Compound for stimulating mitochondrial metabolism in gametes and embryos

Abstract

The present invention relates to 4-hydroxybenzoic acid for use thereof in the stimulation of mitochondrial metabolism from before fertilization and during subsequent embryonic development. The inventors have discovered that 4-hydroxybenzoic, administered orally before the moment of fertilization, induces an increase in coenzyme Q levels and mitochondrial metabolism in the brain of both a control mouse and a mouse with coenzyme Q deficiency due to mutation in the Coq2 gene. The present invention thereby allows the therapeutic use of 4-hydroxybenzoic acid for neurological, neurometabolic, neurodegenerative and cardiometabolic diseases, as well as cases of infertility, associated with coenzyme Q deficiency, mitochondrial dysfunction, impaired energy metabolism and / or increased oxidative stress. The present invention also relates to a pharmaceutical composition, to the non-therapeutic use of 4-hydroxybenzoic acid and to a nutraceutical composition or functional food, dietary product or nutritional supplement. 

Description

DESCRIPTION COMPOUND FOR STIMULATING MITOCHONDRIAL METABOLISM IN GAMETES AND EMBRYOSFieldoftheInvention The present invention is comprised in the field of biomedicine and relates to a compound, 4hydroxybenzoic acid, for use thereof in the stimulation of mitochondrial metabolism from embryonic development. Within this field, the use of this compound is of particular interest for neurological, neurometabolic, neurodegenerative and cardiometabolic diseases, as well as infertility with miscarriages or recurrent miscarriages, associated with coenzyme Q deficiency, mitochondrial dysfunction, impaired energy metabolism and / or increased oxidative stress.  BackgroundoftheInvention Mitochondrial dysfunctionMitochondria are cell organelles that not only participate in energy production, but are also essential in an array of cellular processes. Accordingly, mitochondrial dysfunction is involved, primarily or secondarily, in a wide variety of pathophysiological processes. Among them, mitochondrial diseases constitute highly heterogeneous metabolic disorders from a genetic, molecular, biochemical, pathophysiological and symptomatological viewpoint. However, mitochondrial diseases often occur with a deficit in energy production, increased oxidative stress and other metabolic impairments. Symptoms frequently affect tissues or systems with high energy demand, such as the central nervous system (CNS) or the heart, resulting in neurological, neurometabolic, neurodegenerative or cardiometabolic diseases (Gorman et al., 2016). Likewise, mitochondrial metabolism is essential for the functions required by gametes, as well as for tissue development during embryogenesis, particularly the brain or heart (Oyarzábal, Musokhranova, Barros & García-Cazorla, 2021; Zhao, Sun, Zhou, Liu & Jiao, 2019). No effective treatment is available for most diseases occurring with mitochondrial dysfunction, and interventions are limited to palliative interventions. An essential component of mitochondria is coenzyme Q (CoQ), a molecule that integrates a variety of metabolic pathways with energy metabolism (Hidalgo-Gutierrez et al., 2021), in addition to carrying out important antioxidant and anti-inflammatory activity. In humans and rodents, CoQ is found in the form of CoQ9 and CoQ10. CoQ is synthesized endogenously in mitochondria through a complex biosynthesis pathway involving at least 16 different proteins (Guerra & Pagliarini, 2023). Said pathway appears to be regulated by two of its components, i.e., the activity of COQ2 protein and the levels of its substrate, 4-hydroxybenzoic acid (Fernandez-Del-Rio et al., 2017; Pierrel, 2017). In fact, COQ2 mutations give rise to a mitochondrial disease that leads to death during embryonic development, neurological development disorders, encephalopathy, seizures, sensorineural hearing loss, nephrotic syndrome, cardiomyopathy and / or edema (Alcazar-Fabra, Rodriguez-Sanchez, Trevisson & Brea-Calvo, 2021). COQ2 genetic variants have also been associated with the development of multiple system atrophy (Multiple-System Atrophy Research, 2013). Likewise, secondary CoQ deficiency due to a drop in COQ2 activity has been linked to other mitochondrial diseases and metabolic syndrome (Navas et al., 2021). Conventional treatment for diseases occurring with mitochondrial dysfunction tends to include exogenous supplementation of high doses of CoQ10, which is ineffective in a majority percentage of patients due to the highly lipophilic nature and low bioavailability of exogenous CoQ10 (Wang & Hekimi, 2022). This is particularly relevant in cases in which increased CoQ10 is required in the CNS and / or during embryonic development, given the protection conferred by biological barriers such as the blood-brain or placental barrier. Furthermore, exogenous CoQ10 minimally reaches the mitochondria where CoQ10 is metabolically active (Bentinger, Dallner, Chojnacki & Swiezewska, 2003); and only one of the forms of CoQ, CoQ10, is supplemented, omitting the other form, CoQ9. This is why, although CoQ10 has been conceptually proposed for the treatment of pathophysiological processes occurring with mitochondrial dysfunction, the results have not shown clear effectiveness (Wang & Hekimi, 2022). Given this background, it is necessary to find new therapeutic formulas that increase endogenous levels of CoQ9 and CoQ10 in the CNS and / or during embryonic development, and particularly in the mitochondria of their cells, in order to thereby use these new formulas for the treatment of neurological, neurometabolic, neurodegenerative, cardiometabolic diseases, or infertility with recurrent miscarriages, associated with CoQ deficiency, mitochondrial dysfunction, impaired energy metabolism and / or increased oxidative stress. To that end, control mice and Coq2mutant mice (Coq2A252V), Coq2 beingthe gene which encodes COQ2 protein in the mitochondrial biosynthesis of CoQ, are used.   Uses of 4-hydroxybenzoic acid4-Hydroxybenzoic acid (4HB) belongs to the hydroxybenzoic acid derivatives, a group of natural phenolic compounds present in plants and other organisms. This group also includes beta-resorcylic acid (b-RA or 2,4-dihydroxybenzoic acid) and vanillic acid (VA). 4HB is considered one of the substrates of the mitochondrial CoQ biosynthesis pathway, and its analogs b-RA and VA can also act in the mitochondrial CoQ biosynthesis pathway. In fact, 4HB has been shown to be capable of stimulating CoQ synthesis in skin fibroblasts from a patient with COQ2 mutation(Herebian, Seibt, Smits, Rodenburg, Mayatepek & Distelmaier, 2017), whereas b-RA and VA have been shown to be capable of stimulating CoQ synthesis in skin fibroblasts from patients with COQ7 or COQ9 mutation in the case of b-RA (Freyer et al., 2015; Luna-Sanchez et al., 2015), and COQ6 in the case of VA (Acosta Lopez et al., 2019). However, in vivo experiments have shown that b-RA and VA act on CoQ biosynthesis only in peripheral tissues (mainly kidneys and to a lesser extent liver, skeletal muscle and heart) but not in the CNS (brain), where it does not change CoQ levels (Gonzalez-Garcia et al., 2022; Hidalgo-Gutierrez et al., 2019). This suggests that 4HB could also act in peripheral tissues, but not in the CNS. Likewise, there is no data in the literature showing the effects of oral administration of 4HB on embryonic development, taking into account the protective effect exerted in that context by the possible metabolization by the mother and the protective action of the placental barrier.  BriefDescriptionoftheInvention Surprisingly, the inventors have discovered that 4HB, administered orally before the moment of conception, increases the levels of CoQ9 and CoQ10 in the brain of control mice and mice with CoQ deficiency due to Coq2 mutation (Coq2A252Vmice). This gives rise to an increase in mitochondrial function in the brain of control mice and mice with CoQ deficiency due to Coq2 mutation (Coq2A252V mice). The present invention thereby allows the use of 4HB in neurological, neurometabolic, neurodegenerative and cardiometabolic diseases, as well as in infertility with miscarriages or recurrent miscarriages, associated with CoQ deficiency, mitochondrial dysfunction, impaired energy metabolism and / or increased oxidative stress. Particularly, the treatment is especially relevant for the case of CoQ deficiencies due to Coq2 mutations and / or defects in COQ2 protein function. Coq2A252V mice exhibit severe developmental delay which appears particularly in the CNS and the heart, giving rise to perinatal death, with no animal being born alive. This phenotype is due to a severe CoQ deficiency that is clearly observed in the brain (determination cannot be made for the heart due to limited amount of tissue). 4HB treatment through the feed consumed by a female mouse, with the treatment being started preferably before the moment of conception, is capable of normalizing brain CoQ levels. Accordingly, normal mutant mice, which are indistinguishable from control mice, are born and these mice develop normally during the lactation period and once they are weaned, at which time they start to consume therapeutic feed directly.  Therefore, in a first aspect, the present invention relates to 4HB or pharmaceutically acceptable salts thereof for use in the oral treatment of CoQ deficiencies due to gene and / or COQ2 protein defects, preferably those affecting the CNS (central nervous system) and / or the heart.  In a preferred embodiment, the present invention relates to a composition comprising 4hydroxybenzoic acid (4HB) or pharmaceutically acceptable salts thereof for use in the oral treatment of coenzyme Q (CoQ) deficiencies due to Coq2 mutations and / or defects in COQ2 protein function, wherein the treatment is administered to a subject of reproductive age capable of gestation, and wherein the treatment is administered within the ovarian cycle prior to conception (fertilization) or the start of pregnancy in said subject, wherein conception is understood as the moment in which an ovum from said subject is fertilized by a sperm cell. In the context of the present invention, an ovarian cycle is understood as the hormonal process of about 28 days which all women go through every month during their reproductive age. In other words, according to the present invention, the treatment must be administered at at least any time within the approximately 28 days prior to conception (fertilization) or the start of pregnancy in said subject, wherein conception is understood as the moment in which an ovum from the female subject is fertilized by a sperm cell. In a preferred embodiment, the composition is administered to treat infertility occurring with coenzyme Q (CoQ) deficiencies due to Coq2 mutations and / or defects in COQ2 protein function in the subject.  In another preferred embodiment, the composition is administered to treat severe delay in embryonic development or perinatal death caused by coenzyme Q (CoQ) deficiencies due to Coq2 mutations and / or defects in COQ2 protein function. In another preferred embodiment, the composition is administered to treat diseases caused by coenzyme Q (CoQ) deficiencies due to Coq2 mutations and / or defects in COQ2 protein function which are associated with embryonic development selected from the list consisting of neurological, neurometabolic, neurodegenerative and cardiometabolic diseases.  In another preferred embodiment, the treatment is administered at least within a time interval between the preceding 20 days and the conception (fertilization) or start of pregnancy in said subject. In another preferred embodiment, the treatment is administered within a time interval between the preceding 7 days and the conception (fertilization) or start of pregnancy in said subject. It should be noted that although the treatment is started prior to conception or ovum fertilization, it preferably continues throughout part or all of the gestation period. In this way, by performing administration prior to and after conception, ovum formation and embryonic formation and development are improved, respectively. Preferably, it is possible to continue the treatment after the start of pregnancy or gestation, particularly throughout the entire gestation or even after birth, preferably throughout the entire gestation and lactation period after birth, more preferably, during at least the first weeks or the first months after conception, more preferably, during the course of 1, 2, 3, 4 or more weeks after conception, more preferably, during the course of 1, 2, 3, 4 or more months after conception. In another preferred embodiment, the subject is a female human subject of reproductive age and capable of gestation. In the context of the present invention, capable of gestation is understood as that subject, preferably a human subject, who, being a female or a woman or belonging to various gender identities different from the traditional concept of a female or woman, has a body that is capable of gestation. In another preferred embodiment, oral administration is performed at a dose of 4-hydroxybenzoic acid (4HB) or pharmaceutically acceptable salts thereof of between 5 and 75 mg / kg body weight / day, more preferably between 10 and 60 mg / kg body weight / day. Preferably, said oral administration is performed between 1 and 4 times a day. A second aspect of the present invention relates to a non-therapeutic use of a composition comprising 4-hydroxybenzoic acid (4HB) or pharmaceutically acceptable salts thereof for improving fertility in a subject of reproductive age capable of gestation, preferably in a human subject. In a preferred embodiment of the second aspect of the invention, said composition is a nutraceutical composition, functional food, dietary product or nutritional supplement comprising 4-hydroxybenzoic acid (4HB) or pharmaceutically acceptable salts thereof. A third aspect of the present invention relates to a nutraceutical composition, functional food, dietary product or nutritional supplement comprising 4-hydroxybenzoic acid (4HB) or pharmaceutically acceptable salts thereof, and optionally a nutritionally acceptable excipient.  A fourth aspect of the present invention relates to a pharmaceutical composition suitable for oral administration comprising 4-hydroxybenzoic acid (4HB) or pharmaceutically acceptable salts thereof, preferably in an amount suitable for administering between 5 and 75 mg / kg body weight / day of 4-hydroxybenzoic acid (4HB) or pharmaceutically acceptable salts thereof, more preferably between 10 and 60 mg / kg body weight / day, to a human subject of reproductive age capable of gestation.  A fifth aspect of the present invention relates to a nutraceutical composition, functional food, dietary product or nutritional supplement suitable for oral administration comprising 4-hydroxybenzoic acid (4HB) or pharmaceutically acceptable salts thereof in an amount suitable for administering between 5 and 75 mg / kg body weight / day of 4-hydroxybenzoic acid (4HB), or pharmaceutically acceptable salts thereof, preferably between 10 and 60 mg / kg body weight / day, to a human subject of reproductive age capable of gestation.  BriefDescriptionoftheFigures Figure1. Impactof 4HB treatmenton embryo survival. (A)Number of births per litter after hormonal synchronization. (B) Survival curve. (C) Representative aspect of Coq2+ / + and Coq2A252V mice untreated and treated with 4HB after 17.5 days of embryonic development. N= 10-12 in each experimental group. **** p < 0.0001 vs. litters of female mice not treated with 4HB. Figure 2. Effectof 4HB treatmenton thelevelsof CoQ9and CoQ10 in17.5-day-old embryo brain. (A) Levels of CoQ9. (B) Levels of CoQ10. (C) CoQ9 / CoQ10ratio. N = 5 in each experimental group. *** p < 0.001 vs. Coq2+ / +; # p < 0.05 vs. Coq2+ / + treated with 4HB; ### p < 0.001 vs. Coq2+ / + treated with 4HB; + p < 0.05 vs. Coq2A252V; ++ p < 0.01 vs. Coq2A252V. Figure 3. Effectof 4HB treatmentonthemitochondrial activityofII + III complexesin17.5-day-old embryo brain. N = 5 in each experimental group # p < 0.05 vs. Coq2+ / + treated with 4HB. Figure 4. Consequences of 4HB treatmentonCNSdevelopment during embryogenesis. (A-C) Representative brain reconstruction based on an analysis obtained by HREM at E15.5. (D-F) Representative brain MRI images at E17.5. N = 3-6 in each experimental group. Figure 5. Consequences of 4HB treatmenton heart developmentduring embryogenesis. (A-C) Representative images obtained by HREM at E15.5, where the presence of edema is shown in Coq2A252Vmice. (D-I) Representative images obtained by HREM at E15.5, where incomplete ventricular septal closure and reduced myocardial wall thickness in Coq2A252Vmice are shown. N = 3-6 in each experimental group. Figure 6. Phenotypingofmice with 1 month of lifewhich have been chronically treatedwith 4HB during embryonic development and after birth. (A-C) Expert aspect of the mice. (D) Quantification of the time of fall in the rotarod test. (E-F) Weight of male mice (E) and female mice (F). N = 6-14 in each experimental group. Figure 7. Brain and heart morphologyofmice with 1 month of lifewhich have been chronically treatedwith 4HB during embryonic development and after birth. (A-C) Midbrain magnetic resonance images. (D-E) Images of the heart with hematoxylin and eosin stain. N = 3-6 in each experimental group. Figure 8. Mitochondrial activityofII + III complexesinthe brainofmice with 1 month of lifewhich have been chronically treatedwith 4HB during embryonic development and after birth. N = 5 in each experimental group # p < 0.05 vs. Coq2+ / + treated with 4HB. Figure 9. Effectof 4HB treatmentonthelevelsof CoQ9and CoQ10 inthe cerebrum, cerebellum and heartofmice with 1 month of life. (A-C) Levels of CoQ9. (D-F) Levels of CoQ10. (G-I) CoQ9 / CoQ10 Ratio. N = 5 in each experimental group. *** p < 0.001 vs. Coq2+ / +; # p < 0.05 vs. Coq2+ / + treated with 4HB; ### p < 0.001 vs. Coq2+ / + treated with 4HB. Figure 10. Phenotypic impact of discontinuing 4HB therapy after 90 days of treatment in Coq2A252V mice. (A) Survival curve. (B) Weight gain curve. N=7-8 per experimental group. Figure 11. Effect of stopping 4HB therapy on CoQmetabolism in the cerebrum, cerebellum, and heart. (A-C) CoQ9 levels.(D–F) CoQ10 levels.(G–I) CoQ9 / CoQ10 ratio. N = 5 per experimental group. *** p < 0.001 vs. Coq2A252Vtreated with 4HB; ** p < 0.01 vs. Coq2A252Vtreated with 4HB; * p < 0.05 vs. Coq2A252Vtreated with 4HB. 4HB therapy was discontinued after 90 days of treatment.Figure 12. Comparative analysis of CoQ10 treatment versus 4HB treatment in the Coq2A252V model.(A) Survival curve. (B-C) Photos of Coq2A252Vtreated with CoQ10 (B) and Coq2A252Vtreated with 4HB (C) at 19 days of age. N = 8-15 per experimental group.Figure 13. Analysis of CoQ9 levels in the comparative study of CoQ10 treatment versus 4HB treatment in Coq2A252V mice. (A-C) CoQ9 levels of cerebrum (A), cerebellum (B) and kidney (C). N = 6 – 9 per experimental group. *** p < 0.001 vs. Coq2+ / +; # p < 0.05 vs. Coq2A252Vtreated with 4HB.Figure 14. Morphology of the brain and the kidney from Coq2A252V mice treated with CoQ10 versus 4HB at 21 days of age. (A-I) NeuN stain, indicative of neurons, in cerebral cortex. (J-R) IBA-1 stain, indicative of microglia, in cerebellum. (S-X) PAS stain in kidney. N = 3 in each experimental group. Detailed DescriptionoftheInvention The present invention focuses on the use of 4-hydroxybenzoic acid (4HB) and the salts thereof, including pharmaceutically acceptable salts, for the treatment of metabolic diseases, particularly those that arise due to mitochondrial dysfunction, and particularly those that affect the CNS and the heart, more specifically during embryonic development. The person skilled in the art should understand that the different particular and preferred embodiments described below for each aspect are not limited to each aspect, but can be applied to different aspects. For example, the person skilled in the art should understand that a particular embodiment of a therapeutic use of the invention is also a particular embodiment of a non-therapeutic use or of a pharmaceutical composition. The term “4-hydroxybenzoic acid” or “4HB” refers to a compound of formula (I): (I) Other equivalent names of this compound are “4-hydroxybenzoate”, “4-hydroxybenzoic acid, calcium salt”, 4-hydroxybenzoic acid, copper salt (2+)(1:1)”, 4-hydroxybenzoic acid, dilithium salt”, “4-hydroxybenzoic acid, dipotassium salt”, “4-hydroxybenzoic acid, disodium salt”, “4hydroxybenzoic acid, monopotassium salt”, “4-hydroxybenzoic acid, monosodium salt”, “4hydroxybenzoic acid, monosodium salt, labelled with 11C”, “p-hydroxybenzoate”, “parahydroxybenzoic acid” and “sodium p-hydroxybenzoate tetrahydrate”. Unless otherwise indicated, the present invention does not contemplate 4-hydroxybenzoic acid alone, but also the salts thereof, including pharmaceutically acceptable salts. Non-limiting examples of 4-hydroxybenzoic acid salts are, for example, lithium, monosodium, disodium, monopotassium or dipotassium salt. In the present application, unless otherwise indicated, the term “WT” or “Coq2+ / +” means “wildtype”, in reference to the control mouse group without any genetic mutation or modification. The term Coq2A252V refers to the mouse group having a mutation in the Coq2 gene which causes the COQ2 protein to change the alanine amino acid in position 252 to a valine amino acid, which is similar to the COQ2A302V modification present in two children with CoQ deficiency born through C-section at 6 months of life and developed ingestion problem, edema, seizures and apnea, which resulted in a premature death before 6 months of life.  As used in the present invention, the term “coenzyme Q (CoQ) deficiencies due to COQ2 mutations and / or defects in COQ2 protein function” shall be understood to include, without limitation, any condition, disorder, syndrome, or disease state arising from one or more mutations, sequence variations, substitutions, insertions, deletions, polymorphisms, or other abnormalities in the COQ2 gene (also sometimes referenced as “Coq2”), or from any alteration in the structure, folding, stability, or enzymatic activity of the COQ2 protein such that the biosynthesis, availability, or utilization of coenzyme Q (CoQ) is compromised. This definition is primarily intended with respect to human subjects, although it also extends to conditions in other mammals or organisms where relevant. The COQ2 gene encodes an enzyme (often referred to as para-hydroxybenzoate-polyprenyltransferase or simply COQ2 protein) that catalyses an essential step in the biosynthetic pathway of coenzyme Q (also termed ubiquinone). Coenzyme Q is crucial for mitochondrial electron transport and ATP production, and deficiencies may manifest as multisystemic or tissue-specific pathologies. Examples of mutations associated with CoQ deficiency include, but are not limited to, COQ2 p.Arg197His, p.Arg197Pro, p.Arg360His, p.Arg387, and p.Ala302Val (A302V). Mutations may be homozygous, heterozygous, compound heterozygous, or present as part of a more complex genetic background. Any structural or functional alteration within the COQ2 protein resulting in diminished catalytic activity or decreased protein stability leading to reduced CoQ levels falls within the scope of this definition. The foregoing definition applies broadly to any human condition in which decreased CoQ levels or dysfunctional CoQ metabolism is substantially linked to a defect in COQ2 gene sequence or COQ2 protein function. The mention of particular mutations is illustrative and non-limiting; any mutation in the coding region, intronic region (e.g., splicing defects), or regulatory regions of COQ2 contributing to altered expression or protein function is included. In particular, as used in the present invention, the term “COQ2A302V deficiency” shall be understood to refer to a specific subtype of coenzyme Q deficiency characterized by the amino acid substitution of alanine with valine at position 302 in the COQ2 protein (often noted as A302V or Ala302Val). This definition is mainly intended in the context of human subjects but may likewise be applied to other mammals if clinically relevant. The A302V mutation is typically located in the exon coding region of the COQ2 gene, resulting from a single-nucleotide variant that changes the codon for alanine (A) to valine (V) at the 302nd position of the COQ2 polypeptide. The A302V substitution may reduce the enzymatic activity and / or stability of the COQ2 protein, leading to inadequate synthesis of CoQ. Individuals carrying the A302V mutation (either in the homozygous or compound heterozygous state with other COQ2 variants) exhibit reduced CoQ levels in affected tissues and organ systems. Patients with the A302V mutation may present with neurological symptoms (e.g., ataxia, developmental delays, seizures), renal manifestations (e.g., nephrotic syndromes), muscle weakness, or other clinical syndromes consistent with coenzyme Q deficiency. The severity and age of onset can vary, emphasizing that COQ2A302V deficiency encompasses a clinical spectrum ranging from mild to severe, depending on genetic and environmental modifiers. The information about the human COQ2 gene can be found at ncbi (https: / / www.ncbi.nlm.nih.gov / gene / 27235) or ensembl (https: / / www.ensembl.org / Homo_sapiens / Gene / Summary?db=core;g=ENSG00000173085;r=4:83261536-83284914;t=ENST00000647002). The transcript of this human COQ2 gene has four possible start codons and therefore, there are four possible isoforms with an alternative initiation for the COQ2 protein: 1) Q96H96-1 is considered the common isoform and is noted as the canonical sequence with 371 amino acids (aa); 2) Q96H96-4 has an alternative initiation, having 421 aa, including the 371 aa of the canonical sequence; 3) Q96H96-5 has an alternative initiation, having 413 aa, including the 371 aa of the canonical sequence; 4) Q96H96-6 has an alternative initiation, having 384 aa, including the 371 aa of the canonical sequence. Additionally, there is other isoform (Q96H96-3) of 328 aa produced by an alternative splicing. This isoform has the first 316 aa of the canonical sequence and, therefore, misses the 55 aa of the c-termina region. The pathogenic variants described in patients in the literature are present in the Q96H96-1, Q96H96-4, Q96H96-5 and Q96H96-6 isoforms. Only the pathogenic variants that affect to the 55 c-terminal region of the canonical sequence (from aa 317 to 371) would not be present in the Q96H96-3 isoform. The isoforms used in the literature to describe the pathogenic variants in patients are the Q96H96-1 and Q96H96-4 isoforms. Information about the human COQ2 protein can be found at UNIPROT (https: / / www.uniprot.org / uniprotkb / Q96H96 / entry). The sequence of the five COQ2 isoforms in human are as follow: Canonical sequence (371 aa)>sp|Q96H96-1|COQ2_HUMAN 4-hydroxybenzoate polyprenyltransferase, mitochondrial OS=Homo sapiens OX=9606 GN=COQ2 PE=1 SV=2MLGSRAAGFARGLRAVALAWLPGWRGRSFALARAAGAPHGGDLQPPACPEPRGRQLSLSAAAVVDSAPRPLQPYLRLMRLDKPIGTWLLYLPCTWSIGLAAEPGCFPDWYMLSLFGTGAILMRGAGCTINDMWDQDYDKKVTRTANRPIAAGDISTFQSFVFLGGQLTLALGVLLCLNYYSIALGAGSLLLVITYPLMKRISYWPQLALGLTFNWGALLGWSAIKGSCDPSVCLPLYFSGVMWTLIYDTIYAHQDKRDDVLIGLKSTALRFGENTKPWLSGFSVAMLGALSLVGVNSGQTAPYYAALGAVGAHLTHQIYTLDIHRPEDCWNKFISNRTLGLIVFLGIVLGNLWKEKKTDKTKKGIENKIEN Alternative initiation (421 aa)>sp|Q96H96-4|COQ2_HUMAN Isoform 4 of 4-hydroxybenzoate polyprenyltransferase, mitochondrial OS=Homo sapiens OX=9606 GN=COQ2MTPISQVRMRKGSAHTAAQPGRLGLHPAGATAHACRGMTSIRARPGLTSAMLGSRAAGFARGLRAVALAWLPGWRGRSFALARAAGAPHGGDLQPPACPEPRGRQLSLSAAAVVDSAPRPLQPYLRLMRLDKPIGTWLLYLPCTWSIGLAAEPGCFPDWYMLSLFGTGAILMRGAGCTINDMWDQDYDKKVTRTANRPIAAGDISTFQSFVFLGGQLTLALGVLLCLNYYSIALGAGSLLLVITYPLMKRISYWPQLALGLTFNWGALLGWSAIKGSCDPSVCLPLYFSGVMWTLIYDTIYAHQDKRDDVLIGLKSTALRFGENTKPWLSGFSVAMLGALSLVGVNSGQTAPYYAALGAVGAHLTHQIYTLDIHRPEDCWNKFISNRTLGLIVFLGIVLGNLWKEKKTDKTKKGIENKIEN Alternative initiation (413 aa)>sp|Q96H96-5|COQ2_HUMAN Isoform 5 of 4-hydroxybenzoate polyprenyltransferase, mitochondrial OS=Homo sapiens OX=9606 GN=COQ2MRKGSAHTAAQPGRLGLHPAGATAHACRGMTSIRARPGLTSAMLGSRAAGFARGLRAVALAWLPGWRGRSFALARAAGAPHGGDLQPPACPEPRGRQLSLSAAAVVDSAPRPLQPYLRLMRLDKPIGTWLLYLPCTWSIGLAAEPGCFPDWYMLSLFGTGAILMRGAGCTINDMWDQDYDKKVTRTANRPIAAGDISTFQSFVFLGGQLTLALGVLLCLNYYSIALGAGSLLLVITYPLMKRISYWPQLALGLTFNWGALLGWSAIKGSCDPSVCLPLYFSGVMWTLIYDTIYAHQDKRDDVLIGLKSTALRFGENTKPWLSGFSVAMLGALSLVGVNSGQTAPYYAALGAVGAHLTHQIYTLDIHRPEDCWNKFISNRTLGLIVFLGIVLGNLWKEKKTDKTKKGIENKIEN  Alternative initiation (384 aa)>sp|Q96H96-6|COQ2_HUMAN Isoform 6 of 4-hydroxybenzoate polyprenyltransferase, mitochondrial OS=Homo sapiens OX=9606 GN=COQ2MTSIRARPGLTSAMLGSRAAGFARGLRAVALAWLPGWRGRSFALARAAGAPHGGDLQPPACPEPRGRQLSLSAAAVVDSAPRPLQPYLRLMRLDKPIGTWLLYLPCTWSIGLAAEPGCFPDWYMLSLFGTGAILMRGAGCTINDMWDQDYDKKVTRTANRPIAAGDISTFQSFVFLGGQLTLALGVLLCLNYYSIALGAGSLLLVITYPLMKRISYWPQLALGLTFNWGALLGWSAIKGSCDPSVCLPLYFSGVMWTLIYDTIYAHQDKRDDVLIGLKSTALRFGENTKPWLSGFSVAMLGALSLVGVNSGQTAPYYAALGAVGAHLTHQIYTLDIHRPEDCWNKFISNRTLGLIVFLGIVLGNLWKEKKTDKTKKGIENKIEN  Alternative splicing (328 aa)>sp|Q96H96-3|COQ2_HUMAN Isoform 3 of 4-hydroxybenzoate polyprenyltransferase, mitochondrial OS=Homo sapiens OX=9606 GN=COQ2MLGSRAAGFARGLRAVALAWLPGWRGRSFALARAAGAPHGGDLQPPACPEPRGRQLSLSAAAVVDSAPRPLQPYLRLMRLDKPIGTWLLYLPCTWSIGLAAEPGCFPDWYMLSLFGTGAILMRGAGCTINDMWDQDYDKKVTRTANRPIAAGDISTFQSFVFLGGQLTLALGVLLCLNYYSIALGAGSLLLVITYPLMKRISYWPQLALGLTFNWGALLGWSAIKGSCDPSVCLPLYFSGVMWTLIYDTIYAHQDKRDDVLIGLKSTALRFGENTKPWLSGFSVAMLGALSLVGVNSGQTAPYYAALGAVGAHLTHQKWGLEILPRLV  Nutraceutical is defined as any substance which is a food or part of a food and provides medical and / or health benefits, including the prevention and treatment of a disease. Therapeutic useIn a first aspect, the present invention relates to 4HB or pharmaceutically acceptable salts thereof for use in the oral treatment of CoQ deficiencies due to gene and / or COQ2 protein defects, preferably those affecting the CNS and / or the heart. The inventors have discovered that 4HB stimulates the endogenous synthesis of CoQ by increasing the levels CoQ9 and CoQ10 in the brain of WT mice, and particularly in the brain of Coq2A252Vmice with CoQ9 and CoQ10deficiencies, in both cases during embryonic development. Therefore, a preferred embodiment of the present invention contemplates the use of 4HB to increase the levels of CoQ9 and CoQ10 during embryonic development. The inventors have furthermore discovered that 4HB increases mitochondrial function in the brain of WT mice, and particularly in the brain of Coq2A252V mice having mitochondrial bioenergetics deficit, in both cases during embryonic development. Therefore, a particular embodiment of the present invention contemplates the use of 4HB to increase mitochondrial function / bioenergetics during embryonic development.  The inventors have also discovered that 4HB corrects delay in CNS and heart development, eliminating the onset of edema, in Coq2A252Vmouse embryos. Therefore, a particular embodiment of the present invention contemplates the use of 4HB to stimulate CNS and heart development during embryonic development. Likewise, the inventors have discovered that 4HB increases survival during embryonic development, increasing the number of animals born per litter of mice. Therefore, a particular embodiment of the present invention contemplates the use of 4HB to improve embryonic development.In addition, and importantly, to compare the effect of 4HB treatment versus conventional treatment based on exogenous CoQ10 supplementation, the inventors made certain determinations at 21 days of age because most of the CoQ10-treated Coq2A252V mice did not survive beyond one month of life. After having been treated with CoQ10 via placenta circulation (Example 5) and maternal milk (Example 6) and weaned at 21 days, some mice were sacrificed to perform metabolic and morphological analyses, while the remaining mice started oral treatment through food for the survival study (Example 7). The comparison is made with Coq2+ / +and Coq2A252V mice treated with 4HB. The survival rate of CoQ10-treated mice drops to 20% around one month of age, with a maximum lifespan of 8 months, which is only reached by 5% of the CoQ10-treated mice. In contrast, at 8 months, 100% of the mice treated with 4HB are still alive. The present invention can be used in animals, but it is preferably intended for mammals, preferably humans. Therefore, in a particular embodiment, the use of 4HB is characterized in that it is for use in mammals, preferably in humans. It should be noted that the term “subject”, as used throughout the present invention, relates to any mammal, preferably humans, provided that said human of reproductive age and is capable of gestation. In a particular embodiment of the use of 4HB in humans, the use is characterized in that the humans belong to a population that is sexually developed and, therefore, exhibits the biological conditions to procreate. In a particular embodiment of the invention, the use of 4HB is characterized in that it is for the treatment of neurological, neurometabolic, neurodegenerative and cardiometabolic diseases, as well as infertility with miscarriages or recurrent miscarriages, associated with coenzyme Q deficiency, mitochondrial dysfunction, impaired energy metabolism and / or increased oxidative stress. More specifically, in a preferred embodiment of the first aspect of the present invention, the present invention relates to a composition comprising 4-hydroxybenzoic acid (4HB) or pharmaceutically acceptable salts thereof for use in the oral treatment of coenzyme Q (CoQ) deficiencies due to Coq2 mutations and / or defects in COQ2 protein function, such as, but not limited to, COQ2 p.Arg197His, p.Arg197Pro, p.Arg360His, p.Arg387, and p.Ala302Val (A302V), wherein the treatment is administered to a subject of reproductive age capable of gestation, and wherein the treatment is administered within the ovarian cycle prior to conception (fertilization) or the start of pregnancy in said subject, wherein conception is understood as the moment in which an ovum from said subject is fertilized by a sperm cell. It is noted that the present invention also relates to a composition comprising 4-hydroxybenzoic acid (4HB) or pharmaceutically acceptable salts thereof for use in the oral treatment of coenzyme Q (CoQ) deficiencies due to Coq2 mutations and / or defects in COQ2 protein function, such as any one of the pathogenic variants indicated in table A below, wherein the treatment is administered to a subject of reproductive age capable of gestation, and wherein the treatment is administered within the ovarian cycle prior to conception (fertilization) or the start of pregnancy in said subject, wherein conception is understood as the moment in which an ovum from said subject is fertilized by a sperm cell.  Table A. Pathogenic variants in COQ2 described in the medical literature to date Amino AcidModificationUNIPROT Q96H96-4 Amino AcidModificationUNIPROT Q96H96-1p.Ala60Argfs*33p.Ala10Argfs*33p.Ser146Asnp.Ser96Asnp.Arg173Hisp.Arg123Hisp.Met182Argp.Met132Argp.Arg197Hisp.Arg147His p.Asn228Serp.Asn178Ser  p.Leu234fs*14p.Leu184fs*14 p.Cys278Argp.Cys228Arg  p.Leu296Phep.Leu236Phe p.Thr294Ilep.Thr244Ile p.Tyr297Cysp.Tyr247Cys p.Ala302Valp.Ala252Val p.Thr325Alap.Thr275Ala p.Arg387*p.Arg337* p.Gly390Alap.Gly340Ala p.Asn401Ilefs*15p.Asn351Ilefs*15 p.Ala97Argfs*56p.Ala47Argfs*56 p.Arg126Glyp.Arg76Gly p.Tyr353Cysp.Tyr303Cys p.Pro157Serp.Pro107Ser p.Gly276Valfs*20p.Gly226Valfs*20 p.Tyr245*p.Tyr195* p.Val113_114delinsGlyp.Val63_64delinsGly p.Ala97Argfs*56p.Ala47Argfs*56 p.Phe383Leup.Phe353Leu p.Pro142Alap.Pro92Ala p.Leu371Glnp.Leu321Gln Two references sequence of the COQ2 protein are shown, Q96H96-4 and Q96H96-1. In the case of pathogenic variants in COQ2, the inventors have described that the therapeutic effect of 4HB is mediated by an increase in the intracellular concentration of 4HB and the subsequent increase in COQ2 activity, a mechanism known as substrate enhancement therapy. Therefore, 4HB therapy should work in any case where COQ2 retains some residual activity. In the biological samples of all patients with pathogenic variants in COQ2 described in the literature, some residual levels of CoQ have been detected. This suggests that some residual COQ2 activity is retained since the complete absence of CoQ is not compatible with life. Therefore, 4HB therapy may work independently of the pathogenic variant in COQ2, provided that some residual COQ2 activity remains or endogenous 4HB levels are decreased. In another preferred embodiment, the composition is administered to treat infertility occurring with coenzyme Q (CoQ) deficiencies due to Coq2 mutations and / or defects in COQ2 protein function in the subject.  In another preferred embodiment, the composition is administered to treat severe delay in embryonic development or perinatal death caused by coenzyme Q (CoQ) deficiencies due to Coq2 mutations and / or defects in COQ2 protein function. In another preferred embodiment, the composition is administered to treat diseases caused by coenzyme Q (CoQ) deficiencies due to Coq2 mutations and / or defects in COQ2 protein function which are associated with embryonic development selected from the list consisting of neurological, neurometabolic, neurodegenerative and cardiometabolic diseases.  In another preferred embodiment, the treatment is administered at least within a time interval between the preceding 20 days and the conception (fertilization) or start of pregnancy in said subject.  In another preferred embodiment, the treatment is administered within a time interval between the preceding 7 days and the conception (fertilization) or start of pregnancy in said subject.  Preferably, it is possible to continue the treatment after the start of pregnancy or gestation, particularly throughout the entire gestation or even after birth, preferably throughout the entire gestation and lactation period after birth, more preferably, during at least the first weeks or the first months after conception, more preferably, during the course of 1, 2, 3, 4 or more weeks after conception, more preferably, during the course of 1, 2, 3, 4 or more months after conception.  In another preferred embodiment, the subject is a female human subject of reproductive age and capable of gestation. In the context of the present invention, capable of gestation is understood as that subject, preferably a human subject, who, being a female or a woman or belonging to various gender identities different from the traditional concept of a female or woman, has a body that is capable of gestation. In another preferred embodiment, oral administration is performed at a dose of 4-hydroxybenzoic acid (4HB) or pharmaceutically acceptable salts thereof of between 5 and 500 mg / kg body weight / day, more preferably between 10 and 250 mg / kg body weight / day. Preferably, said oral administration is performed between 1 and 4 times a day. In another preferred embodiment, treatment may be continued or initiated after pregnancy or gestation begins, particularly throughout the entire gestation period and optionally during the postnatal and lactation periods. More preferably, the subject of reproductive age capable of gestation continues to receive treatment after the onset of pregnancy or gestation, throughout the entirety of the gestation period, and optionally beyond birth (e.g., during lactation). Furthermore, upon the child’s birth, treatment may be administered directly to the child, preferably over the child’s entire lifetime. Pharmaceutical composition In a second aspect, the present invention relates to a pharmaceutical composition comprising 4HB or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient, for use in the oral treatment of CoQ deficiencies due to gene and / or COQ2 protein defects, preferably those affecting the CNS and / or the heart, such as, but not limited to, any one of the pathogenic variants indicated in table A. In a particular embodiment, the pharmaceutical composition is characterized by increasing the levels of CoQ9 and CoQ10 during embryonic development. In another particular embodiment, the pharmaceutical composition is characterized in that it stimulates CNS and heart development during embryonic development. In a particular embodiment of the present invention, the pharmaceutical composition is characterized by improving embryonic development. In another particular embodiment, the pharmaceutical composition is characterized in that it is for use in mammals, preferably in humans. In another particular embodiment, the pharmaceutical composition is characterized by use thereof in humans belonging to a population that is sexually developed and, therefore, exhibits the biological conditions to procreate. In some embodiments, 4HB can be administered using veterinary or pharmaceutical or nutraceutical compositions including 4HB, where appropriate, in the form of salt, or used alone or in the form of a combination with one or more carriers that are compatible and acceptable from the veterinary, pharmaceutical or nutraceutical viewpoint, such as diluents or adjuvants, or with another agent. Remington’s The Science and Practice of Pharmacy, 21st edition, A. R. Gennaro, (Lippincott, Williams & Wilkins, Baltimore, MD, 2006) discloses a variety of excipients used in the formulation of pharmaceutical compositions and techniques known for preparing same. In one embodiment, compositions comprising 4HB or a salt thereof, and an excipient, acceptable carrier or diluent are provided. The composition can also be in a variety of forms including, but not limited to, oral formulations, injectable formulations and topical, dermal or subdermal formulations. In a preferred embodiment, the composition is an oral composition, i.e., it is formulated in a form suitable for oral use, for example, as dietary supplements, lozenges, chewable products, tablets, soft or hard capsules, emulsions, aqueous or oily suspensions, aqueous or oily solutions, dispersible granules or powder, syrups or elixirs. The compositions intended for oral use can be prepared according to any method known in the art for manufacturing veterinary, pharmaceutical or nutraceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, bittering agents, flavoring agents, coloring agents and preservation agents in order to provide elegant and acceptable preparations. In a tablet format, they may contain 4HB admixed with non-toxic pharmaceutically acceptable excipients which are suitable for manufacturing tablets. These excipients can be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, cornstarch or alginic acid; binding agents, for example, starch, gelatin or gum arabic, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be not coated or may be coated by means of known techniques in order to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action throughout a more prolonged time period. The formulations for oral use can be hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. The capsules can also be soft gelatin capsules in which the active ingredient is mixed with water or miscible solvents such as propylene glycol, PEG and ethanol, or an oil medium, for example, peanut out, liquid paraffin or olive oil. The compositions can also be in the form of oil-in-water or water-in-oil emulsions. The oily phase can be a plant oil, for example, olive oil or peanut oil, or a mineral oil, for example, liquid paraffin or mixtures thereof. Suitable emulsifying agents can be naturally occurring phosphatides, for example, soybean, lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening agents, bittering agents, flavoring agents and preservatives. Aqueous suspensions may contain 4HB admixed with excipients suitable for manufacturing aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and gum arabic; the dispersing or wetting agents can be a naturally occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example, heptadecaethyleneoxyethanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitan monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents and / or bittering agents, such as those set forth above. Suitable dispersible granules and powder for the preparation of an aqueous suspension by means of adding water provide 4HB admixed with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are shown by way of example by means of those already mentioned above. Additional excipients, for example, sweetening agents, bittering agents, flavoring agents and coloring agents may also be present. Syrups and elixirs can be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring agent(s) and coloring agent(s). The compositions can be in the form of a sterile, injectable, aqueous or oily suspension. This suspension can be formulated according to the known technique using suitable dispersing or wetting agents and suspending agents that have already been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic diluent or solvent acceptable from the parenteral viewpoint such as, for example, a solution in 1,3-butanediol. The acceptable vehicles and solvents that can be used include, among others, water, Ringer’s solution and isotonic sodium chloride solution. Co-solvents such as ethanol, propylene glycol or polyethylene glycols can also be used. Preservatives, such as phenol or benzyl alcohol can be used. Furthermore, sterile fixed oils are used conventionally as a suspension medium or solvent. For this purpose, any fixed bland oil including synthetic mono- or diglycerides can be used. Furthermore, fatty acids such as oleic acid are useful in the preparation of injectable products. As a vehicle or diluent, the compositions of the present invention may include plant oils such as, but not limited to, soybean oil, peanut oil, castor oil, corn oil, cottonseed oil, olive oil, grapeseed oil, sunflower oil, etc.; mineral oils such as, but not limited to, petroleum jelly, paraffin, silicone, etc.; aliphatic or cyclic hydrocarbons or, alternatively, for example, intermediate-chain triglycerides (such as C8-C12). The dosage forms for human use can be from 5 mg to 10 g of 4HB. In a particular embodiment, the pharmaceutical composition for human use is administered orally and 4HB is at a dose of between 5 and 500 mg / kg body weight / day, preferably between 10 and 250 mg / kg body weight / day. The dosage forms for other mammals can be from 5 mg to 10 g of 4HB. In a particular embodiment, the pharmaceutical composition for use in other mammals is administered orally and 4HB is at a dose of between 5 and 750 mg / kg body weight / day. In a particular embodiment of the invention, the pharmaceutical composition is characterized by an oral administration regimen of between 1 and 4 times a day. In an embodiment of the invention, 4HB is present in a veterinary, pharmaceutical or nutraceutical composition at a concentration of 0.05 to 100% w / w, preferably 0.05 to 95%, 0.05 to 90%, 0.05 to 85%, 0.05 to 80%, 0.05 to 70%, 0.05 to 60%, 0.05 to 50%, 0.05 to 40%, 0.05 to 30%, 0.05 to 20% or 0.05 to 10% w / w. In a particular embodiment, the pharmaceutical composition is characterized in that it is for use in mammals, preferably humans. Preferably, the humans belong to a population that is sexually developed and, therefore, exhibits the biological conditions to procreate. In yet another particular embodiment of the present invention, the pharmaceutical composition is used for any of the embodiments expressly indicated in the “Therapeutic use” section. Non-therapeutic uses  The present invention also contemplates the use of 4HB as a nutraceutical or food supplement to improve fertility in mammals, even more preferably in humans, in a preferred embodiment in humans who do not necessarily suffer a disease. Therefore, in a third aspect, the invention relates to a non-therapeutic use of 4HB or salts thereof for improving fertility. The person skilled in the art will understand that all the particular and preferred embodiments described above for therapeutic uses shall apply to the non-therapeutic uses described in this section, provided that they are compatible. In a particular embodiment of the third aspect, 4HB or salts thereof are provided in a nutraceutical composition comprising a nutritionally acceptable excipient. Preferably, said nutraceutical composition is a functional food, a dietary product or a nutritional supplement.  Nutraceutical composition A fourth aspect of the invention relates to a nutraceutical composition, which can be a functional food, dietary product or nutritional supplement, comprising 4HB, characterized in that 4HB is found at a concentration above 5% w / w, preferably 10%, above 20%, above 30%, above 40%, above 50%, or above 60% w / w. The general expression “nutraceutical composition”, which contemplates “functional food”, “dietary product” or “nutritional supplement” or simply “food” is used herein in a broad sense and encompasses foods for human beings, as well as foods for animals (i.e., feed). Preferably, the food is for human consumption. Said food can be in the form of a solution or a solid, depending on the use and / or the mode of application and / or the mode of administration.  A nutraceutical composition can be based on milk or milk-derived beverages such as drinking yoghurt or common yoghurt, any other type of common yoghurt beverage, any other type of beverage, including water, acidic fruit juice or beverages flavored with additional fruits having a pH in the interval of 2 to 8, in the form of chocolate, ice cream, nutrient bars or any food. The following examples serve to further illustrate the present invention, but do not limit same.  Examples.The invention will be illustrated below by means of assays performed by the inventors, clearly showing the usefulness of 4HB for the oral treatment of CoQ deficiencies due to gene and / or COQ2 protein defects that affect the CNS and / or the heart, for the oral treatment of infertility with recurrent miscarriages that occur with low levels of CoQ and / or impaired CoQ metabolism in the mother, in order to provide the energy and metabolic requirements of fertilization and embryonic development, and for the treatment of neurological, neurometabolic, neurodegenerative, cardiometabolic diseases, as well as infertility, associated with mitochondrial dysfunction, impaired energy metabolism and / or increased oxidative stress. For the studies, Coq2+ / + mice (also known as wild-type or control), Coq2+ / A252V mice (also known as heterozygotes for the mutation) and Coq2A252V / A252V mice (known as Coq2A252V, as well as homozygotes for the mutation) were used under the protocols approved by the Ethics Committee for Animal Experimentation of Universidad de Granada and registered by the competent body, General Directorate of Agricultural and Livestock Production of the Department of Agriculture, Livestock, Fisheries and Sustainable Development of the Regional Government of Andalusia., with reference 30 / 06 / 2022 / 097.  Data was expressed as mean ± standard deviation of 4-10 experiments per group. To compare the differences among 3 experimental groups, a one-way ANOVA analysis with post-hoc Tukey test was carried out. A p-value of < 0.05 was considered statistically significant. Survival curve was analyzed through the log-rank (Mantel-Cox) test and Gehan-Breslow-Wilcoxon test.  Example 1 – Oral administrationof 4HB throughthemother, from fertilization and throughout the entire embryonic development In this example, treatment is started from the moment in which a male Coq2+ / A252V mouse and a female Coq2+ / A252V mouse in a state of ovulation are placed in a cage together. The experimental treatment was based on the administration of 4HB in the feed at a concentration of 0.33% (w / w), representing a dose of 0.15-0.75 g / kg body weight / day in the pregnant female mouse. Therefore, 4HB reaches the embryos through placental circulation. The embryos contain Coq2+ / +, Coq2+ / A252V and Coq2A252Vgenotypes. Analyses were performed on the offspring at embryonic development day 17.5 (E17.5), with the exception of HREM analyses which were performed at embryonic development day 15.5 (E15.5). The results are compared with untreated mice. Example 2 – Oral administrationof 4HB through the mother, after birth In this example, 4HB continues to be administered to the female Coq2+ / A252V mouse that, after the period of pregnancy, has given birth to litter of mice. The experimental treatment is based on the administration of 4HB in the feed at a concentration of 0.33% (w / w), representing a dose of 0.15-0.75 g / kg body weight / day. Therefore, 4HB reaches the suckling pups through breast milk. The pups contain Coq2+ / +, Coq2+ / A252V and Coq2A252V genotypes. Comparison is made in this case with untreated Coq2+ / +mice, given that no Coq2A252Vmice are born as a result of perinatal death. Example 3 – Oral administrationof 4HB directlyafter weaning In this example, 4HB is administered to the offspring directly from day 21 of birth, at the time of weaning. The experimental treatment is based on the administration of 4HB in the feed at a concentration of 0.33% (w / w), representing a dose of 0.15-0.75 g / kg body weight / day. Therefore, 4HB reaches the mice through food consumption. The mice contain Coq2+ / +, Coq2+ / A252V and Coq2A252Vgenotypes.  Analyses were performed at one month of life. Comparison is made in this case with untreated Coq2+ / +mice, given that no Coq2A252Vmice are bornas a result of perinatal death. Example 4 – Discontinuation of oral administration of 4HB, after 90 days of treatment.In this example, 4HB treatment is discontinued at 90 days of age, when the animal reaches adulthood. Until day 90, the experimental treatment is based on the administration of 4HB in the food at a concentration of 0.33% (weight / weight), which corresponds to a dose of 0.15–0.75 g / kg body weight / day. Therefore, 4HB reaches the mice through the placental circulation in a first phase, the maternal milk in a second phase and their food intake in a third phase. Starting from day 90, the 4HB-supplemented diet is removed and replaced with standard animal facility chow. The analyses were conducted at 160 days of age (70 days without 4HB), at this point, we start to find differences between experimental groups. The comparison is made with Coq2A252V mice treated with 4HB. Example 5 – Oral administration of CoQ10 through the mother, from fertilization and throughout embryonic development. In this example, treatment begins when a male Coq2+ / A252V mouse and a female Coq2+ / A252V mouse in ovulation are placed together in a cage. The experimental treatment is based on the administration of CoQ10 in the food at a concentration of 0.33% (weight / weight), which corresponds to a dose of 0.15-0.75 g / kg body weight / day for the pregnant female mouse. Therefore, CoQ10 reaches the embryos through the placental circulation. The embryos are genotyped Coq2+ / +, Coq2+ / A252V, and Coq2A252V. Example 6 – Oral administration of CoQ10 through the mother, after birth. In this example, the CoQ10 continues to be administered to the female Coq2+ / A252V mouse after the pregnancy period, which has resulted in the birth of a litter of mice. The experimental treatment is based on the administration of CoQ10 in the food at a concentration of 0.33% (weight / weight), which corresponds to a dose of 0.15-0.75 g / kg body weight / day. Therefore, 4HB reaches the nursing pups through the maternal milk. The pups are genotyped Coq2+ / +, Coq2+ / A252V, and Coq2A252V. The comparison is made with untreated Coq2+ / + mice and Coq2A252V treated with 4HB to compared the effect of both treatments. Example 7 – Direct oral administration of CoQ10, after weaning In this example, CoQ10 is administered directly to the offspring from day 21 of birth, which is the time of weaning. The experimental treatment is based on the administration of CoQ10 in the food at a concentration of 0.33% (weight / weight), which corresponds to a dose of 0.15-0.75 g / kg body weight / day. Therefore, CoQ10 reaches the mice through their food intake. The comparison is made with untreated Coq2+ / + mice and Coq2A252V treated with 4HB to compare the effect of both treatments.  RESULTS Example8– Effectof 4HB onthe survivalandphenotypic state ofmiceon standard diet Example 1 describes the administration of 4HB in the feed of the pregnant female mouse at a concentration of 0.33% (w / w), representing a dose of 0.15-0.75 g / kg body weight / day. Therefore, 4HB has been administered chronically through the oral route and is available to the embryos through placental circulation. Survival determination was performed through continuous recording by sacrificing pregnant females at different days of pregnancy and genotyping the available embryos. After the chronic administration of 4HB (Example 1), litters with a larger number of animals (Figure 1A), an increase in the survival of Coq2A252V embryos (Figure 1B) and a normalized external appearance of Coq2A252Vembryos were observed in comparison to the same untreated mice (Figure 1C). The composition has shown to be effective using a dose of between 0.15 and 0.75 g / kg weight of the mouse. This may correspond to a dose comprised between 10 and 65 mg / kg weight in humans according to the body surface area-based dose translation formula (Reagan-Shaw, Nihal & Ahmad, 2008).  Example9– Effectof 4HBonthelevelsofCoQinthe brainofembryos Given that CoQ deficiencies due to Coq2 defects often occur with neurological symptoms that are more difficult to treat as a result of the limited bioavailability of exogenous CoQ10, the effects of 4HB on the endogenous synthesis of CoQ9 and CoQ10 in 17.5-day-old embryos are measured instead.  CoQ9 and CoQ10 are determined separately by HPLC and detected with an electrochemical detector, after lipid extraction with 1-propanol. Quantification is performed with respect to a standard curve of CoQ9 and CoQ10 and the results normalized per milligram of proteins in tissue (Hidalgo-Gutierrez et al., 2019).  The results show that 4HB treatment induces a tendency to increase the levels of CoQ9 (Figure 2A) and CoQ10 (Figure 2B) in the brain of Coq2+ / +embryos, when compared with the same untreated embryos. Moreover, the brain of Coq2A252V embryos presents severe CoQ9 (Figure 2A) and CoQ10 (Figure 2B) deficiency, when compared with the levels of CoQ9 (Figure 2A) and CoQ10 (Figure 2B) in Coq2+ / +mice. CoQ9 deficiency represents approximate relative levels of 15% residual, when compared with Coq2+ / +embryos. 4HB treatment increases the levels of CoQ9 (Figure 2A) and CoQ10 (Figure 2B) in the brain of Coq2A252Vembryos, when compared with the same untreated mutant homozygote embryos. The CoQ9 / CoQ10 ratio does not change among experimental groups. Example10– Effectof 4HB on themitochondrial functionin the brainofembryos In order to evaluate whether changes in the levels of CoQ are accompanied by modifications in mitochondrial function, mitochondrial activity of complexes II+III, which depends on the levels of CoQ, is measured. The activity of complexes II+III is measured in a brain homogenate by spectrophotometry, normalizing the results by citrate synthase activity, a mitochondrial mass marker (Hidalgo-Gutierrez et al., 2019).  The results show that 4HB treatment induces a tendency to increase the activity of complexes II+III (Figure 3) in the brain of Coq2+ / +embryos, when compared with the brains of untreated Coq2+ / + embryos. Moreover, the brains of Coq2A252V embryos exhibit a reduced activity of complexes II+III (Figure 23), when compared with the activity in the brain of Coq2+ / +embryos. 4HB treatment increases the activity of complexes II+III (Figure 2B) in the brain of Coq2A252Vembryos, when compared with untreated mutant homozygote embryos. Example11– Effectof 4HB on embryo morphology In order to evaluate whether changes in mitochondrial metabolism induce modifications in embryo structure and morphology, an analysis of E15.5 embryos by high-resolution episcopic microscopy (HREM) is developed (Wendling et al., 2021). HREM consists of sectioning the embryos in a Histo3D system, acquiring about 800 images per embryo, subsequently aligning the images and converting same to a set of volumetric data segmented with the Avizo 9.4.0. software, then creating 2D and 3D images. HREM analyses were complemented with an evaluation of the brain of E17.5 embryos by MRI. These images were acquired in embryos fixed and embedded in 4% agarose gel, with the images being acquired in 9.4 T Bruker Biospec MRI equipment for a time of about 24 hours.  The results show that the brains of E15.5 Coq2A252V embryos exhibit a delay in telencephalon development and a slightly smaller volume of the lateral ventricles (Figure 4B), compared with Coq2+ / + embryos (Figure 4A). 4HB treatment normalizes these parameters in Coq2A252V embryos (Figure 4C). This data is corroborated by means of 17.5 MRI analysis, in which an obvious delay is observed in the neurodevelopment of Coq2A252V embryos (Figure 4E), when compared with Coq2+ / + embryos (Figure 4D) and 4HB-treatedCoq2A252V embryos (Figure 4F). Example12– Effectof chronic 4HB treatmentonthephenotypeofmice with 1 month of life Given that 4HB-treatedCoq2A252V mice can be born and seem to be indistinguishable from Coq2+ / +mice, the inventors decide to perform certain determinations at one month of life, once the mice have been taking the treatment through breast milk (Example 2) and have weaned off after 21 days, therefore, being under oral treatment through feed for 9 days (Example 3). In this case, comparison is made with Coq2+ / + mice and 4HB-treated Coq2+ / + mice, given that untreated Coq2A252V are not born as a result of perinatal death.  The analyses show that Coq2+ / +mice, 4HB-treated Coq2+ / + mice and 4HB-treatedCoq2A252V mice cannot be distinguished from one another in terms of appearance (Figures 6A-C). The motor coordination activity, measured through the rotarod test (Hidalgo-Gutierrez et al., 2019) (Figure 6D), and body weight (Figures 6E-F) also cannot be distinguished among the three experimental groups. Example13– Effectof chronic 4HB treatmentonthetissue morphologyofmice with 1 month of life To evaluate whether the seemingly normal phenotype of 4HB-treated Coq2A252V mice is due accordingly to a normal tissue structure, the inventors evaluate the structure of the brain by MRI and heart morphology by histological staining with hematoxylin and eosin. MRI brain analysis was performed in a Bruker Biospec TM 70 / 20 USR system. After scanning with a locator, sets of high-resolution axial and coronal T2-weighted data were acquired to visualize any brain or structural atrophy and to investigate possible focal pathologies (Hidalgo-Gutierrez et al., 2019). For heart staining, the hearts were fixed in formalin (24 h), processed and embedded in paraffin. Several sections (of 4 µm thick) were subjected to deparaffinization with xylene and stained with hematoxylin and eosin (H&E). The sections were examined with 40 to 400 magnifications under a Nikon Eclipse Ni-U microscope (Werfen, Madrid, Spain) and the images were scanned under the same illumination conditions with the computer software NIS-Elements Br, performing reconstruction for the global visualization of the hearts (Werfen, Madrid, Spain) (Hidalgo-Gutierrez et al., 2019). The analyses show that Coq2+ / +mice, 4HB treated Coq2+ / + mice and 4HB treatedCoq2A252V mice cannot be distinguished from one another in terms of brain structure and morphology (Figures 7A-C) and heart structure and morphology (Figures 7D-F).  Example 14– Effect of chronic 4HB treatment on mitochondrial function in the brain of 1-month-old mice To evaluate whether the morphological normality of 4HB treated Coq2A252V mice is preceded by a functional normality of the mitochondrial respiratory chain, the activity of complexes II+III, which depends on the levels of CoQ, is measured. The activity of complexes II+III is measured in a brain homogenate by spectrophotometry, normalizing the results by citrate synthase activity, a mitochondrial mass marker (Hidalgo-Gutierrez et al., 2019). The analyses show that the brain of 4HB treated Coq2A252V mice exhibit an activity of complexes II+III similar to that in Coq2+ / + mice(Figure 8). It should be noted that the brain of 4HB treated Coq2+ / + mice exhibit an activity of complexes II+III above that of their untreated Coq2+ / + homologs (Figure 8). Example 15– Effect of chronic 4HB treatment on CoQ metabolism in the brain, cerebellum, and heart of 1-month-old mice Improvement in mitochondrial bioenergetics must be the result of the stimulation of CoQ biosynthesis. CoQ9 and CoQ10 are determined separately by HPLC and detected with an electrochemical detector, after lipid extraction with 1-propanol. Quantification is performed with respect to a standard curve of CoQ9 and CoQ10 and the results normalized per milligram of proteins in tissue (Hidalgo-Gutierrez et al., 2019).  The analyses show that, although the cerebrum and cerebellum of 4HB treated Coq2A252V mice exhibit CoQ9 and CoQ10deficiency when compared with the levels in control mice (Figures 9A-B, D-E), in relative terms said deficiency being about 40% residual. This differs substantially from the 15% residual shown for the brain of E17.5 embryos (Example 5). In the heart, 4HB normalizes the levels of CoQ9 and CoQ10 in 4Hb treated Coq2A252V mice (Figures 9C, F). The result of stimulating the synthesis of both CoQ9 and CoQ10 is that the values of CoQ9 / CoQ10 remain similar in the 3 experimental groups (Figures 9G-I), except for the heart in which CoQ9 increases slightly more than CoQ10 in the 4HB treated Coq2A252V group (Figure 9H). Example 16 – Phenotypic impact of 4HB discontinuation after 90 days of treatment on Coq2A252V mice.To assess the impact of 4HB discontinuationas explained in example 4, Coq2A252V mice were continuously treated with 4HB until reaching adulthood (at 90 days of age), after which 4HB supplementation was discontinued (Coq2A252V – 4HB). The comparison is made with Coq2A252V mice treated continuously with 4HB (Coq2A252V + 4HB).We assessed survival (Figure 10A), and calculated weight gain every two weeks, starting from the time of 4HB discontinuation (Figure 10B). The survival of Coq2A252V without 4HB began to decline around 300 days of age (210 days after 4HB removal), reaching 100% mortality before 500 days of age (410 days without 4HB).Example 17 –Effect of 4HB discontinuation after 90 days of treatment following 70 days without treatment on CoQ metabolism in the cerebrum, cerebellum, and heart.The reduction in weight gain in Coq2A252V without 4HB begins around day 160 of life (corresponding to 70 days without 4HB treatment). This time point was selected to measure CoQ levels, comparing CoQ9, CoQ10, and the CoQ9 / CoQ10 ratio between the group continuously treated with 4HB (Coq2A252V + 4HB) and the group in which 4HB was discontinued after 90 days of treatment, followed by 70 days without treatment (Coq2A252V – 4HB).CoQ9 and CoQ10 determinations were performed by HPLC separation and detection using an electrochemical detector after lipid extraction with 1-propanol. Quantification was carried out against a standard curve of CoQ9 and CoQ10, and the results were normalized per milligram of tissue protein (Hidalgo-Gutierrez et al., 2019).In this comparison, a significant decrease was observed in CoQ9 levels (Figures 11A, 11B, and 11C), CoQ10 levels (Figures 11D, 11E, and 11F), and the CoQ9 / CoQ10 ratio (Figures 11G, 11H, and 11I) in mice after 70 days without treatment in the cerebrum, cerebellum, and heart. These results suggest that the decrease in CoQ levels is associated with both reduced weight gain and increased mortality.Example 18 – Comparative analysis of CoQ10 and 4HB treatments: assessment of survival rates and phenotypic outcomes.To compare the effect of 4HB treatment versus conventional treatment based on exogenous CoQ10 supplementation, we made certain determinations at 21 days of age because most of the CoQ10-treated Coq2A252V mice did not survive beyond one month of life. After having been treated with CoQ10 via maternal milk (Example 6) and weaned at 21 days, some mice were sacrificed to perform metabolic and morphological analyses, while the remaining mice started oral treatment through food for the survival study (Example 7). The comparison is made with Coq2+ / +and Coq2A252V mice treated with 4HB The survival rate of CoQ10-treated mice drops to 20% around one month of age, with a maximum lifespan of 8 months, which is only reached by 5% of the CoQ10-treated mice. In contrast, at 8 months, 100% of the mice treated with 4HB are still alive.Example 19 – Effect of chronic CoQ10 treatment on CoQ metabolism in the cerebrum, cerebellum, and kidney compared to 4HB treatment.To evaluate whether the decline in survival of Coq2A252V mice treated with CoQ10 is due to the inability of CoQ10 to increase CoQ levels because of its low bioavailability, CoQ9 levels were measured in the cerebrum, cerebellum, and kidney.CoQ9 determination was performed by HPLC separation and detection using an electrochemical detector after lipid extraction with 1-propanol. Quantification was carried out against a standard curve of CoQ9, and the results were normalized per milligram of tissue protein (Hidalgo-Gutierrez et al., 2019).The comparison is made with Coq2+ / + mice and Coq2A252Vmice treated with 4HB at 21 days of age. We observed a decrease in CoQ9 levels in the cerebrum (Figure 13A), cerebellum (Figure 13B), and kidney (Figure 13C) of CoQ10-treated mice. However, treatment with 4HB resulted in an increase in CoQ9 levels in these tissues. This difference in CoQ9 levels explains the different effects observed with both treatments.Example 20 – Effect of chronic CoQ10 and 4HB treatments on kidney and brain morphology in 21-days-old mice.After the results in the phenotypic evaluation, we aimed to evaluate whether the Coq2A252Vmice treated with CoQ10 exhibited any nervous system alterations. Therefore, we analyzed brain tissues to detect neurodegeneration by quantifying neurons (NeuN, 1:300, Merck Millipore) and neuroinflammation by measuring microglia (Iba1, 1:500, Wako), through immunohistochemical staining. Briefly, after deparaffinization, sections were heated in 0.1 M sodium citrate buffer (pH 6) at 90°C in a water bath for 40 minutes. After several washes in phosphate-buffered saline (PBS, 0.1 M, 0.02% Triton X-100), sections were incubated with primary antibodies overnight at 4°C. Then, secondary antibodies conjugated with Alexa Fluor 488 or 594 were used at 37ºC during 2h. Finally, slides were mounted with ProLong™ Gold Antifade Mountant with DAPI (Invitrogen). Sections were examined under 40–400x magnification using a Nikon Eclipse Ni-U microscope (Werfen, Madrid, Spain), and images were captured under consistent lighting conditions with NIS-Elements Br software (Werfen, Madrid, Spain) (Gonzalez-Garcia et al., 2022).To evaluate renal morphology, we performed Periodic acid-Schiff staining (PAS), which highlights the glomerular basement membrane and glycogen in the renal tubules. The kidneys were fixed in formalin (24 hours), processed, and embedded in paraffin. Multiple sections (4 µm thick) were deparaffinized and incubated in 1% periodic acid. Then, staining was performed using Schiff's reagent and hematoxylin. Sections were examined under 40 to 400x magnification with a Nikon Eclipse Ni-U microscope (Werfen, Madrid, Spain), and the images were scanned under identical lighting conditions using NIS-Elements Br software (Werfen, Madrid, Spain). Coq2A252V mice treated with CoQ10 exhibit a reduced number of neurons (Figure 14D-F) compared to Coq2+ / + mice (Figure 14A-C) and Coq2A252V mice treated with 4HB (Figure 14G-I). Additionally, Coq2A252V mice treated with CoQ10 show microglia in a pro-inflammatory state (Figure 14M-O), in contrast to Coq2+ / + mice (Figure 14J-L) and Coq2A252V mice treated with 4HB (Figure P-R). At the renal level, CoQ10-treated mice exhibit glomerular atrophy (Figure 14U-V), a pathology not observed in Coq2+ / + mice (Figure 14S-T) or Coq2A252V mice treated with 4HB (Figure 14W-X). These morphological alterations in the brain and kidneys result in a severe phenotype and early mortality in CoQ10-treated mice.  BibliographyAcosta Lopez MJ, Trevisson E, Canton M, Vazquez-Fonseca L, Morbidoni V, Baschiera E, et al. (2019). Vanillic Acid Restores Coenzyme Q Biosynthesis and ATP Production in Human Cells Lacking COQ6. Oxid Med Cell Longev 2019: 3904905. Alcazar-Fabra M, Rodriguez-Sanchez F, Trevisson E, & Brea-Calvo G (2021). Primary Coenzyme Q deficiencies: A literature review and online platform of clinical features to uncover genotype-phenotype correlations. Free Radic Biol Med 167: 141-180. Bentinger M, Dallner G, Chojnacki T, & Swiezewska E (2003). Distribution and breakdown of labeled coenzyme Q10 in rat. Free Radic Biol Med 34: 563-575. Fernandez-Del-Rio L, Nag A, Gutierrez Casado E, Ariza J, Awad AM, Joseph AI, et al. (2017). Kaempferol increases levels of coenzyme Q in kidney cells and serves as a biosynthetic ring precursor. 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Claims

1. A composition comprising 4-hydroxybenzoic acid (4HB) or pharmaceutically acceptable salts thereof for use in the oral treatment of coenzyme Q (CoQ) deficiencies due to Cog2 mutations and / or defects in COQ2 protein function, wherein the treatment is administered to a mammal (subject) of reproductive age capable of gestation, and wherein the treatment is administered within the ovarian cycle prior to conception (fertilization) in said subject, wherein conception is understood as the moment in which an ovum from the subject is fertilized by a sperm cell and continues for at least a part of pregnancy or gestation.

2. The composition for use according to claim 1, wherein the use thereof is for the oral treatment of infertility occurring with coenzyme Q (CoQ) deficiencies due to Coq2 mutations and / or defects in COQ2 protein function in the subject.

3. The composition for use according to claim 1, wherein the use thereof is in the treatment of a severe delay in embryonic development, or the perinatal death caused by coenzyme Q (CoQ) deficiencies due to Cog2 mutations and / or defects in COQ2 protein function.

4. The composition for use according to claim 1, wherein the use thereof is in the treatment of diseases caused by coenzyme Q (CoQ) deficiencies due to Cog2 mutations and / or defects in COQ2 protein function which are associated with embryonic development selected from the list consisting of neurological, neurometabolic, neurodegenerative and cardiometabolic diseases.

5. The composition for use according to any of claims 1 to 4, wherein the treatment is administered within the ovarian cycle prior to conception (fertilization) in said subject and continues for at least the first 1, 2, 3, or 4 months of said pregnancy or gestation.

6. The composition for use according to any of claims 1 to 5, wherein said subject is a human subject.

7. The composition for use according to claim 6, characterized in that said oral administration is performed at a dose of 4-hydroxybenzoic acid (4HB) or pharmaceutically acceptable salts thereof of between 5 and 500 mg / kg body weight / day.

8. The composition for use according to claim 6, characterized in that said oral administration is performed at a dose of 4-hydroxybenzoic acid (4HB) or pharmaceutically acceptable salts thereof of between 10 and 250 mg / kg body weight / day.

9. A pharmaceutical composition for use according to any one of claims 7 or 8, characterized by an oral administration regimen of between 1 and 4 times a day.

10. Non-therapeutic use of a composition comprising 4-hydroxybenzoic acid (4HB) or pharmaceutically acceptable salts thereof for improving fertility in a subject of reproductive age and capable of gestation, preferably a human subject.

11. Use according to claim 10, wherein said composition is a nutraceutical composition, functional food, dietary product or nutritional supplement comprising 4-hydroxybenzoic acid (4HB) or pharmaceutically acceptable salts thereof. 

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