, and refers to a mammalian subject to be treated, with human patients being preferred. In some cases, the methods of the invention find use in experimental animals, in veterinary application, and in the development of animal models for disease, including, but not limited to, C. elegans (nematodes), D. rerio (zebrafish), D. melanogaster (fruit flies), M. musculus (mice), rats, hamsters, primates, and mammals. "Sample" is used herein in its broadest sense. A sample comprising polynucleotides, polypeptides, peptides, antibodies and the like may comprise a bodily fluid; a soluble fraction of a cell preparation, or media in which cells were grown; a chromosome, an organelle, or membrane isolated or extracted from a cell; genomic DNA, RNA, or cDNA, polypeptides, or peptides in solution or bound to a substrate; a cell or cell extract; a tissue or tissue extract; a tissue print; a fingerprint, skin or hair; metabolites; enzymes; and the like. A "genetic or protein alteration" as used herein, includes without limitation, naturally occurring mutations, chemically induced mutations, genetic alterations generated via introduction of siRNA, antisense oligonucleotides, Talens, and CRISPR-CAS 9 targeted gene constructs. Protein alterations can be generated via pharmacological inhibition or modification of proteins involved in mitochondrial respiratory chain function, composition, or regulation. As noted above, there are many different mutations associated with mitochondrial disease and dysfunction. See for example Mitochondrial Disease Genes Compendium - 1st Edition on the world wide web at elsevier.com; McCormick EM, et al. Expert Panel Curation of 113 Primary Mitochondrial Disease Genes for the Leigh Syndrome Spectrum. Ann Neurol. 2023 May 31. doi: 10.1002 / ana.26716; ClinGen gene curation expert panel on the world wide web at clinicalgenome.org; and Clin Gene Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel - ClinGen | Clinical Genome Resource. Also see the annotated locus- specific database of pathogenic variants for mitochondrial diseases on the world wide web at mseqdr.org / mb.php?url=genes.php. "Treatment" is an intervention performed with the intention of preventing or inhibiting the development of a mitochondrial disorder, and, or altering the pathology or symptoms of a disorder. Accordingly, "treatment" refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with occurrence or manifestations of a mitochondrial disorder as well as those in which occurrence or manifestations of the disorder is to be inhibited or prevented. As used herein, "ameliorated" or "treatment" refers to modulation of at least one symptom which approaches a normalized value (for example a value obtained in a healthy patient or individual), e.g., is less than 50% different from a normalized value, preferably is less than about 25% different from a normalized value, more preferably, is less than 10% different from a normalized value, and still more preferably, is not significantly different from a normalized value as determined using routine statistical tests. The terms "agent" and "test compound" are used interchangeably herein and denote a chemical compound, a mixture of chemical compounds, a biological macromolecule, or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. Biological macromolecules include siRNA, shRNA, antisense oligonucleotides, peptides, peptide / DNA complexes, CRISPR complexes, base editing complexes, enzymes, and any nucleic acid-based molecule which exhibits the capacity to modulate the activity of a mitochondrial disease associated gene. The term “synergy” or “synergistic” refers to the interaction or cooperation of two or more substances, or other agents to produce a combined effect greater than the sum of their separate effects. In certain embodiments, the combinations provided herein act synergistically. Monosodium tartrate or sodium bitartrate is a sodium acid salt of tartaric acid. It has previously been used as a food additive to regulate acidity and has the Formula: C4H5NaO6. The present inventors have determined that pharmaceutical formulations comprising sodium bitartrate, alone and in combination with a variety of other agents can be used to advantage to ameliorate symptoms of mitochondrial diseases and disorders. Agents useful for this purpose can include, for example, one or more of N-acetylcysteine, nicotinic acid (niacin), niacinamide, nicotinamide riboside, nicotinamide mononucleotide, probucol, glucose, 2-deoxyglucose, delta- aminolevulinic acid, lipoic acid, resveratrol, thiamine, riboflavin, leucine, uridine, 3-methyl- adenine, hemin, trypterin, (+) epicatechin, (-) epicatechin, 11-hydroxyprogesterone, 11- hydroxypregnenolone, cycloheximide, rapamycin, lithium chloride, creatine, dichloroacetate, omaveloxolone, elamipretide, dimethylfumarate, a deubiquitalase (DUB) modulating agent a PPAR alpha a deubiquitalase (DUB) modulating agent, PPAR gamma a deubiquitalase (DUB) modulating agent, a PPAR delta modulating, an AMPK modulating agent, a sirtuin modulating agent, a mTORC1 modulating agent, a MAPK modulating agent, a PGC1-alpha modulating agent, a HIF1-alpha modulating agent, a mitochondrial biogenesis modulating agent, an antioxidant, a phosphodiesterase modulator, sildenafil, doxycycline, tetracycline, trapidil, a calcium channel modulator, flunarizine, folinic acid, metformin, valproic acid, dexamethasone, etoposide, vorinostat, quercitin, hydralazine, pfithrin-α, ginsenoside, sulfonsuccinimidyl oleate, carnitine, levocarnitine, AICAR, GSK2578215A, bezafibrate, vatiquinone, coenzyme Q10, alpha-tocopherolquinone, a coenzyme Q10 analog, ubiquinone, ubiquinol, cytochrome C, 5-I-2- (4-hydroxyphenyl)-ethenyl] benzene-1,3 diol, flavin mononucleotide, urolithin A, idebenone, latrepirdine, 2′,3′,5′-tri-O-acetyluridine, olesoxime, thiamine diphosphate, vitamin C, vitamin D, vitamin E, magnesium, calcium, phosphate, membrane phospholipid, unsaturated fatty acid, pyruvate, nicotinamide adenine dinucleotide, cysteamine bitartrate, acipimox, glutathione, a redox-modulating agent, curcumin, schisandrin, triheptanoin, an inhibitory nucleic acid targeting an upregulated gene associated with mitochondrial dysfunction, an activating genetic construct for increasing expression of a mitochondrial disease modulator protein, a nucleic acid / protein complex for genetic and / or base editing suitable for replacement therapies for primary mitochondrial diseases, a viral or non-viral vector gene therapy targeting a mitochondrial disease mutation, or a combination of any 2, 3, 4, 5 or 6 agents listed above. Preferred synergistic combinations comprise at least sodium bitartrate and (-) epicatechin and optionally N-acetyl cysteine. As used herein, "mitochondrial related disorders" are related to disorders which are due to abnormal mitochondria such as for example, a mitochondrial genetic mutation, enzyme, pathways, etc. Examples of disorders include and are not limited to: loss of motor control, loss of sensation, muscle weakness, muscle pain, imbalance, coordination problems, peripheral neuropathy, migraines, headaches, cognitive problems, memory problems, strokes, seizures, autonomic dysfunction, sleep problems, exercise intolerance, chronic fatigue, gastro-intestinal disorders and swallowing difficulties, poor growth, cardiac muscle and / or rhythm disease, liver disease, diabetes mellitus, respiratory complications and insufficiency, visual / hearing problems, vestibular problems, lactic acidosis, metabolic instability, developmental delays, immune dysfunction, and susceptibility to infection. The mitochondrial abnormalities are associated with "mitochondrial diseases" which include, but not limited to: ADOA: Autosomal Dominant Optic Atrophy; AD: Alzheimer's Disease; ADPD: Alzheimer's Disease and Parkinsons's Disease; AMDF: Ataxia, Myoclonus and Deafness CIPO: Chronic Intestinal Pseudo-obstruction with myopathy and Ophthalmoplegia; CPEO: Chronic Progressive External Ophthalmoplegia; CPEO plus including multi-systemic symptoms; MID: Maternally inherited deafness or aminoglycoside-induced Deafness; DEMCHO: Dementia and Chorea; DMDF: Diabetes Mellitus & Deafness; Exercise Intolerance; ESOC: Epilepsy, Strokes, Optic atrophy, & Cognitive decline; FBSN: Familial Bilateral Striatal Necrosis; FICP: Fatal Infantile Cardiomyopathy Plus, a MELAS-associated cardiomyopathy; GER: Gastrointestinal Reflux; KSS: Kearns Sayre Syndrome; LDYT: Leber's hereditary optic neuropathy and Dystonia; LHON: Leber Hereditary Optic Neuropathy; LIMM: Lethal Infantile Mitochondrial Myopathy; LSS: Leigh syndrome spectrum; MDM: Myopathy and Diabetes Mellitus; MELAS: Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes; MEPR: Myoclonic Epilepsy and Psychomotor Regression; MERME: MERRF / MELAS overlap disease; MERRF: Myoclonic Epilepsy and Ragged Red Muscle Fibers; MHCM: Maternally Inherited Hypertrophic Cardioyopathy; MICM: Maternally Inherited Cardiomyopathy; MILS: Maternally Inherited Leigh Syndrome; Mitochondrial Encephalocardiomyopathy; Mitochondrial Encephalomyopathy; MM: Mitochondrial Myopathy; MMC: Maternal Myopathy and Cardiomyopathy; Multisystem Mitochondrial Disorder (myopathy, encephalopathy, blindness, hearing loss, peripheral neuropathy); NARP: Neurogenic muscle weakness, Ataxia, and Retinitis Pigmentosa; alternate phenotype at this locus is reported as Leigh Disease; NIDDM: Non-Insulin Dependent Diabetes Mellitus; PEM: Progressive Encephalopathy; PME: Progressive Myoclonus Epilepsy; PS: Pearson syndrome; RTT: Rett Syndrome; SIDS: Sudden Infant Death Syndrome; SLSMDs, single large-scale mtDNA deletion syndrome; Multiple large-scale deletion disorders; and pathogenic mitochondrial cytopathies caused by point mutations or deletions / duplications in the mitochondrial DNA genome. The term "effective amount" or "therapeutically effective amount" refers to the amount of an agent that is sufficient to effect beneficial or desired results. The therapeutically effective amunt may vary depending upon one or more of: the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose of agent that will provide an image or biological parameter for detection by any one of the imaging or detection methods described herein. The specific dose may vary depending on one or more of: the particular agent chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to be imaged, and the physical delivery system in which it is carried. As used herein, “Structure-Activity Relationship (SAR)” refers to determination of relationships between chemical structure (or structural-related properties) and biological activity (or target property) of compounds and derivatives thereof which inhibit or enhance mitophagy in order to create more efficacious therapeutics for the treatment of this disorder. The terms "polynucleotide", "nucleotide", "nucleotide sequence", "nucleic acid", and "oligonucleotide" are used interchangeably in this disclosure. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides may have any three-dimensional structure, and may perform any function, known or unknown. The following are non-limiting examples of polynucleotides: single-, double-, or multi-stranded DNA or RNA, genomic DNA, cDNA, DNA-RNA hybrids, or a polymer comprising purine and pyrimidine bases or other natural, chemically, or biochemically modified, non-natural, or derivatized nucleotide bases. The terms "polynucleotide" and "nucleic acid" should be understood to include, as applicable to the embodiment being described, single- stranded (such as sense or antisense) and double-stranded polynucleotides. A polynucleotide may comprise one or more modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component. Nucleic acid molecules that inhibit expression of a gene or nucleic acid can be referred to as “inhibitory nucleic acid” (referring to their composition). Inhibitory nucleic acid technologies are known in the art and include, but are not limited to, antisense oligonucleotides, catalytic nucleic acids such as ribozymes and deoxyribozymes, aptamers, triplex forming nucleic acids, external guide sequences, and RNA interference molecules (RNAi), particularly small nucleic acid molecules, such as short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (mRNA), and short hairpin RNA (shRNA) molecules capable of mediating RNA interference (RNAi). In certain approaches, an inhibitory nucleic acid can reduce expression of a protein encoded by a gene selected from atg-9, dct-1, pink-1, sqst-1, hrdl-1, mul-1, pdr-1, plastin-1, siah- 1, unc-51, thereby modulating mitophagy modulator protein function(s). The inhibitory nucleic acid can reduce expression of an mRNA sequence encoding the mitophagy modulator proteins or genomic DNA encoding the mRNA. Such agents can be used in combination with the agents described above. The expression or amount of a protein which modulates mitochondrial function or activity can be reduced in some approaches using RNA interference, whereby double-stranded RNA (dsRNA, also referred to herein as siRNAs or ds siRNAs, for double-stranded small interfering RNAs) induces the sequence-specific degradation of targeted mRNA in cells (Hutvagner and Zamore, Curr. Opin. Genet. Dev.: 12, 225-232 (2002); Sharp, Genes Dev., 15:485-490 (2001)). In mammalian cells, RNAi can be triggered by 21-nucleotide (nt) duplexes of small interfering RNA (siRNA) (Chiu et al., Mol. Cell. 10:549-561 (2002); Elbashir et al., Nature 411:494-498 (2001)), or by micro-RNAs (miRNA), functional small-hairpin RNA (shRNA), or other dsRNAs which can be expressed in vivo using DNA templates with RNA polymerase III promoters (Zeng et al., Mol. Cell 9:1327-1333 (2002); Paddison et al., Genes Dev. 16:948-958 (2002); Lee et al., Nature Biotechnol. 20:500-505 (2002); Paul et al., Nature Biotechnol. 20:505-508 (2002); Tuschl, T., Nature Biotechnol. 20:440-448 (2002); Yu et al., Proc. Natl. Acad. Sci. USA 99(9):6047-6052 (2002); McManus et al., RNA 8:842-850 (2002); Sui et al., Proc. Natl. Acad. Sci. USA 99(6):5515-5520 (2002)). In a preferred embodiment, the inhibitory nucleic acid is an siRNA. In one embodiment, the inhibitory nucleic acid has 100% sequence identity with at least a part of the target mRNA. However, inhibitory nucleic acids having 70%, 80% or greater than 90% or 95% sequence identity may be used. Thus, sequence variations that might be expected due to genetic mutation, strain polymorphism, or evolutionary divergence can be tolerated. siRNA specific for the mitochondrial protein or modulatory proteins are commercially available from Dharmacon, upon request, along with other companies that will generate interfering RNAs for a specific gene. Thermo Electron Corporation (Waltham, MA) has launched a custom synthesis service for synthetic short interfering RNA (siRNA). Each strand is composed of 18-20 RNA bases and two DNA bases overhang on the 3’ terminus. As mentioned, Dharmacon, Inc. (Lafayette, CO) provides siRNA duplexes using the 2’-ACE RNA synthesis technology. Qiagen (Valencia, CA) uses TOM-chemistry to offer siRNA with high individual coupling yields (Li, et al., Nat. Med., 11(9):944-951 (2005). In some forms the inhibitor of the mitochondrial protein or modulator is an antisense oligonucleotide. An “antisense” nucleic acid sequence (antisense oligonucleotide) can include a nucleotide sequence that is complementary to a “sense” nucleic acid encoding a protein, e.g., complementary to the coding strand of a double-stranded cDNA molecule or complementary to a target sequence encoding the mitochondrial modulator protein. Antisense nucleic acid sequences and delivery methods are well known in the art (Goodchild, Curr. Opin. Mol. Ther., 6(2):120- 128 (2004); Clawson, et al., Gene Ther., 11(17):1331-1341 (2004)), which are incorporated herein by reference in their entirety. An antisense nucleic acid can be constructed using chemical synthesis and enzymatic ligation reactions using procedures known in the art. For example, an antisense nucleic acid (e.g., an antisense oligonucleotide) can be chemically synthesized using naturally occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used. The antisense nucleic acid also can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest, described further in the following subsection). In some forms the inhibitor of mitochondrial protein or modulatory proteins expression is a ribozyme specific for a nucleic acid encoding the protein. Ribozymes are a type of RNA that can be engineered to enzymatically cleave and inactivate other RNA targets in a specific, sequence-dependent fashion. Ribozymes and methods for their delivery are well known in the art (Hendry, et al., BMC Chem. Biol., 4(1):1 (2004); Grassi, et al., Curr. Pharm. Biotechnol., 5(4):369-386 (2004); Bagheri, et al., Curr. Mol. Med., 4(5):489-506 (2004); Kashani-Sabet M., Expert Opin. Biol. Ther., 4(11):1749-1755 (2004), each of which are incorporated herein by reference in its entirety. By cleaving the target RNA, ribozymes inhibit translation, thus preventing the expression of the target gene. Ribozymes can be chemically synthesized in the laboratory and structurally modified to increase their stability and catalytic activity using methods known in the art. Alternatively, ribozyme genes can be introduced into cells through gene-delivery mechanisms known in the art. “Native RNA” is naturally occurring RNA (i.e., RNA with normal C, G, U and A bases, ribose sugar and phosphodiester linkages). As used herein, “antisense activity” means any detectable and / or measurable change attributable to the hybridization of an antisense compound to its target nucleic acid. As used herein, “detecting” or “measuring” means that a test or assay for detecting or measuring is performed. Such detection and / or measuring may result in a value of zero. Thus, if a test for detection or measuring results in a finding of no activity (activity of zero), the step of detecting or measuring the activity has nevertheless been performed. As used herein, “detectable and / or measurable activity” means a measurable activity that is not zero. As used herein, “essentially unchanged” means little or no change in a particular parameter, particularly relative to another parameter which changes much more. In certain embodiments, a parameter is essentially unchanged when it changes less than 5%. In certain embodiments, a parameter is essentially unchanged if it changes less than two-fold while another parameter changes at least ten-fold. For example, in certain embodiments, an antisense activity is a change in the amount of a target nucleic acid. In certain such embodiments, the amount of a non-target nucleic acid is essentially unchanged if it changes much less than the target nucleic acid does, but the change need not be zero. As used herein, “expression” means the process by which a gene ultimately results in a protein. Expression includes, but is not limited to, transcription, post-transcriptional modification (e.g., splicing, polyadenylation, addition of 5′-cap), translation, and post-translational modification. As used herein, “translation” means the process in which a polypeptide (e.g. a protein) is translated from an mRNA. In certain embodiments, an increase in translation means an increase in the number of polypeptide (e.g. a protein) molecules that are made per copy of mRNA that encodes said polypeptide. As used herein, “targeting” or “targeted to” means the association of an inhibitory nucleic acid compound to a particular target nucleic acid molecule or a particular region of a target nucleic acid molecule. For example, an antisense compound targets a target nucleic acid if it is sufficiently complementary to the target nucleic acid to allow hybridization under physiological conditions. As used herein, “mismatch” means a nucleobase of a first oligomeric compound that is not capable of pairing with a nucleobase at a corresponding position of a second oligomeric compound, when the first and second oligomeric compound are aligned. Either or both of the first and second oligomeric compounds may be oligonucleotides. The terms "construct", “cassette”, "expression cassette", “plasmid”, “vector”, or “expression vector” is understood to mean a recombinant nucleic acid, generally recombinant DNA, which has been generated for the purpose of the expression or propagation of a nucleotide sequence(s) of interest or is to be used in the construction of other recombinant nucleotide sequences. The term “promoter” or “promoter polynucleotide” is understood to mean a regulatory sequence / element or control sequence / element that is capable of binding / recruiting an RNA polymerase and initiating transcription of sequence downstream or in a 3’ direction from the promoter. A promoter can be, for example, constitutively active, or always on, or inducible in which the promoter is active or inactive in the presence of an external stimulus. Example of promoters include T7 promoters or U6 promoters. The term “operably linked” can mean the positioning of components in a relationship which permits them to function in their intended manner. For example, a promoter can be linked to a polynucleotide sequence to induce transcription of the polynucleotide sequence. The terms "complementarity" or “complement” refer to the ability of a nucleic acid to form hydrogen bond(s) with another nucleic acid sequence by either traditional Watson-Crick or other non-traditional types. A percent complementarity indicates the percentage of residues in a nucleic acid molecule which can form hydrogen bonds (e.g., Watson-Crick base pairing) with a second nucleic acid sequence (e.g., 4, 5, and 6 out of 6 being 66.67%, 83.33%, and 100% complementary). "Perfectly complementary" means that all the contiguous residues of a nucleic acid sequence will hydrogen bond with the same number of contiguous residues in a second nucleic acid sequence. "Substantially complementary" as used herein refers to a degree of complementarity that is at least 40%, 50%, 60%, 62.5%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100%, or percentages in between over a region of 4, 5, 6, 7, and 8 nucleotides, or refers to two nucleic acids that hybridize under stringent conditions. A nucleic acid as described herein can be “modified” to increase stability in vivo. Such modifications include, without limitation, sugar modifications such as 2’fluoro, 2’-O- methyl, 2’- NH2. The phosphodiester backbone linkage can also be substituted with phosphorothioate as disclosed herein, but other backbone modifications such as triazole linked, or phNA are known to the skilled artisan. Additionally, modified bases can be employed, including without limitation, 7-deaza-dA, and carboxamide-dU. These 2′ substituents influence ASO molecular conformation, resulting in improved RNA target binding affinity and, with the exception of 2′- fluoro, increased nuclease resistance. Like phosphorodiamidate-modified morpholino oligomers, fully 2′-modified ASOs do not recruit RNase H1. Although less common, nucleobase modifications can also be incorporated into ASO design. Numerous modifications have been identified, e.g., replacing cytosine with 5-methylcytosine has proved beneficial: 5- methylcytosine substitution reduces ASO immunostimulatory effects without compromising Watson−Crick complementarity. Third-generation modifications more extensively alter ASO chemistry to further enhance stability and potency post-administration and provide greater control over both target affinity and cellular tropism. These modifications may alter nucleoside connectivity and restrict ASO stereochemistry, as in locked nucleic acids, constrained ethyl nucleoside analogues and artificial amido-bridged nucleic acids; change the backbone charge (phosphorodiamidate-modified morpholino oligomers are third-generation modified ASOs); or link ASOs to ligands, as in cholesterol- and GalNAc-conjugated ASOs. In some aspects, the invention provides methods comprising delivering one or more polynucleotides, such as or one or more vectors as described herein (e.g., encoding all or portions of the base editing complexes discussed below), one or more transcripts thereof, and / or one or proteins transcribed therefrom, to a host cell. In some aspects, the invention further provides cells produced by such methods, and organisms (such as animals, plants, or fungi) comprising or produced from such cells. Conventional viral and non-viral based gene transfer methods can be used to introduce nucleic acids in mammalian cells or target tissues. Such methods can be used to administer nucleic acids encoding components of a base editing system to cells in culture, or in a host organism. Non-viral vector delivery systems include DNA plasmids, RNA (e.g. a transcript of a vector described herein), naked nucleic acid, and nucleic acid complexed with a delivery vehicle, such as a liposome. Viral vector delivery systems include DNA and RNA viruses, which have either episomal or integrated genomes after delivery to the cell. For a review of gene therapy procedures, see Anderson, Science 256:808-813 (1992); Nabel & Felgner, TIBTECH 11:211-217 (1993); Mitani & Caskey, TIBTECH 11:162-166 (1993); Dillon, TIBTECH 11:167-175 (1993); Miller, Nature 357:455-460 (1992); Van Brunt, Biotechnology 6(10):1149-1154 (1988); Vigne, Restorative Neurology and Neuroscience 8:35- 36 (1995); Kremer & Perricaudet, British Medical Bulletin 51(1):31-44 (1995); Haddada et al., in Current Topics in Microbiology and Immunology Doerfler and Bihm (eds) (1995); and Yu et al., Gene Therapy 1:13-26 (1994). Methods of non-viral delivery of nucleic acids for use in combination with the agents described herein include lipofection, nucleofection, microinjection, biolistics, virosomes, liposomes, immunoliposomes, polycation or lipid:nucleic acid conjugates, naked DNA, artificial virions, and agent-enhanced uptake of DNA. Lipofection is described in e.g., U.S. Pat. Nos. 5,049,386, 4,946,787; and 4,897,355) and lipofection reagents are sold commercially (e.g., TransfectamTMand LipofectinTM). Cationic and neutral lipids that are suitable for efficient receptor-recognition lipofection of polynucleotides include those of Feigner, WO 91 / 17424; WO 91 / 16024. Delivery can be to cells (e.g. in vitro or ex vivo administration) or target tissues (e.g. in vivo administration). The preparation of lipid:nucleic acid complexes, including targeted liposomes such as immunolipid complexes, is well known to one of skill in the art (see, e.g., Crystal, Science 270:404-410 (1995); Blaese et al., Cancer Gene Ther. 2:291-297 (1995); Behr et al., Bioconjugate Chem. 5:382-389 (1994); Remy et al., Bioconjugate Chem. 5:647-654 (1994); Gao et al., Gene Therapy 2:710-722 (1995); Ahmad et al., Cancer Res. 52:4817-4820 (1992); U.S. Pat. Nos. 4,186,183, 4,217,344, 4,235,871, 4,261,975, 4,485,054, 4,501,728, 4,774,085, 4,837,028, and 4,946,787). The use of RNA or DNA viral based systems for the delivery of nucleic acids take advantage of highly evolved processes for targeting a virus to specific cells in the body and trafficking the viral payload to the nucleus. Viral vectors can be administered directly to patients (in vivo) or they can be used to treat cells in vitro, and the modified cells may optionally be administered to patients (ex vivo). Conventional viral based systems could include retroviral, lentivirus, adenoviral, adeno-associated and herpes simplex virus vectors for gene transfer. Integration in the host genome is possible with the retrovirus, lentivirus, and adeno-associated virus gene transfer methods, often resulting in long term expression of the inserted transgene. Additionally, high transduction efficiencies have been observed in many different cell types and target tissues. The tropism of a retrovirus can be altered by incorporating foreign envelope proteins, expanding the potential target population of target cells. Lentiviral vectors are retroviral vectors that are able to transduce or infect non-dividing cells and typically produce high viral titers. Selection of a retroviral gene transfer system would therefore depend on the target tissue. Retroviral vectors are comprised of cis-acting long terminal repeats with packaging capacity for up to 6-10 kb of foreign sequence. The minimum cis-acting LTRs are sufficient for replication and packaging of the vectors, which are then used to integrate the therapeutic gene into the target cell to provide permanent transgene expression. Widely used retroviral vectors include those based upon murine leukemia virus (MuLV), gibbon ape leukemia virus (GaLV), Simian Immuno deficiency virus (SIV), human immuno deficiency virus (HIV), and combinations thereof (see, e.g., Buchscher et al., J. Virol. 66:2731-2739 (1992); Johann et al., J. Virol. 66:1635-1640 (1992); Sommnerfelt et al., Virol. 176:58-59 (1990); Wilson et al., J. Virol. 63:2374-2378 (1989); Miller et al., J. Virol. 65:2220-2224 (1991); PCT / US94 / 05700). In applications where transient expression is preferred, adenoviral based systems may be used. Adenoviral based vectors are capable of very high transduction efficiency in many cell types and do not require cell division. With such vectors, high titer and levels of expression have been obtained. This vector can be produced in large quantities in a relatively simple system. Adeno-associated virus ("AAV") vectors may also be used to transduce cells with target nucleic acids, e.g., in the in vitro production of nucleic acids and peptides, and for in vivo and ex vivo gene therapy procedures (see, e.g., West et al., Virology 160:38-47 (1987); U.S. Pat. No. 4,797,368; WO 93 / 24641; Kotin, Human Gene Therapy 5:793-801 (1994); Muzyczka, J. Clin. Invest. 94:1351 (1994). Construction of recombinant AAV vectors are described in a number of publications, including U.S. Pat. No. 5,173,414; Tratschin et al., Mol. Cell. Biol. 5:3251-3260 (1985); Tratschin, et al., Mol. Cell. Biol. 4:2072-2081 (1984); Hermonat & Muzyczka, PNAS 81:6466-6470 (1984); and Samulski et al., J. Virol. 63:03822-3828 (1989). Packaging cells are typically used to form virus particles that are capable of infecting a host cell. Such cells include 293 cells, which package adenovirus, and ψ2 cells or PA317 cells, which package retrovirus. Viral vectors used in gene therapy are usually generated by producing a cell line that packages a nucleic acid vector into a viral particle. The vectors typically contain the minimal viral sequences required for packaging and subsequent integration into a host, other viral sequences being replaced by an expression cassette for the polynucleotide(s) to be expressed. The missing viral functions are typically supplied in trans by the packaging cell line. For example, AAV vectors used in gene therapy typically only possess ITR sequences from the AAV genome which are required for packaging and integration into the host genome. Viral DNA is packaged in a cell line, which contains a helper plasmid encoding the other AAV genes, namely rep and cap, but lacking ITR sequences. The cell line may also be infected with adenovirus as a helper. The helper virus promotes replication of the AAV vector and expression of AAV genes from the helper plasmid. The helper plasmid is not packaged in significant amounts due to a lack of ITR sequences. Contamination with adenovirus can be reduced by, e.g., heat treatment to which adenovirus is more sensitive than AAV. In some embodiments, a host cell is transiently or non-transiently transfected with one or more vectors described herein. In some embodiments, a cell is transfected as it naturally occurs in a subject. In some embodiments, a cell that is transfected is taken from a subject. In some embodiments, the cell is derived from cells taken from a subject, such as a cell line. In one aspect, the invention provides for methods of modifying a target polynucleotide in a eukaryotic cell, which may be in vivo, ex vivo or in vitro. In some embodiments, the method comprises sampling a cell or population of cells from a human or non-human animal and modifying the cell or cells. Culturing may occur at any stage ex vivo. The cell or cells may be re- introduced into the human or non-human animal. Pharmaceutical Formulations For clinical applications, pharmaceutical compositions will be prepared in a form appropriate for the intended application. Generally, this will entail preparing compositions (e.g., expression vector) that are essentially free of pyrogens, as well as other impurities that could be harmful to humans or animals. One will generally desire to employ appropriate salts and buffers to render drugs stable and allow for uptake by target cells. Aqueous compositions of the present disclosure comprise an effective amount of the drug dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium. The phrase "pharmaceutically or pharmacologically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or a human. As used herein, "pharmaceutically acceptable carrier" includes solvents, buffers, solutions, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like acceptable for use in formulating pharmaceuticals, such as pharmaceuticals suitable for administration to humans. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredients of the present disclosure, its use in therapeutic compositions is contemplated. Supplementary active ingredients also can be incorporated into the compositions, provided they do not inactivate the vectors or cells of the compositions. The active compositions of the present disclosure may include classic pharmaceutical preparations. Administration of these compositions according to the present disclosure may be via any common route so long as the target tissue is available via that route. This includes oral, nasal, or buccal, as well as through nasal feeding tubes or gastrostomy or jejunual ports and tubes that are commonly needed in primary mitochondrial disease patients. Alternatively, administration may be by intradermal, subcutaneous, intramuscular, intrathecal, intraocular, intraperitoneal or intravenous injection. Such compositions would normally be administered as pharmaceutically acceptable compositions, as described supra. The active compounds may also be administered parenterally or intraperitoneally. By way of illustration, solutions of the active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations generally contain a preservative to prevent the growth of microorganisms. The pharmaceutical forms suitable for injectable use include, for example, sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. Generally, these preparations are sterile and fluid to the extent that easy injectability exists. Preparations should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms, such as bacteria and fungi. Appropriate solvents or dispersion media may contain, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions may be prepared by incorporating the active compounds in an appropriate amount into a solvent along with any other ingredients (for example as enumerated above) as desired, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the desired other ingredients, e.g., as enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation include vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient(s) plus any additional desired ingredient from a previously sterile-filtered solution thereof. The compositions of the present disclosure generally may be formulated in a neutral or salt form. Pharmaceutically acceptable salts include, for example, acid addition salts (formed with the free amino groups of the protein) derived from inorganic acids (e.g., hydrochloric or phosphoric acids, or from organic acids (e.g., acetic, oxalic, tartaric, mandelic, and the like). Salts formed with the free carboxyl groups of the protein can also be derived from inorganic bases (e.g., sodium, potassium, ammonium, calcium, or ferric hydroxides) or from organic bases (e.g., isopropylamine, trimethylamine, histidine, procaine and the like). Upon formulation, solutions are preferably administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations may easily be administered in a variety of dosage forms such as injectable solutions, drug release capsules and the like. For parenteral administration in an aqueous solution, for example, the solution generally is suitably buffered and the liquid diluent first rendered isotonic for example with sufficient saline or glucose. Such aqueous solutions may be used, for example, for intravenous, intramuscular, subcutaneous and intraperitoneal administration. Preferably, sterile aqueous media are employed as is known to those of skill in the art, particularly in light of the present disclosure. By way of illustration, a single dose may be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion, (see for example, "Remington's Pharmaceutical Sciences" 15th Edition, pages 1035-1038 and 1570-1580). Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject. Moreover, for human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologics Standards. Therapies In another embodiment, combinatorial treatment of mitochondrial disease is contemplated. Combinations may be achieved by treating patients with a single composition or pharmacological formulation that includes two or more agents, or by treating the patient with distinct compositions or formulations, at the same time, wherein each composition includes a distinct agent. Suitable agents include, without limitation, sodium bitartrate, sodium tartrate, and derivatives thereof, the agents listed in Figure 9, overexpressing genes encoding proteins inhibited in mitochondrial disease, and inhibitory nucleic acids targeting over-expressed genes encoding proteins associated with mitochondrial disease. Alternatively, the various agents may be given in a staggered fashion ranging from minutes, to hours, to weeks. In such embodiments, one would generally ensure that the period of time between each delivery was such that the agents would still be able to exert an advantageously combined effect on the cell or subject. In such instances, it is contemplated that one would typically contact the cell with both modalities within about 12-24 hours of each other and, more preferably, within about 6-12 hours of each other, with a delay time of only about 12 hours being most preferred. In some situations, it may be desirable to extend the time period for treatment significantly, however, where several days (2, 3, 4, 5, 6 or 7) to several weeks (1, 2, 3, 4, 5, 6, 7 or 8) lapse between the respective administrations. Furthermore, multiple administrations of the cocktail itself are contemplated, such as in an ongoing or chronic basis. The administrations may be four times daily, three times daily, twice daily, daily, twice weekly, weekly, every other week, or monthly. They may also be administered for therapeutic purposes to mitochondrial disease patients who are acutely decompensating on a continual or more frequent basis in an acute medical setting (emergency department, intensive care unit, etc). In another aspect, the present disclosure provides compositions comprising one or more of compounds as described above and an appropriate carrier, excipient or diluent. The exact nature of the carrier, excipient or diluent will depend upon the desired use for the composition and may range from being suitable or acceptable for veterinary uses to being suitable or acceptable for human use. The composition may optionally include one or more additional compounds. When used to treat or prevent such diseases, the compounds described herein may be administered singly, as mixtures of one or more compounds or in mixture or combination with other agents useful for treating such diseases and / or the symptoms associated with such diseases. The compounds may also be administered in mixture or in combination with agents such as those described in Example 2. The compounds may be administered in the form of compounds per se, or as pharmaceutical compositions comprising a compound. Pharmaceutical compositions comprising the compound(s) may be manufactured by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilization processes. The compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the compounds into preparations which can be used pharmaceutically. The compounds may be formulated in the pharmaceutical composition per se, or in the form of a hydrate, solvate, N-oxide or pharmaceutically acceptable salt, as previously described. Typically, such salts are more soluble in aqueous solutions than the corresponding free acids and bases, but salts having lower solubility than the corresponding free acids and bases may also be formed. Pharmaceutical compositions may take a form suitable for virtually any mode of administration, including, for example, oral, topical, ocular, buccal, systemic, intrathecal, nasal, injection, transdermal, rectal, vaginal, etc., or a form suitable for administration by inhalation or insufflation. For oral administration, the pharmaceutical compositions may take the form of, for example, lozenges, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pre-gelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). The tablets may be coated by methods well known in the art with, for example, sugars, films or enteric coatings. Liquid preparations for oral administration may take the form of, for example, elixirs, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, CremophoreTM. or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p- hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, preservatives, flavoring, coloring and sweetening agents as appropriate. Preparations for oral administration may be suitably formulated to give controlled release of the compound, as is well known. For topical administration, the compound(s) may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art. Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration. Useful injectable preparations include sterile suspensions, solutions or emulsions of the active compound(s) in aqueous or oily vehicles. The compositions may also contain formulating agents, such as suspending, stabilizing and / or dispersing agent. The formulations for injection may be presented in unit dosage form, e.g., in ampules or in multidose containers, and may contain added preservatives. Alternatively, the injectable formulation may be provided in powder form for reconstitution with a suitable vehicle, including but not limited to sterile pyrogen free water, buffer, dextrose solution, etc., before use. To this end, the active compound(s) may be dried by any art-known technique, such as lyophilization, and reconstituted prior to use. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are known in the art. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner. For rectal and vaginal routes of administration, the compound(s) may be formulated as solutions (for retention enemas) suppositories or ointments containing conventional suppository bases such as cocoa butter or other glycerides. For nasal administration or administration by inhalation or insufflation, the compound(s) can be conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges for use in an inhaler or insufflator (for example capsules and cartridges comprised of gelatin) may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. For ocular administration, the compound(s) may be formulated as a solution, emulsion, suspension, etc. suitable for administration to the eye. A variety of vehicles suitable for administering compounds to the eye are known in the art. For prolonged delivery, the compound(s) can be formulated as a depot preparation for administration by implantation or intramuscular injection. The compound(s) may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt. Alternatively, transdermal delivery systems manufactured as an adhesive disc or patch which slowly releases the compound(s) for percutaneous absorption may be used. To this end, permeation enhancers may be used to facilitate transdermal penetration of the compound(s). Alternatively, other pharmaceutical delivery systems may be employed. Liposomes and emulsions, nanoparticles, lipid-nanoparticles, are well-known examples of delivery vehicles that may be used to deliver compound(s). Certain organic solvents such as dimethylsulfoxide (DMSO) may also be employed, although usually at the cost of greater toxicity. The pharmaceutical compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the compound(s). The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The compound(s) described herein, or compositions thereof, will generally be used in an amount effective to achieve the intended result, for example in an amount effective to treat or prevent the particular disease being treated. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated and / or eradication or amelioration of one or more of the symptoms associated with the underlying disorder such that the patient reports an improvement in feeling or condition, notwithstanding that the patient may still be afflicted with the underlying disorder. Therapeutic benefit also generally includes halting or slowing the progression of the disease, regardless of whether improvement is realized. The amount of compound(s) administered will depend upon a variety of factors, including, for example, the particular indication being treated, the mode of administration, whether the desired benefit is prophylactic or therapeutic, the severity of the indication being treated and the age and weight of the patient, and the bioavailability of the particular compound(s). The following materials and methods are provided to facilitate the practice of the present invention. They are not intended to limit the invention in any way. Quantification of UPRmtinduction using RNAi in C. elegans by large particle flow cytometry. RNAi bacteria of the target gene(s) of interest (such as K09A9.5 (gas-1) shown in Fig. 7), was inoculated into LBAmpmedia and seeded onto NGM plates with 0.4 mM isopropyl β-D-1- thiogalactopyranoside (IPTG) and 100 μg / mL ampicillin. Hsp-6p::GFP reporter worms were hypochlorite treated, and eggs were transferred to NGM plates seeded with RNAi bacteria. GFP reporter worms were grown to the young adult stage (after 3 days), were washed from the RNAi plates, and mean green fluorescence for each worm was obtained using the Union Biometrica BioSorter®. Fluorescence of each worm was normalized to its size, approximated by time of flight (TOF)*extinction outputs from the BioSorter. Fluorescence of all worms for a given replicate were averaged and are represented relative to untreated empty vector L4440 control (0) and untreated K09A9.5. All replicates are shown relative to their corresponding same-day controls. The significance between each condition was assessed by Student’s t-test in Graphpad Prism 7.04 (San Diego, CA: GraphPad Software Inc.). Lifespan analysis of combinatorial treatment effects in C. elegans, relative quantitation of mitochondrial matrix superoxide burden, mitochondrial membrane potential and mitochondria content analysis by fluorescence microscopy in young adult C. elegans, and whole worm amino acid profiling and stable-isotopic intermediary metabolic flux analysis in C. elegans were performed as disclosed in US Patent application number 17 / 256,406 and in Haroon et al., 2023, supra. The ‘406 patent application also discloses methods for zebrafish brain death and neuromuscular dysfunction assessment in RC complex IV dysfunction, neuromuscular swimming activity in RC complex I and IV dysfunction, and human fibroblast survival analyses. The ‘406 patent and Haroon et al.2023 are incorporated herein by reference as though set forth in full. Zebrafish brain death assessment in RC complex IV dysfunction and neuromuscular swimming activity in RC complex I and IV dysfunction. All protocols and methods were performed in accordance with CHOP IACUC number 18– 001154 regulations for care and use of D. rerio at the Children’s Hospital of Philadelphia Research Institute. Embryos and larvae were maintained at 28°C. Adult zebrafish (AB strains) were set pairwise in undivided mating tanks in order to collect and sort embryos. For brain death experiments, embryos were placed in E3 media with phenylthiourea (PTU) at 0.03 μg per liter to prevent larval pigment formation. For Zebrabox (ViewPoint Life Sciences) neuromuscular activity assessment, embryos were not exposed to PTU so that the system could observe the highest contrast of the zebrafish embryos. Unless otherwise specified, all reagents were obtained from Sigma-Aldrich (St Louis, MO, USA). AB strain zebrafish larvae were pre-treated with single or combination treatments starting at 5 days post-fertilization (dpf). Azide stock solutions (100 mM) were prepared in ethanol by sonication. Drug stocks of sodium bitartrate or sodium tartrate were prepared in E3 with Tris (10 mM) pH 7.2 and 0.1% DMSO. Zebrafish were co-exposed to combinational treatments and azide on 7 dpf, and larvae were scored for toxic effects. Brain death was scored by presence or absence of gray brain phenotype after approximately 5 h of co-exposure of rotenone. Neuromuscular assessment was scored after approximately 3 to 10 h of co-exposure with 150 nM rotenone. Larvae were transferred on 7 dpf to 96-well 650 μL square well plates, with one larva per well (catalogue number 7701–1651), with a final volume of 200 μL. The combinational treatments were evaluated using the automated imaging system ZebraBox, and data were collected using the ZebraLab software (ViewPoint Life Sciences). Larvae were acclimatized to 60% light for 20 min to achieve a stable level of activity. Larvae were then exposed to 20 min of dark (0% light) to produce a startle response, in which locomotion increases to a maximum movement for the first 5 min and then decreases gradually to a stable level. This light cycling of 20 min of on and off periods was repeated to observe the rescue effects of the compound. The maximum movement of the larvae for the first 5 min of the dark cycles was analyzed in Graphpad Prism 7.04. Sample comparisons were performed with a FDR adjusted Q value provided to correct for multiple testing using Benjamini and Hochberg approach. Zebrafish brain death and neuromuscular activity assessment in rotenone-induced RC complex I dysfunction. All protocols and methods are performed in accordance with CHOP IACUC number 18– 001154 regulations for care and use of D. rerio at the Children’s Hospital of Philadelphia Research Institute. Embryos and larvae are maintained at 28°C. Adult zebrafish (AB strains) were set in pairwise in undivided mating tanks as described in reference 15 in the ‘406 application referenced above. n order to collect and sort embryos. For brain death experiments, embryos are placed in E3 with phenylthiourea (PTU) at 0.03 μg per liter to prevent larval pigment formation. For Zebrabox (ViewPoint Life Sciences) neuromuscular activity assessment, embryos ae not exposed to PTU so that the system could observe the highest contrast of the zebrafish embryos. Unless otherwise specified, all reagents are obtained from Sigma-Aldrich (St Louis, MO, USA). AB strain zebrafish larvae are pre-treated with test compound, e.g., tartrate, bitartrate, derivatives thereof, or positive controls consisting of either 1 mM nicotinic acid (NA), 2.5 mM N-acetylcysteine (NAC), 10 mM glucose (Glu) or combinations of these treatments starting at 5 days post-fertilization (dpf). Rotenone stock solutions (1 mM) are prepared in ethanol by sonication. Drug stocks of NA (100 mM) pH 7.0, NAC (250 mM) pH 7.0 and glucose (1 M) were prepared in E3 with Tris (10 mM) pH 7.2 and 0.1% DMSO. Zebrafish are co- exposed to combinational treatments and 150 nM of rotenone on 7 dpf, and larvae are score for toxic effects. Brain death is scored by presence or absence of gray brain phenotype after approximately 5 h of co-exposure of rotenone, as previously described by (32). Neuromuscular assessment is scored after approximately 3 to 10 h of co-exposure with 150 nM rotenone. Larvae are transferred on 7 dpf to 96-well 650 μL square well plates, with one larva per well (catalogue number 7701–1651), with a final volume 200 μL. The combinational treatments are evaluated using the automated imaging system ZebraBox, data iscollected using the ZebraLab software (ViewPoint Life Sciences). Larvae are acclimatized to 60% light for 20 min to achieve a stable level of activity. Larvae are then exposed to 20 min of dark (0% light) to produce a startle response, in which locomotion increases to a maximum movement for the first 5 min and then decreases gradually to a stable level. This light cycling of 20 min of on and off periods is repeated to observe the rescue of the compound. The maximum movement of the larvae for the first 5 min of the dark cycles is analyzed in Graphpad Prism 7.04. Sample comparisons are performed with a FDR adjusted Q value provided to correct for multiple testing using Benjamini and Hochberg approach. Zebrafish larval treatment and sample preparation for biochemical analyses. Larvae were pre-treated from 5 dpf with sodium bitartrate at 100 µM, 200 µM, and 500 µM concentrations and on 6-dpf were co-exposed to sodium bitartrate and 35 µM sodium azide (complex IV inhibitor). Zebrafish larval brain clarity (where gray brain indicates brain death), startle response, touch response, and survival (presence or absence of heartbeat) were measured as previously described (Haroon, 2023, supra). For ATP, lactate, pyruvate or NAD+assays, frozen embryos were homogenized in 100 μL of ice-cold 0.5 molar perchloric acid (PCA) by a combination of grinding, 1 s sonication and freeze / thaw cycles in liquid nitrogen and water. After centrifuging at 16000 xg for 15 min at 4°C, the supernatant was collected and neutralized by ice-cold 1 molar potassium carbonate. Pellets were dissolved in one molar sodium hydroxide (NaOH) and kept at −80°C until protein estimation. For NADH assays, frozen embryos were homogenized in 100 μL of argon-bubbled ice- cold acetonitrile / 50 mM ammonium acetate (1:1 v / v) containing 50 mM NaOH by grinding on ice for 2 min. The suspension was vigorously vortexed followed by freeze / thaw cycles in liquid nitrogen and water, and then centrifuged at 16000 × g for 15 min to remove insoluble material. The supernatant was transferred to a spin column (50 kDa MWCO) and subsequently centrifuged at 16000 × g for 90 min to remove macromolecules in the sample. The eluate was transferred to a new tube and further dried up under pure argon gas stream for 60 min and stored at −80°C until HPLC analysis. Dried up samples were reconstituted with 20 mM Tris–HCl buffer right before HPLC analysis. For GSH and GSSG assays, frozen embryos were homogenized in 150 μL of ice-cold water by a combination of grinding, 1 s sonication and freeze / thaw cycles in liquid nitrogen and water. After centrifuging at 20000 xg for 15 min at 4°C, the supernatant was collected and divided into three tubes at 40, 80 and 10 μL volumes for GSH, GSSG and protein analyses, respectively. For GSH analysis, 120 μL of ice-cold 1:1 mixture of methanol and ethanol solution was added to 40 μL of the supernatant for deproteinization. Samples were vigorously vortexed and kept on ice for 15 min. After centrifuging at 20000 xg for 15 min at 4°C, the supernatant was collected and stored at −80°C until HPLC analysis. For GSSG analysis, N-ethylmaleimide (NEM), a thiol modifier, was added to 80 μL of the supernatant at a final concentration of 2 mM. Samples were vigorously vortexed for 30 s and kept on ice for 30 min. Then, in order to remove GS-NEM (modified GSH with NEM) and excess NEM, ice-cold dichloromethane (DCM) was added at 1:1 ratio followed by vortexing for 15 s. After centrifuging at 1000 xg for 10 min, the upper (aqueous) layer was collected and followed by deproteinization (as described above for GSH sample treatment). The resultant supernatant was further dried under pure argon gas stream for 30 min and stored at −80°C until HPLC analysis. Dried samples were reconstituted with dH2O, and freshly prepared sodium borohydride was added at a final concentration of 10 mM to reduce GSSG to GSH right before HPLC analysis, typically 3 min before each injection. ATP, NAD+and NADH measurements by HPLC coupled with photodiode array detection. Separation of ATP, NAD+and NADH was carried out on an YMC-Pack ODS-A column (5 mm, 4.6 × 250 mm) preceded by a guard column at 5°C. Flow rate was set at 0.4 mL / min. For ATP analysis, the mobile phase was initially 100% of mobile phase A1 (0.1 M sodium phosphate buffer, pH 6.0). The methanol was linearly increased with mobile phase B (0.1 M sodium phosphate buffer, pH 6.0, containing 25% methanol) increasing to 20% over 10 min. The column was washed by increasing mobile phase B to 100% for 5 min. For NAD+and NADH analyses, the mobile phase was initially 100% of mobile phase A2 (0.1 M sodium phosphate buffer, pH 6.0, containing 3.75% methanol). The methanol was linearly increased with mobile phase B (0.1 M sodium phosphate buffer, pH 6.0, containing 25% methanol) increasing to 50% over 15 min. The column was washed after each separation by increasing mobile phase B to 100% for 5 min. UV absorbance was monitored at 260 and 340 nm with Shimadzu SPD-M20A. Pertinent peak areas were integrated by the LabSolution software from Shimadzu, and quantified using standard curves. GSH and GSSG measurements by HPLC coupled with electrochemical detection Separation of GSH was carried out on an YMC-Pack ODS-A column (5 μm, 4.6 × 250 mm) preceded by a guard column at 25°C with flow rate of 0.4 mL / min. An HPLC system consisting of an LC-20 AD pump (Shimadzu, Kyoto, Japan) and an electrochemical detection-300 electrochemical detector (Eicom, Kyoto, Japan) equipped with a WE-AU gold electrode (Eicom) and a 25 μm GS-50 gasket (Eicom) was used. The mobile phase consisted of 100 mM sodium phosphate buffer (pH 2.5), 75 mg / L sodium octanesulfonate and 5 mg / L EDTA. The voltage of the gold electrode was set at +400 mV against the Ag / AgCl reference electrode. The examples below are provided to illustrate certain embodiments of the invention. They are not intended to limit the invention to such embodiments. EXAMPLE 1 Sodium bitartrate rescues impaired swimming activity, neuromuscular functions, and metabolism of mitochondrial complex I deficient ndufs2- / -zebrafish larvae and in mitochondrial complex IV deficient surf1- / -zebrafish larvae, as well as survival in human surf1- / -patient fibroblast cells. Using a zebrafish model developed in the lab previously, we identified new agents which have an impact on Complex I (CI) and Complex IV (CIV) of the electron transport chain. See Figures 1 and 2. ndufs2- / -zebrafish larvae were treated with either 500 µM cysteamine bitartrate, 500 µM cysteamine hydrochloride, 500 µM sodium bitartrate, or 10 mM of glucose (positive treatment control) and compared relative to wild-type (ndufs2-+ / +and ndufs2+ / -) and untreated mutant (ndufs2- / -) zebrafish larvae. In all conditions, zebrafish larvae treatment with different compounds was initiated on 5 days post fertilization (dpf). On 7 dpf, zebrafish swimming activity was collected by ZebraBox (Viewpoint Life Sciences), where larvae were exposed to repetitive light cycles of 60% light for 20 min followed by 0% light for 20 min. Swimming activity was calculated as the average of the first 5 minutes of three sequential dark periods in one experiment averaged across three biological replicate experiments. Data were normalized as percent of wild-type buffer-only exposed control animals for each independent biological replicate. Data is shown as scatter plot, where each dot indicates swim activity of a single animal and horizontal lines convey mean as well as 25th and 75th percentiles. We also observed that sodium bitartrate rescues neuromuscular function and swimming activity in mitochondrial complex IV deficient surf1- / -zebrafish larvae. See Figure 3 which shows the effects of sodium bitartrate on surf1- / -zebrafish larvae brain health and neuromuscular function after previous treatment with low-dose azide, a known stressor (Fig. 3B). Larvae were pre-treated from 5 dpf with sodium bitartrate at 100 µM, 200 µM, and 500 µM concentrations and on 6-dpf were co-exposed to sodium bitartrate and 35 µM sodium azide (complex IV inhibitor). Zebrafish larval brain clarity (where gray brain indicates brain death), startle response, touch response, and survival (presence or absence of heartbeat) were measured as previously described (Haroon et al. (2023), supra). Data shown represent combined results across three biological replicate experiments. Sodium bitartrate effects on SURF1- / -zebrafish larvae swimming activity with low-dose (Fig. 3B) and high-dose azide stress (Fig. 3C) was also measured. Specifically, zebrafish larvae were exposed on 5 dpf to 500 µM sodium bitartrate, and on 6 dpf were co-exposed to sodium bitartrate and either 35 µM or 40 µM sodium azide (complex IV inhibitor). Zebrafish swimming activity was measured on 7 dpf activity. Data is shown as scatter plot, where each dot indicates swim activity of a single animal and horizontal lines convey mean as well as 25thand 75thpercentiles. Data shown represent combined results across five biological replicate experiments. The effects of sodium bitartrate and sodium tartrate on SURF1- / -zebrafish larvae brain health and neuromuscular function and swimming activity with high-dose azide stress were also measured. Larvae were pre-treated from 5 dpf with 500 µM sodium bitartrate or 500 µM sodium tartrate. On 6-dpf zebrafish larvae were co-exposed to sodium bitartrate or sodium tartrate together with 40 µM sodium azide. As comparison, SURF1- / -zebrafish larvae were treated only with buffer (first column) or sodium bitartrate pre-treated and then only exposed to sodium azide (without sodium bitartrate treatment) on 6-dpf (last column). Zebrafish larval brain clarity (where gray brain indicates brain death), startle response, touch response, and survival (presence or absence of heartbeat) were measured as previously described (PMID: 36795052). Figures 4A to 4E show that bitartrate treatment rescued biochemical alterations in mitochondrial complex I deficient Ndufs2- / -zebrafish. Zebrafish larvae were pre-treated on 5 dpf with 500 µM sodium bitartrate (Figs. 4A and 4B) or 2 mM sodium bitartrate (Figs. 4C to 4E) in E3 buffer with 10 mm Tris–HCl (pH 7.2). In some cases (Figs. 4D and 4E), at 7 dpf, the zebrafish larvae were further co-exposed to sodium bitartrate and the complex I inhibitor, rotenone, at 35 nM for 1-2h before sample collections. At 7 dpf, 20 embryos were collected per tube and washed two times with E3 buffer. After buffer removal, embryos were flash frozen in liquid nitrogen, then stored at −80◦C until ready for biochemical analyses. Zebrafish samples were prepared separately depending on each biochemical analysis. Fig. 4A shows500 µM sodium bitartrate effects on ATP, NAD+, and Lactate levels measured in Ndufs2- / -zebrafish larvae. Whole animal population tissue samples were extracted using perchloric acid (PCA) extraction. Tissue ATP and lactate levels were significantly increased by 86.5% and 179% in Ndufs2- / -, respectively, as compared to wild-type (WT) healthy control sibling animals, but upon sodium bitartrate treatment these levels were normalized to wild-type control level for ATP (p < 0.01) and by 80% for lactate (p = 0.09). 500 µM sodium bitartrate effects on reduced glutathione (GSH) levels, oxidized glutathione (GSSG) levels, and GSH / GSSG redox ratio were measured in zebrafish larvae. The results are shown in Fig. 4B. GSH and GSH / GSSG were increased in Ndufs2- / -zebrafish relative to controls. Upon bitartrate treatment a trend was seen of decreased GSSG (oxidized glutathione) levels and GSH / GSSG ratio, as well as significantly decreased GSH (reduced glutathione) levels. The effects of 2 mM bitartrate effects were measured in Ndufs2- / -zebrafish at baseline. Lactate and pyruvate levels, as well as lactate / pyruvate ratio were significantly increased in Ndufs2- / -as shown in Fig. 4C, 2 mM sodium bitartrate treatment showed a trend toward decreased lactate levels and lactate / pyruvate ratio. While NAD+levels (performed with acetonitrile extraction) were unchanged, NADH and NADH / NAD+ratio were increased in Ndufs2- / -zebrafish relative to WT controls. 2 mM sodium bitartrate treatment significantly normalized NADH levels, and showed a trend in reducing NAD+level and NADH / NAD ratio. Finally, while hydrogen peroxide (H2O2) levels, measured by amplex red assay as an indicator of ROS production levels, were significantly low in Ndufs2- / -zebrafish tissue homogenate as compared to WT sibling animals, 2 mM bitartrate did not alter the ROS production levels in Ndufs2- / -zebrafish. In Fig. 4D: 2 mM bitartrate effects were measured in complex I inhibitor (rotenone)-exposed Ndufs2- / -zebrafish. ATP levels in rotenone-treated Ndufs2- / -zebrafish larvae were significantly decreased by 56% compared to WT sibling animals. The data show that co-treatment with 2 mM sodium bitartrate minimized rotenone effects and increased ATP levels by 42.4%. NAD+levels in rotenone-treated NDUFS2- / -zebrafish larvae were significantly decreased by 68.2% compared to WT sibling animals, however co-treatment with 2 mM bitartrate showed did not alter these levels. NDUFS2- / -zebrafish co-treatment comprising 2 mM sodium bitartrate and rotenone did not alter lactate and pyruvate levels, although 2 mM bitartrate showed a trend of decreasing the extremely high pyruvate levels (and increased the Lactate / Pyruvate tissue ratio) in Ndufs2- / -zebrafish larvae. 2 mM bitartrate effects on whole animal protein levels were measured in Ndufs2- / -zebrafish as shown in Fig. 2E. Extracted protein levels were significantly lower in Ndufs2- / -zebrafish larvae by 26.2% as compared to WT sibling animals, consistent with their smaller body sizes at 7 dpf. 2 mM sodium bitartrate treatment increased protein levels by 22% in the Ndufs2- / -zebrafish, reflecting improved animal growth. A similar trend was seen in rotenone-exposed Ndufs2- / -zebrafish. Principal Component Analysis (PCA) of GC / MS metabolite data was performed comparing each condition with and without sodium bitartrate in zebrafish larvae, as shown in Fig. 5. PCA is a dimensionality reduction method that is often used to reduce the dimensionality of large data sets, by transforming a large set of variables into a smaller one that still contains most of the information in the large set. Upon PCA analysis, each zebrafish mutant condition was found to be distinct, showing that the primary mitochondrial disease and treatment conditions could be distinguished from their whole animal metabolite profiles as measured by gas chromatography / mass spectrometry (GC / MS). Importantly, sodium bitartrate (NaBit) rescues the Surf1- / -and AB treated with sodium azide (AB+Az) complex IV deficient zebrafish condition towards the AB wild-type control zebrafish population, which could suggest partial rescue of intermediary metabolism defects. The complex I deficient population of Ndufs2- / -is also moved by treatment with NaBit, highlighting its clear biological effect on mitochondrial disease zebrafish metabolism. The gray arrows depict the effect of NaBit on the different conditions. n=6 biological replicate experiments performed for all conditions except Surf1- / -+ NaBit for which n=4. Each biological replicate was comprised of 100 pooled 7 days post fertilization (dpf) zebrafish larvae, which are each represented by a single point. 40 µM sodium azide exposure occurred for 24 h prior to freezing the animal populations. 500 µM NaBit treatment occurred for 48 h prior to freezing the animal populations. ‘Ndufs2 Mix’ indicates a mixture of Ndufs2+ / +and Ndufs2+ / -genotypes and collectively are considered as wild-type siblings. Sodium bitartrate induced significant metabolic changes in intermediary metabolism as measured by GC / MC in Ndufs2- / -complex I deficient larvae and in azide-treated AB complex IV deficient zebrafish larvae. The metabolites shown in Figure 6 are a subset of all of the organic acid and amino acid metabolites measured by GC / MS, where each biological replicate was comprised of 100 pooled 7 days post fertilization (dpf) zebrafish larvae (as described above). Graphs show organic acid levels in different biologic conditions. Fig. 6A shows that citrate levels were significantly increased upon NaBit supplementation in Ndufs2- / -larvae, suggesting a possible anaplerotic (providing carbon into the tricarboxylic acid cycle) mechanism of action. All other mitochondrial disease conditions also trended towards an increase in citrate levels upon NaBit supplementation. Succinate levels were significantly decreased in AB (wild-type) larvae exposed to sodium azide (AB+ Az) and trended towards a decrease in Surf1- / -larvae upon NaBit supplementation that indicates a possible reduction in the NADH / NAD+reduction-oxidation (redox) ratio. See Fig. 6B. Fig. 6C shows 4-OH-butyrate, with undetected points indicated as zero), while Fig. 6D shows the data with undetected points removed. Fig. 6E shows 2-OH- butyrate, with undetected points indicated as zero), while Fig. 6F shows the data with undetected points removed. AB + Az larvae showed significantly decreased 2-OH-butyrate and 4-OH- butyrate with NaBit. Ndufs2- / -larvae trended towards decreased 2-OH-butyrate with NaBit. The reactions for butyrate biosynthesis also produce NAD+, which may represent a cellular mechanism to restore the NADH / NAD+ ratio that is increased in primary mitochondrial disease. Therefore, a reduction in both hydroxy butyrate species suggest NaBit treatment restores redox balance toward wild-type levels. Lactate (Fig. 6G) and alanine (Fig. 6H) were also assessed under all conditions. The data show a trend in lactate decreasing in Ndufs2- / -and Surf1- / -upon NaBit supplementation. Alanine appears to be decrease in Surf1- / -upon NaBit supplementation. Lactate biosynthesis also produces NAD+. Sodium bitartrate reduced mitochondrial stress in C. elegans in complex I deficient gas- 1(fc21) ndufs2- / -worms, as shown in Fig. 7. A significant reduction in mitochondrial stress occurred with 2 mM sodium bitartrate, as well as with positive treatment control (N- acetylcysteine). A trend toward reduced stress was also seen with 1 mM and 4 mM sodium bitartrate treatments. In all conditions, mitochondrial stress was measured as a read out of induction of the mitochondrial unfolded stress response pathway (UPRmt) as quantified by analysis of green (stress) to red (number of worms) normalized fluorescence in a triple transgenic hsp-6p::gfp C. elegans complex I deficient gas-1(fc21) strain stably crossed to a myo- 2p::mCherry reporter that quantifies animal number. Approximately 50 larval L4 stage worms were sorted into each well of a 384-well plate with a BioTek’s MultiFlo FX with a final volume of 50 µL, in liquid nematode growth media (OD6000.7). Compound was added each well, and after 24 hours fluorescence intensity was measured using a Cellinsight CX5 (Thermo Scientific). Each point represents an individual well. Sodium bitartrate rescued survival in human fibroblasts from mitochondrial complex IV disease SURF1- / -patients, as shown in Fig. 8. Cell viability assay was performed under buthionine sulfoximine (BSO) + sodium azide (NaAzide) induced stress. BSO is a glutathione synthesis inhibitor that causes the depletion of cellular glutathione (GSH) and increased reactive oxygen species (ROS) production, thereby inducing apoptosis. NaAzide is a mitochondrial complex IV inhibitor. The concentration of BSO and NaAzide was optimized at 50 μM and 50 μM, respectively, to obtain a 10% to 15% survival rate of human mitochondrial disease patient fibroblasts. Fibroblasts from 3 healthy control subjects and 3 complex IV deficient SURF1- / -Leigh Syndrome patients were cultured until they reached semi-confluence and then seeded at 5,000 cells per well in a 96-well plate. After 24 h incubation, each cell line was divided into 5 different conditions with 6 replicates in 10 mM galactose media, including: BSO + NaAzide; BSO + NaAzide + NaBitartrate 500 μM; NaAzide, BSO + NaAzide + NaBitartrate 2 mM; BSO + NaAzide + NaBitartrate 10 mM. After 72 h incubation, cell survival rates were quantified using CellTiter-Glo ® viability assay. Fig. 8A shows that 500 μM NaBitartrate and 2 mM NaBitartrate increased cell survival by 60-80%. However, 10 mM NaBitartrate did not improve cell survival in early passage number cells. Cell survival was tested at passage 12 cells, where NaBitartrate 10 mM improved cell survival by up to 80% in SURF1- / -patient cells as shown in Fig. 8B. Notably, in passage 16 cells, NaBitartrate improved cell survival up to 60% in SURF1- / -patient cells. See Fig. 8C. Sodium bitartrate and sodium tartrate structure-activity relationship (SAR) assays facilitate design of new of active compounds with modified chemical structures similar to sodium bitartrate and sodium tartrate, as shown in Fig 9. New compounds which demonstrate improved structural-related properties, biological activity, and / or targeting activity can be used to advantage for ameliorating phenotypes, symptoms, and / or biochemical abnormalities associated with mitochondrial disease. Additional data confirm that certain combinations of drugs act synergistically to ameliorate mitochondrial disease symptoms on worms and in human cells. See Figures 9 and 10. In Fig. 9A, synergism was assessed in complex I deficient gas-1(fc21) ndufs2- / - worms, and a significant reduction in mitochondrial unfolded protein response (UPRmt) stress was observed for treatment with 2 mM sodium bitartrate (NaBit) and a positive treatment control compound (2.5 mM N-acetylcysteine). In addition, treatment with 25 mM sodium dichloroacetate (DCA), 1 mM nicotinic acid (NA) and 20 mM lithium chloride (LiCl) significantly decreased mitochondrial stress. Fig. 9B shows a trend toward reduced UPRmtstress was observed for treatment with 10 nM (-) epicatechin (p= 0.0781), which was further reduced by treatment with pair-wise combination of 10 nM epicatechin and 2 mM sodium bitartrate, showing a synergistic effect. EXAMPLE 2 Diagnosis, Treatment and Management of Mitochondrial Disease and Dysfunction The compositions and methods described can be used to ameliorate symptoms associated with mitochondrial disfunction, particularly deficiencies associated with impairment of the OXPHOS system. In some embodiments, the mitochondrial dysfunction is assessed, monitored, or diagnosed by a method comprising: (i) measuring one or more clinical symptoms or signs of mitochondrial dysfunction or mitochondrial disease in a subject, (ii) combining the measurements obtained into a single composite measurement, and (iii) assessing the overall severity of, or change in, the mitochondrial dysfunction or mitochondrial disease in the subject by comparing the composite measurement to a reference value or another composite measurement in the same subject. The (i) one or more composite measurements are employed to measure the clinical effect on the subject of a diagnostic, therapeutic or other type of medical intervention; (ii) for each of the measurements tested, the subject is classified as: (a) a responder or a non-responder, (b) a member of a clinical category, or (c) a member of a metric range, based on the change in said one or more clinical symptoms as measured using the particular clinical symptom or metabolic pathway assessed; and (iii) the measurements obtained are combined into a single composite measurement, by either: (a) separately assessing the change in each measurement obtained from each assay conducted prior to combining each measurement into a single composite measurement, or (b) combining measurements obtained from a first time point and generating a single composite measurement for said first time point and then comparing the single composite measurement for the first time point to a single composite measurement generated from the same assay for a second time point. Important clinical assessments for mitochondrial disease or dysfunction include one or more of Motor Function Measure, Dynamometry Measures, Cardiopulmonary exercise Test (CPET), Creatine-CEST MRI measures of post-exercise creatine and phosphocreatine levels recovery in muscle, Twelve Minute Walk Test, Six Minute Walk Test Total Distance Walked, Six Minute Walk Distance Per Minute Distance Walked, Two Minute Walk Test, Modified Fatigue Impact Scale, MM-COAST Mitochondrial Myopathy Composite Assessment Tool, Finger Dexterity Score (9-hole peg test), Barry Albright Dystonia Scale (BADS), Friedreich's Ataxia Rating Scale (FARS), Scale for the Rating and Assessment of Ataxia (SARA), Movement Disorders Childhood Rating Scale (CRS), Patient-Reported Outcomes Measurement Information System Gastrointestinal Symptom Scales, 30-Second Sit to Stand Test, Muscle Strength by Myometry Test, Newcastle Mitochondrial Disease Adult Scale, Newcastle Mitochondrial Disease Pediatric Scale, 36-Item Short Form Survey, PediCAT score of function, Peds-QL Quality of Life Score, Karnofsky-Lansky Scale, Caregiver Burden Scale, Observer Reported Outcome (ObsRO) scale, Clinical Global Impression of Change, Patient's Global Impression of Change, Patient-Reported Initial Mitochondrial Personalized Composite Scale (MitoPC) Symptoms, Patient-Reported MitoPC Symptom Changes, Columbia Suicide Severity Rating Scale, Neuropathy Impairment Score, Migraine Disability Assessment Test, Quick Inventory of Depressive Symptomatology—Self-Report, Montreal Cognitive Assessment, NY Heart Association Functional Classification, Diabetes Health Profile, Hemoglobin A1C measure, Lactate measure, Pyruvate measure, Lactate:Pyruvate ratio measure, Alanine measure, Alanine- linked amino acid ratios measure, ketone body levels and ratio of acetoacetate: β- hydroxybutyrate, 2-hydroxy-butyrate level, glutathione GSH (reduced) and GSSG (oxidized) levels and ratio, CoQ10 level, creatine level, creatinine level, transaminase (ALT and AST) levels, urine organic acid levels, carnitine and acylcarnitine levels, N-lactoyl-amino acids, β- hydroxy acylcarnitines, β-hydroxy fatty acids, Ocular Motility Assessments, Marginal Reflex Distance, Ocular Motility & Fixation in 8 Gaze Directions, Degree of Ocular Saccades, Visual Function Test, Logarithm of Minimum Angle of Resolution, Pelli-Robson Score, Humphrey Visual Field mean deviation, or a combination thereof. A preferred subset of such assessments can include, for example, MM-COAST, Motor Function Measure, Six Minute Walk Test, Modified Fatigue Impact Scale, Friedreich's Ataxia Rating Scale, and the Patient-Reported Outcomes Measurement Information System Gastrointestinal Symptom Scales. In some embodiments, two, three, four, five or more assessments are performed, which include but are not limited to, Motor Function Measure, Six Minute Walk Test, Modified Fatigue Impact Scale, Friedreich's Ataxia Rating Scale, and the Patient-Reported Outcomes Measurement Information System Gastrointestinal Symptom Scales. The bitartrate, or tartrate, or a pharmaceutically acceptable salt thereof, is administered at a dose of about .01 mg, .02 mg, .05 mg, 1 mg, 2 mg, about 10 mg, about 100 mg, about 250 mg, about 500 mg, about 1 g, about 2 g, about 5 g, or about 10 g. In some embodiments, the bitartrate, tartrate, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 1 mg / day, about 10 mg / day, about 100 mg / day, about 250 mg / day, about 500 mg / day, about 1 g / day, about 2 g / day, about 5 g / day, or about 10 g / day. The bitartrate or tartrate or a pharmaceutically acceptable salt thereof can be administered as a liquid formulation. In some embodiments, the liquid formulation is administered by a route selected from the group consisting of oral, enteral, gastrostomy tube, jejunostomy tube, orogastric tube, nasogastric tube, parenteral, intravenous, subcutaneous, intramuscular, intraperitoneal, intracisternal, intraarticular, intracerebral, intraparenchymal, intracerebro- ventricular, intrathecal, nasal, vaginal, sublingual, intraocular, intravitreal, rectal, topical, transdermal and inhalation. In some embodiments, the bitartrate, tartrate, or a pharmaceutically acceptable salt thereof, is administered in the form of a tablet. The bitartrate or tartrate, or a pharmaceutically acceptable salt thereof, can be administered on a continuous dosing schedule. In some embodiments, the bitartrate, tartrate, or a pharmaceutically acceptable salt thereof, is administered four times per day, three times per day, twice per day, once per day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks or once per month. In some embodiments, the bitartrate, tartrate, or a pharmaceutically acceptable salt thereof, is administered initially in a loading dose that is higher than a subsequent dose. For maximum therapeutic efficacy, the bitartrate or tartrate can be administered with one or more additional pharmaceutical agents that may complement one another or act synergistically. In some embodiments, the one or more additional pharmaceutical agents are selected from N-acetylcysteine, nicotinic acid (niacin), niacinamide, nicotinamide riboside, nicotinamide mononucleotide, probucol, glucose, 2-deoxyglucose, delta-aminolevulinic acid, lipoic acid, resveratrol, thiamine, riboflavin, leucine, uridine, 3-methyl-adenine, hemin, trypterin, (+) epicatechin, (-) epicatechin, 11-hydroxyprogesterone, 11-hydroxypregnenolone, cycloheximide, rapamycin, lithium chloride, creatine, dichloroacetate, omaveloxolone, elamipretide, dimethylfumarate, a PPAR alpha modulating agent, PPAR gamma modulating agent, a deubiquitalase (DUB) modulating agent, a PPAR delta modulating agent, an AMPK modulating agent, a sirtuin modulating agent, a mTORC1 modulating agent, a MAPK modulating agent, a PGC1-alpha modulating agent, a HIF1-alpha modulating agent, a mitochondrial biogenesis modulating agent, an antioxidant, a phosphodiesterase modulator, sildenafil, doxycycline, tetracycline, trapidil, a calcium channel modulator, flunarizine, folinic acid, metformin, valproic acid, dexamethasone, etoposide, vorinostat, quercitin, hydralazine, pfithrin-α, ginsenoside, sulfonsuccinimidyl oleate, carnitine, levocarnitine, AICAR, GSK2578215A, bezafibrate, vatiquinone, coenzyme Q10, alpha-tocopherolquinone, a coenzyme Q10 analog, ubiquinone, ubiquinol, cytochrome C, 5-I-2-(4-hydroxyphenyl)-ethenyl] benzene- 1,3 diol, flavin mononucleotide, urolithin A, idebenone, latrepirdine, 2′,3′,5′-tri-O-acetyluridine, olesoxime, thiamine diphosphate, vitamin C, vitamin D, vitamin E, magnesium, calcium, phosphate, membrane phospholipid, unsaturated fatty acid, pyruvate, nicotinamide adenine dinucleotide, cysteamine bitartrate, acipimox, glutathione, a redox-modulating agent, curcumin, schisandrin, triheptanoin, an inhibitory nucleic acid targeting an upregulated gene associated with mitochondrial dysfunction, an activating genetic construct for increasing expression of a mitochondrial disease modulator protein, a nucleic acid / protein complex for genetic and / or base editing suitable for replacement therapies for primary mitochondrial diseases, a viral or non-viral vector gene therapy targeting a mitochondrial disease mutation, or a combination of any 2, 3, 4, 5 or 6 agents listed above.

[0002] TABLE I: Therapeutically targeting specific alterations in the nutrient-sensing signaling network and cellular processes that regulate proteotoxic stress. Agents may be administered both individually and in combination SIRT Agonists Translation Inhibitors Mitochondrial Biogenesis Agents • Nicotinic Acid • Cycloheximide • (+) or (-) Epicatechin • Nicotinamide • Actinomycin • Hydroxysterols (11- • Nicotinamide • Anisomycin hydroxyprogesterone or 11- mononucleotide hydroxypregnenolone) • Nicotinamide Riboside Autophagy Modulators • Resveratrol Intermediary Metabolic Modifiers • Lithium chloride • 3-Methyladenine • Dichloroacetate mTORC1 Inhibitors • Urolithin A • Creatine • Rapamycin • Hemin • Dimethylfumarate • Probucol • Tripterin • Folinic Acid • Leucine • Elamipretide • Vitamin B1 (thiamine) Nutrients • Vitamin B2 (riboflavin) PPAR Agonists • Glucose • Vitamin D robucol • 2-deo • Vitamin C • P xyglucose • Rosiglitazone Nitric Oxide Agonists • Fenofibrate Antioxidants • Omaveloxolone • Arginine • Vitamin E • Citrulline AMPK Agonists • N-acetylcysteine • Soluble cGMP agonists • Lipoic Acid Preferred combination bitartrate or tartrate formulations include, without limitation, 1, 2, 3, or more of one of the agents numbered 1-12 below. 1. nicotinic acid (NIC) / N-acetycysteine (NAC) / Glucose (individually or combined) 2. probucol 3. NIC / NAC / Glucose 4. Antioxidant (CoQ10 (ubiquinol or ubiquinone), vitamin E, or lipoic acid) 5. Flavonoids (+ epicatechin, - epicatechin, 11-hydroxyprogesterone, 11 hydroxypregnenolone) 6. Resveratrol 7. Thiamine 8. Rapamycin 9. Lithium chloride 10. Elamipretide 11. Omaveloxolone 12. Urolitihin A. In certain aspects, the combined agents act synergistically. In other embodiments, the agents address different clinical symptoms, therefore providing improved therapeutic benefit and reducing dysfunction. In other aspects, certain agents are excluded. For example, the combined formulation can exclude at least one, two or three of agents selected from N-acetylcysteine, nicotinic acid, niacinamide, nicotinamide riboside, nicotinamide mononucleotide, trypterin, hemin, (+) epicatechin, (-) epicatechin, 11-hydroxyprogesterone, 11-hydroxypregnenolone, and probucol. Particularly preferred combinations include, without limitation sodium bitartrate, (-) epicatechin with or without N-acetylcysteine. Combinations of sodium bitrate with at least one, at least 2 or at least three of (+) epicatechin, 11-hydroxyprogesteron, 11-hydroxypregnonlone as they are all are in same class but possess different potencies / isomers are also preferred. Also disclosed herein are methods of managing patients with mitochondrial dysfunction or mitochondrial disease and / or assessing the response of said patients to therapeutic intervention through the use of a composite endpoint that measures clinically significant improvements, comprising (i) measuring relevant and / or prevalent symptoms affecting patients with mitochondrial disease; (ii) performing a baseline assessment of a patient using two or more clinical assessments such as those described above; (iii) performing a subsequent assessment of a patient using the same clinical assessments; and (iv) an algorithm to compare the result of the subsequent assessment to the baseline assessment. REFERENCES Haroon S, Yoon H, Seiler C, Osei-Frimpong B, He J, Nair RM, Mathew ND, Burg L, Kose M, Venkata CRM, Anderson VE, Nakamaru-Ogiso E, Falk MJ. N-acetylcysteine and cysteamine bitartrate prevent azide-induced neuromuscular decompensation by restoring glutathione balance in two novel surf1- / - zebrafish deletion models of Leigh syndrome. Hum Mol Genet. 2023 Jun 5;32(12):1988-2004. doi: 10.1093 / hmg / ddad031. PMID: 36795052; PMCID: PMC10244219. Guha S, Konkwo C, Lavorato M, Mathew ND, Peng M, Ostrovsky J, Kwon YJ, Polyak E, Lightfoot R, Seiler C, Xiao R, Bennett M, Zhang Z, Nakamaru-Ogiso E, Falk MJ. Pre-clinical evaluation of cysteamine bitartrate as a therapeutic agent for mitochondrial respiratory chain disease. Hum Mol Genet. 2019 Jun 1;28(11):1837-1852. doi: 10.1093 / hmg / ddz023. PMID: 30668749; PMCID: PMC6522065. Xia Q, Lu S, Ostrovsky J, McCormack SE, Falk MJ, Grant SFA. PARP-1 Inhibition Rescues Short Lifespan in Hyperglycemic C. Elegans And Improves GLP-1 Secretion in Human Cells. Aging Dis. 2018 Feb 1;9(1):17-30. doi: 10.14336 / AD.2017.0230. PMID: 29392078. Kwon YJ, Falk MJ, Bennett MJ. Flunarizine rescues reduced lifespan in CLN3 triple knock-out Caenorhabditis elegans model of batten disease. J Inherit Metab Dis. 2017 Mar;40(2):291-296. doi: 10.1007 / s10545-016-9986-1. Epub 2016 Oct 20. PMID: 27766444. Polyak E, Ostrovsky J, Peng M, Dingley SD, Tsukikawa M, Kwon YJ, McCormack SE, Bennett M, Xiao R, Seiler C, Zhang Z, Falk MJ. N-acetylcysteine and vitamin E rescue animal longevity and cellular oxidative stress in pre-clinical models of mitochondrial complex I disease. Mol Genet Metab. 2018 Apr;123(4):449-462. doi: 10.1016 / j.ymgme.2018.02.013. Epub 2018 Feb 23. PMID: 29526616. Guha S, Mathew ND, Konkwo C, Ostrovsky J, Kwon YJ, Polyak E, Seiler C, Bennett M, Xiao R, Zhang Z, Nakamaru-Ogiso E, Falk MJ. Combinatorial glucose, nicotinic acid and N- acetylcysteine therapy has synergistic effect in preclinical C. elegans and zebrafish models of mitochondrial complex I disease. Hum Mol Genet. 2021 May 12;30(7):536-551. doi: 10.1093 / hmg / ddab059. PMID: 33640978. Flickinger J, Fan J, Wellik A, Ganetzky R, Goldstein A, Muraresku CC, Glanzman AM, Ballance E, Leonhardt K, McCormick EM, Soreth B, Nguyen S, Gornish J, George-Sankoh I, Peterson J, MacMullen LE, Vishnubhatt S, McBride M, Haas R, Falk MJ, Xiao R, Zolkipli- Cunningham Z. Development of a Mitochondrial Myopathy-Composite Assessment Tool. JCSM Clin Rep. 2021 Oct;6(4):109-127. Epub 2021 Aug 30. PMID: 35071983. While certain of the preferred embodiments of the present invention have been described and specifically exemplified above, it is not intended that the invention be limited to such embodiments. Various modifications may be made thereto without departing from the scope and spirit of the present invention, as set forth in the following claims.

Claims

WHAT IS CLAIMED IS:

1. A composition which modulates at least one of primary, secondary, acute and chronic, mitochondrial disease or dysfunction for the treatment of mitochondrial disease or dysfunction, comprising an effective amount of at least one of bitartrate or tartrate in a pharmaceutically acceptable formulation.

2. The composition of claim 1, comprising one or more agents shown in Table 1, Figure 9 or modified derivatives thereof.

3. The composition of claim 1 or claim 2, comprising one or more of N-acetylcysteine, nicotinic acid (niacin), niacinamide, nicotinamide riboside, nicotinamide mononucleotide, probucol, glucose, 2-deoxyglucose, lipoic acid, resveratrol, thiamine, riboflavin, leucine, uridine, 3-methyl-adenine, hemin, trypterin, (+) epicatechin, (-) epicatechin, 11- hydroxyprogesterone, 11-hydroxypregnenolone, cycloheximide, rapamycin, lithium chloride, creatine, dichloroacetate, omaveloxolone, elamipretide, dimethylfumarate, a deubiquitalase (DUB) modulating agent, a PPAR alpha modulating agent, PPAR gamma modulating agent, a PPAR delta modulating agent , an AMPK modulating agent, a sirtuin modulating agent, a mTORC1 modulating agent, a MAPK modulating agent, a PGC1-alpha modulating agent, a HIF1-alpha modulating agent, a mitochondrial biogenesis modulating agent, an antioxidant, a phosphodiesterase modulator, sildenafil, doxycycline, tetracycline, trapidil, a calcium channel modulator, flunarizine, folinic acid, metformin, valproic acid, dexamethasone, etoposide, vorinostat, quercitin, hydralazine, pfithrin-α, ginsenoside, sulfonsuccinimidyl oleate, carnitine, levocarnitine, AICAR, GSK2578215A, bezafibrate, vatiquinone, coenzyme Q10, alpha- tocopherolquinone, a coenzyme Q10 analog, ubiquinone, ubiquinol, cytochrome C, 5-I-2-(4- hydroxyphenyl)-ethenyl] benzene-1,3 diol, flavin mononucleotide, urolithin A, idebenone, latrepirdine, 2′,3′,5′-tri-O-acetyluridine, olesoxime, thiamine diphosphate, vitamin C, vitamin D, vitamin E, magnesium, calcium, phosphate, membrane phospholipid, unsaturated fatty acid, pyruvate, nicotinamide adenine dinucleotide, cysteamine bitartrate, acipimox, glutathione, a redox-modulating agent, curcumin, schisandrin, triheptanoin, an inhibitory nucleic acid targeting an upregulated gene associated with mitochondrial dysfunction, an activating genetic construct for increasing expression of a mitochondrial disease modulator protein, a nucleic acid / proteincomplex for genetic and / or base editing suitable for replacement therapies for primary mitochondrial diseases, a viral or non-viral vector gene therapy targeting a mitochondrial disease mutation, or a combination of any 2, 3, 4, 5 or 6 agents listed above.

4. The composition of claim 3, wherein said combination includes tartrate or bitartrate and (-) epicatechin, said combination acting synergistically to reduce mitochondrial disease symptoms.

5. The composition of claim 3, wherein said combination includes tartrate or bitartrate and probucol or N-acetylcysteine.

6. The composition of claim 3, wherein said combination includes tartrate or bitartrate and CoQ10.

7. The composition of claim 3, wherein said combination includes tartrate or bitartrate and vitamin E.

8. The composition of claim 3, wherein said combination includes tartrate or bitartrate and a flavonoid.

9. The composition of claim 3, wherein said combination includes tartrate or bitartrate and + epicatechin.

10. The composition of claim 3, wherein said combination includes tartrate or bitartrate and nicotinic acid.

11. The composition of claim 3, wherein said combination includes tartrate or bitartrate and 11-hydroxyprogesterone.

12. The composition of claim 3, wherein said combination includes tartrate or bitartrate and 11-hydroxypregnenolone.

13. The composition of claim 3, wherein said combination includes tartrate or bitartrate and nicotinamide.

14. The composition of claim 3, wherein said combination includes tartrate or bitartrate and nicotinamide riboside.

15. The composition of claim 3, wherein said combination includes tartrate or bitartrate and nicotinamide mononucleotide.

16. The composition of claim 3, wherein said combination includes tartrate or bitartrate and glucose.

17. The composition of claim 3, wherein said combination includes tartrate or bitartrate and trypterin.

18. The composition of claim 3, wherein said combination includes tartrate or bitartrate and hemin.

19. The composition of claim 3, wherein said combination includes tartrate or bitartrate and dichloroacetate.

20. The composition of any one of claims 1, 2 and 6 to 19, which corrects a deficiency in oxidative phosphorylation (OXPHOS), wherein said deficiency is associated with mitochondrial respiratory chain complex I, complex II, complex III, complex IV, and / or complex V dysfunction alone or in combination.

21. The composition of claim 20, wherein said respiratory chain complex dysfunction is caused by a genetic mutation or exposure to a toxic agent.

22. The composition of any one of claims 1 to 21, which reduces or inhibits one or more of acute stressor induced decompensation, neurologic and / or neuromuscular dysfunction, cell death, whole animal death, brain death, impairment of tricarboxylic acid cycle anaplerosis, impairment of intermediary metabolism, impairment of NADH:NAD+redox state, aberrant alteration in glutathione (GSH:GSSG) redox metabolic stroke, aberrant mitophagy, and aberrant mitochondrial energy production.

23. The composition of any one of claims 1 to 22, which provides protective effects selected from one or more of improvement in cell viability, cell proliferation, ATP production, mitochondrial stress, mitochondrial unfolded protein response, mitochondrial integrated stress response, mitochondrial membrane potential, mitochondrial oxygen consumption capacity, mitochondrial coupling of oxidation to phosphorylation, mitochondrial electron transport chain enzyme activities, mitochondrial metabolite levels, mitochondrial mass or content, mitochondrial oxidant levels, cellular or mitochondrial oxidant scavenging capacity, mitochondrial DNA mutation, reduced oxidative stress, improvement in total cellular oxidant levels, increases in cellular antioxidant defense enzymes, improved glutathione metabolism, improved cellular pH, improved anaplerosis, improved pyruvate dehydrogenase capacity, and improved cellular oxygen capacity consumption.

24. The composition of any one of the preceding claims, wherein at least two agents, at least three agents or at least four agents are present and are administered separately.

25. The composition of any one of the preceding claims, wherein said combination of agents act synergistically.

26. The composition of any one of claims 1 to claim 25, wherein said composition excludes at least two, at least three, or at least 4 of agents selected from N-acetylcysteine, nicotinic acid, niacinamide, nicotinamide riboside, nicotinamide mononucleotide, glucose, trypterin, hemin, (+) epicatechin, (-) epicatechin, 11-hydroxyprogesterone, 11-hydroxypregnenolone, dichloroacetate, and probucol.

27. A method for treatment or ameliorating symptoms of a mitochondrial disease in a patient in need thereof comprising administration of an effective amount of a composition claimed in any one of claims 1 to 26, thereby treating mitochondrial disease in said patient.

28. The method of claim 27, wherein said mitochondrial disease is caused by a genetic alteration in a gene listed in in one or all of Mitochondrial Disease Genes Compendium - 1st Edition on the world wide web at elsevier.com; McCormick EM, et al. Expert Panel Curation of 113 Primary Mitochondrial Disease Genes for the Leigh Syndrome Spectrum. Ann Neurol. 2023 May 31. doi: 10.1002 / ana.26716; ClinGen gene curation expert panel on the world wide web at clinicalgenome.org; the Clin Gene Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel - ClinGen | Clinical Genome Resource and the annotated locus-specific database of pathogenic variants for mitochondrial diseases on the world wide web at mseqdr.org / mb.php?url=genes.php.

29. The method of claim 27, wherein at least two agents or at least three agents are administered simultaneously in separate pharmaceutically acceptable formulations.

30. The method of claim 27, wherein at least two agents or at least three agents are administered sequentially in separate pharmaceutically acceptable formulations.

31. The method of claim 27, wherein two or more agents are combined in a single pharmaceutically acceptable formulation.

32. The method of claim 27, wherein said composition is screened for efficacy prior to said treatment in at least one model of mitochondrial disease selected from a C. elegans model, a D. rerio model, a mouse model,and a H. sapiens cell line model.

33. The method of treatment in any one of claims 27 to 32, wherein said disease is selected from ADOA: Autosomal Dominant Optic Atrophy; AD: Alzheimer's Disease; ADPD: Alzheimer's Disease and Parkinsons's Disease; AMDF: Ataxia, Myoclonus and Deafness CIPO: Chronic Intestinal Pseudo-obstruction with myopathy and Ophthalmoplegia; CPEO: Chronic ProgressiveExternal Ophthalmoplegia; CPEO plus including multi-systemic symptoms; MID: Maternally inherited deafness or aminoglycoside-induced Deafness; DEMCHO: Dementia and Chorea; DMDF: Diabetes Mellitus & Deafness; Exercise Intolerance; ESOC: Epilepsy, Strokes, Optic atrophy, & Cognitive decline; FBSN: Familial Bilateral Striatal Necrosis; FICP: Fatal Infantile Cardiomyopathy Plus, a MELAS-associated cardiomyopathy; GER: Gastrointestinal Reflux; KSS: Kearns Sayre Syndrome; LDYT: Leber's hereditary optic neuropathy and Dystonia; LHON: Leber Hereditary Optic Neuropathy; LIMM: Lethal Infantile Mitochondrial Myopathy; LSS: Leigh syndrome spectrum; MDM: Myopathy and Diabetes Mellitus; MELAS: Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes; MEPR: Myoclonic Epilepsy and Psychomotor Regression; MERME: MERRF / MELAS overlap disease; MERRF: Myoclonic Epilepsy and Ragged Red Muscle Fibers; MHCM: Maternally Inherited Hypertrophic Cardiomyopathy; MICM: Maternally Inherited Cardiomyopathy; MILS: Maternally Inherited Leigh Syndrome; Mitochondrial Encephalocardiomyopathy; Mitochondrial Encephalomyopathy; MM: Mitochondrial Myopathy; MMC: Maternal Myopathy and Cardiomyopathy; Multisystem Mitochondrial Disorder (myopathy, encephalopathy, blindness, hearing loss, peripheral neuropathy); NARP: Neurogenic muscle weakness, Ataxia, and Retinitis Pigmentosa; alternate phenotype at this locus is reported as Leigh Disease; NIDDM: Non-Insulin Dependent Diabetes Mellitus; PEM: Progressive Encephalopathy; PME: Progressive Myoclonus Epilepsy; PS: Pearson syndrome; RTT: Rett Syndrome; SIDS: Sudden Infant Death Syndrome, SLSMDs, single large-scale mtDNA deletion syndrome; Multiple large-scale deletion disorders; and pathogenic mitochondrial cytopathies caused by point mutations or deletions / duplications in the mitochondrial DNA genome, said composition alleviating one or more symptoms of said mitochondrial disease.

34. The method of claim 33, wherein said disease is Leigh syndrome or Leigh syndrome spectrum.

35. The method of claim 34, wherein said patient is assessed using one or more assessment tests selected from Motor Function Measure, Dynamometry Measures, Cardiopulmonary exercise Test (CPET), Creatine-CEST MRI measures of post-exercise creatine and phosphocreatine levels recovery in muscle, Twelve Minute Walk Test, Six Minute Walk TestTotal Distance Walked, Six Minute Walk Distance Per Minute Distance Walked, Two Minute Walk Test, Modified Fatigue Impact Scale, MM-COAST Mitochondrial Myopathy Composite Assessment Tool, Finger Dexterity Score (9-hole peg test), Barry Albright Dystonia Scale (BADS), Friedreich's Ataxia Rating Scale (FARS), Scale for the Rating and Assessment of Ataxia (SARA), Movement Disorders Childhood Rating Scale (CRS), Patient-Reported Outcomes Measurement Information System Gastrointestinal Symptom Scales, 30-Second Sit to Stand Test, Muscle Strength by Myometry Test, Newcastle Mitochondrial Disease Adult Scale, Newcastle Mitochondrial Disease Pediatric Scale, 36-Item Short Form Survey, PediCAT score of function, Peds-QL Quality of Life Score, Karnofsky-Lansky Scale, Caregiver Burden Scale, Observer Reported Outcome (ObsRO) scale, Clinical Global Impression of Change, Patient's Global Impression of Change, Patient-Reported Initial Mitochondrial Personalized Composite Scale (MitoPC) Symptoms, Patient-Reported MitoPC Symptom Changes, Columbia Suicide Severity Rating Scale, Neuropathy Impairment Score, Migraine Disability Assessment Test, Quick Inventory of Depressive Symptomatology—Self-Report, Montreal Cognitive Assessment, NY Heart Association Functional Classification, Diabetes Health Profile, Hemoglobin A1C measure, Lactate measure, Pyruvate measure, Lactate:Pyruvate ratio measure, Alanine measure, Alanine-linked amino acid ratios measure, ketone body levels and ratio of acetoacetate: β- hydroxybutyrate, 2-hydroxy-butyrate level, glutathione GSH (reduced) and GSSG (oxidized) levels and ratio, CoQ10 level, creatine level, creatinine level, transaminase (ALT and AST) levels, urine organic acid levels, carnitine and acylcarnitine levels, N-lactoyl-amino acids, β- hydroxy acylcarnitines, β-hydroxy fatty acids, Ocular Motility Assessments, Marginal Reflex Distance, Ocular Motility & Fixation in 8 Gaze Directions, Degree of Ocular Saccades, Visual Function Test, Logarithm of Minimum Angle of Resolution, Pelli-Robson Score, Humphrey Visual Field mean deviation, or a combination thereof.

36. The method of claim 27, wherein said patient is assessed using 1, 2, 3, 4, 5, 6, or 7 of tests selected from MM-COAST, Motor Function Measure, Six Minute Walk Test, Modified Fatigue Impact Scale, Friedreich's Ataxia Rating Scale, and the Patient-Reported Outcomes Measurement Information System Gastrointestinal Symptom Scales.

37. A method for identifying compositions having efficacy for the treatment of mitochondrial disease symptoms, comprising, a) determining levels of one or more of parameters associated with mitochondrial dysfunction in a biological sample from the subject, b) comparing said levels of said one or more parameters to levels observed i) prior to administration of the composition, or ii) after administration of the composition; and c) identifying agents which alter levels of one or more of cellular OXPHOS function, blood pH, levels of cellular redox molecules selected from NADH, NAD+, NADH / NAD+, glutathione, GSH:GSSG ratio, reduced GSH, oxidized GSSG, ketone body, beta- hydroxybutyrate:acetoacetate, citrate, lactate, succinate, fumarate, alanine, 2-hydroxy-butyrate, 4-hydroxy-butyrate, methylglutaconic acid, ethylmalonic acid in plasma or urine, hemoglobin A1C, lactate , pyruvate , lactate:pyruvate ratios, alanine-linked amino acids, acetoacetate: β- hydroxybutyrate ratio, CoQ10 level, creatine, creatinine, transaminase ALT, transaminase AST, urine organic acid, carnitine, acylcarnitine, a N-lactoyl-amino acid, a β-hydroxy acylcarnitine, a β-hydroxy fatty acid, ATP in whole blood or platelets, agents altering said levels while reducing mitochondrial dysfunction, having efficacy for the treatment of mitochondrial disease.

38. The method of claim 37, wherein said OXPHOS function is determined in platelets, whole blood, cells, or tissues.

39. The method of claim 37, wherein said mitochondrial disease is selected from ADOA: Autosomal Dominant Optic Atrophy; AD: Alzheimer's Disease; ADPD: Alzheimer's Disease and Parkinsons's Disease; AMDF: Ataxia, Myoclonus and Deafness CIPO: Chronic Intestinal Pseudo-obstruction with myopathy and Ophthalmoplegia; CPEO: Chronic Progressive External Ophthalmoplegia; CPEO plus including multi-systemic symptoms; MID: Maternally inherited deafness or aminoglycoside-induced Deafness; DEMCHO: Dementia and Chorea; DMDF: Diabetes Mellitus & Deafness; Exercise Intolerance; ESOC: Epilepsy, Strokes, Optic atrophy, & Cognitive decline; FBSN: Familial Bilateral Striatal Necrosis; FICP: Fatal Infantile Cardiomyopathy Plus, a MELAS-associated cardiomyopathy; GER: Gastrointestinal Reflux; KSS: Kearns Sayre Syndrome; LDYT: Leber's hereditary optic neuropathy and Dystonia;LHON: Leber Hereditary Optic Neuropathy; LIMM: Lethal Infantile Mitochondrial Myopathy; LSS: Leigh syndrome spectrum; MDM: Myopathy and Diabetes Mellitus; MELAS: Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes; MEPR: Myoclonic Epilepsy and Psychomotor Regression; MERME: MERRF / MELAS overlap disease; MERRF: Myoclonic Epilepsy and Ragged Red Muscle Fibers; MHCM: Maternally Inherited Hypertrophic Cardiomyopathy; MICM: Maternally Inherited Cardiomyopathy; MILS: Maternally Inherited Leigh Syndrome; Mitochondrial Encephalocardiomyopathy; Mitochondrial Encephalomyopathy; MM: Mitochondrial Myopathy; MMC: Maternal Myopathy and Cardiomyopathy; Multisystem Mitochondrial Disorder (myopathy, encephalopathy, blindness, hearing loss, peripheral neuropathy); NARP: Neurogenic muscle weakness, Ataxia, and Retinitis Pigmentosa; alternate phenotype at this locus is reported as Leigh Disease; NIDDM: Non-Insulin Dependent Diabetes Mellitus; PEM: Progressive Encephalopathy; PME: Progressive Myoclonus Epilepsy; PS: Pearson syndrome; RTT: Rett Syndrome; SIDS: Sudden Infant Death Syndrome, SLSMDs, single large-scale mtDNA deletion syndrome; Multiple large-scale deletion disorders; and pathogenic mitochondrial cytopathies caused by point mutations or deletions / duplications in the mitochondrial DNA genome.

40. The method of claim 37, wherein said composition alters a parameter resulting in amelioration of symptoms associated with mitochondrial dysfunction, selected from improved cell viability, improved cell proliferation, increased ATP production, reduction in mitochondrial stress, improved mitochondrial unfolded protein response, mitochondrial integrated stress response, improved mitochondrial membrane potential, increased mitochondrial oxygen consumption capacity, increased mitochondrial coupling of oxidation to phosphorylation, improved mitochondrial electron transport chain enzyme activities, increased mitochondrial metabolite levels, improved mitochondrial mass or content, improved mitochondrial oxidant levels, cellular or mitochondrial oxidant scavenging capacity, corrects a mitochondrial DNA mutation, reduces oxidative stress, improves total cellular oxidant levels, increases in cellular antioxidant defense enzyme levels, improved glutathione metabolism, improved cellular pH, improved anaplerosis, improved pyruvate dehydrogenase capacity, and improved cellular oxygen capacity consumption.

41. The method of claim 27, wherein said alteration is in mitochondrial DNA in one or more genes selected from MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND4L, MT-ND5, MT-ND6, MT-CYB, MT-CO1, MT-CO2, MT-CO3, MT-RNR1, MT-RNR2, MT-TA, MT-TC, MT-TE, MT-TF, MT-TH, MT-TI, MT-TK, MT-TL1, MT-TL2, MT-TM, MT-TN, MT-7-Q, MT-TS1, MT-TS2, MT- TV, MT-TW, MT-ATP6, and MT-ATP8.

42. The method of claim 27, wherein said alteration is in nuclear DNA in one or more genes selected from AARS2, ABCB7, ABCC8, ACAD8, ACAD9, ACADM, ACADS, ACADSB, ACADVL, ACAT1, ACO2, ADCK3, ADRB2, ADRB3, AFG3L2, AGK, AGRP, AlFM1, AK2, AKAP10, AKT2, ALAS2, ALDH2, ALDH4A1, ALDH6A1, AMACR, AMT, APOPT1, APTX, ARMS2, ATP5A1, ATP5E, ATP5F1A, APT5F1D, ATP5F1E, ATPAF2, AUH, BAX, BCAT2, BCKDHA, BCKDHB, BCL2, BCS1L, BOLA3, C8orf38, C10orf2, C12orf62, C12orf65, C19orf12, C20orf7, C1QBP, CAPN10, CARS2, CARTPT, CDH23, CDKAL1, CHCHD10, CHKB, CISD2, CLRN1,C0A5, COA7, COA10, COQ2, COQ4, COQ6, COQ7, COQ8A, COQ9, COX10, COX14, COX15, COX20, C0X412, COX6B1, COX8A, CPS1, CPT1A, CPT2, CRAT, CYB5R3, CYC1, CYC5, CYCS, CYP11A1, CYP1161, CYP1162, CYP24A1, CYP27A1, CYP2761, D2HGDH, DARS2, DBT, DECR1, DFNB31, DGUOK, DHODH, DIABLO, DLD, DLAT, DMGDH, DNA2, DNAJC19, DNM1L, EARS2, ECHS1, ELAC2, ENPP1, ETFA, ETFB, ETFDH, ETHE1, FARS2, FASTKD2, FBXL4, FOXRED1, FH, FXN, GA TM, GCDH, GCGR, GCK, GCSH, GDAP1, GFER, GFM1, GHRL, GJB2, GJB3, GJB6, GK, GLDC, GLRX5, GLUD1, GPD2, GPR98, GTPBP3, HADH, HADHA, HADHB, HARS2, HCCS, HIBCH, HK1, HLCS, HMGA1, HMGCS2, HMGCL, HNF1A, HNF1B, HNF4A, HOGA1, HSD17610, HSPD1, HTRA1, HTRA2, IBA57, IDH2, IDH3B, IGF2BP2, IL6, INSR, IRS1, IRS2, ISCA1, ISCA2, ISCU, IVD, KANK1, KARS, KCNJ11, KIF1B, L2HGDH, LARS2, LEPR, LIAS, LIPC, LRPPRC, LRRK2, LYRM4, LYRM7, MAOA, MAPK8IP1, MAR52, MC4R, MCCC1, MCCC2, MCEE, ME2, MFF, MFN2, MGME1, MIPEP, MLYCD, MMAA, MMAB, MMADHC, MPC1, MPV17, MRAP2, MRPL3, MRPL44, MRPS2, MRPS7, MRPS16, MRPS22, MRPS34, MST01, MTFMT, MT01, MTPAP, MUT, MY07A, NAGS, NARS2, NDUFA1, NDUFA2, NDUFA6, NDUFA9, NDUFA10, NDUFA11, NDUFA12, NDUFA13, NDUFAF1, NDUFAF2, NDUFAF3, NDUFAF4, NDUFAF5, NDUFAF6, NDUFB3, NDUFB8, NDUFB9, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS5, NDUFS6, NDUFS7, NDUFS8, NDUFV1, NDUFV2, NEUROD1, NF2, NFU1, NGLY1, NROB2,NUBPL, NUP62, OAT, OGDH, OPA1, OPA3, OTC, OXCT1, PANK2, PARK2, PARK7, PAX4, PC, PCCA, PCCB, PCDH15, PCK2, PDHA1, PDHB, PDHX, PDP1, PDSS1, PDSS2, PDX1, PET100, PINK1, PNKD, PNPT1, POLG, POLG2, POMC, PPARG, PPARGC1B, PPDX, PPP1R3A, PUS1, PYCR1, PYY, RARS2, REEP1, RMRP, RMND1, RNASEH1, RRM2B, SACS, SARDH, SARS2, SC01, SCO2, SC03, SDHA, SDHAF1, SDHAF2, SDHB, SDHC, SDHD, SERAC1, SFXN4, SIM1, SLC2A2, SLC2A4, SLC22A5, 5LC25A1, 5LC25A3, 5LC25A4, 5LC25Al2, 5LC25A13, 5LC25A15, 5LC25A19, 5LC25A20, 5LC25A22, 5LC25A26, 5LC25A38, SLC30A8, 50D2, SPG7, SPG20, STAR, SUCLA2, SUCLG1, SURF1, TAC01, TARS2, TAZ, TDF7L2, TFAM, TIMM8A, TIMMDC1, TK2, TMEM70, TMEM126, TMEM126B, TOP3A, TRIT1, TRMT10C, TRMT5, TRMU, TRNT1, TSFM, TTC19, TUFM, TWNK, UCP1, UCP2, UCP3, UNG, UQCC2, UQCC3, UQCRB, UQCRC2, UQCRQ, USMG5, USH1C, USH1G, USG2A, VARS2, WARS2, WFS1, WWOX, XPNPEP3, YARS2.

43. The method of claim 42, wherein said gene mutation or loss of function is in NDUFS2 or SURF1.

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