The role of CoQ10 in embryonic development

Abstract

Coenzyme Q10 (CoQ10) is a natural component widely present in the inner membrane of mitochondria. CoQ10 functions as a key cofactor for adenosine triphosphate (ATP) production and exhibits antioxidant properties in vivo. Mitochondria, as the energy supply center of cells, play a crucial role in germ cell maturation and embryonic development, a complicated process of cell division and cellular differentiation that transforms from a single cell (zygote) to a multicellular organism (fetus). Here, we discuss the effects of CoQ10 on oocyte maturation and the important role of CoQ10 in the growth of various organs during different stages of fetal development. These allowed us to gain a deeper understanding of the pathophysiology of embryonic development and the potential role of CoQ10 in improving fertility quality. They also provide a reference for further developing its application in clinical treatments.

Introduction

Defective embryonic development and abnormal pregnancy include a variety of factors, such as maternal factors (e.g., uterine dysplasia, reproductive infections, alloimmune abnormalities, endocrine dysfunction), environmental factors (physical, chemical, and lifestyle habits, etc.), and genetic abnormalities. Among them, inherited genetic defects, such as gene mutations, may lead to abnormal spermatogenesis, poor oocyte quality, placental defects, growth retardation, and other embryonic developmental disorders, the main reasons for early embryonic abortion [1–3]. Because fertilization-triggered autophagy degrades paternally mitochondria, it is maternal mitochondria that provide energy to the early embryo through oxidative phosphorylation prior to blastocyst implantation [4, 5]. After implantation of the blastocyst into the uterus, intracellular energy is primarily supplied through glycolysis [6]. Thus, it is clear that mitochondrial function is vital for the energy supply for embryonic development. Indeed, mutations in genes involved in embryonic energy supply, such as CoQ10[7], NrasG12D [8], and Rab1a [9], are associated with developmental disabilities, leading to abnormal pregnancies. Furthermore, mitochondrial dysfunction has been associated with various developmental abnormalities in infants and young children caused by genetic disorders, such as ADCK4-related glomerulopathy [10] and fragile X syndrome [11], which reinforces the focus on the link between mitochondria and embryonic development.

CoQ10 was first discovered in 1955 and named quinone. Later in 1957, CoQ10 was found to play a crucial role in the mitochondrial electron transport chain as a core component in mitochondrial oxidative phosphorylation. It transfers electrons to form an electrochemical gradient in mitochondria for subsequent production of adenosine triphosphate (ATP) by ATP synthase. Ogasahara et al. reported that CoQ10 could be used in the clinical treatment of oxidative phosphorylation deficiency [12]. In addition, CoQ10 is an endogenous membrane-localized potent antioxidant that protects circulating lipoproteins from lipid peroxidation [13]. Several recent clinical studies have shown that exogenous supplementation of CoQ10 has antioxidant effects and may be a potential therapy to reduce oxidative stress [14].

Based on the function of CoQ10 in mitochondrial electron transport and redox control, we aim to explore the relationship between CoQ10 and embryonic development from the perspective of energy metabolism and oxidative stress. In this review, we discussed the activity and status of CoQ10 in germ cells during early development, the regulatory role of CoQ10 in embryonic organ and system development, and the role of CoQ10 supplementation in embryonic development, which gives us a deeper understanding of the pathophysiology of embryonic development and the potential role of CoQ10 in regulating fertility quality, providing a reference for further development of its application in clinical treatments.

CoQ10

The description of CoQ10

Coenzyme Q (CoQ) is a lipid molecule composed of a benzoquinone ring and isoprenoid chains and is widely distributed in cell membranes of all eukaryotic cells. CoQ10 participates in redox reactions via accepting or donating two electrons or protons and can be present in oxidized form (ubiquinone), reduced form (ubiquinol), and free radical intermediate (ubiquinone radical). CoQ10 is considered to be a key electron carrier in the mitochondrial electron transport chain (ETC) through transferring electrons to complex III from complex I or complex II. The number of isoprene units in CoQs varies among species, with six isoprene units forming CoQ6 in Saccharomyces cerevisiae, eight isoprene-unit CoQ8 in Escherichia coli, and CoQ10 containing ten isoprene units in humans [15, 16].

Physiological basis of CoQ10

CoQ10 in tissues is mainly derived from intracellular biosynthetic pathways, which involve at least 11 highly conserved CoQ genes. Isoprenoid chains are generated via the mevalonate pathway, which produces farnesyl pyrophosphate (FPP), a common substrate for the synthesis of CoQ10. The head group of CoQ is a benzoquinone ring derived from 4-hydroxybenzoate (4-HB), which is converted from tyrosine. A heterotetramer consisting of prenyldiphosphate synthase subunit 1(PDSS1) and decaprenyl diphosphate synthase subunit 2 (PDSS2) is involved in the assembly of tail subunits in the mitochondria. It starts with combining the head and tail subunits at C3 in the inner mitochondrial membrane via COQ2, the modification sequence of the proposed CoQ groups following the chemical logic of electrophilic aromatic substitution. Subsequently, a hydroxyl group is introduced into C5 by the hydroxylase COQ6, which is further modified by COQ3. DDMQ10 is then formed after hydroxylation at C1 by unknown enzymes, followed by several further modifications, including methylation at C2 by COQ5, hydroxylation at C6 by COQ7, and final O-methylation at C6 by COQ3, to generate a fully functional CoQ10 molecule [17, 18] (Fig. 1).

Fig. 1.

CoQ biosynthesis pathway

In addition to internal synthesis, the body also absorbs high levels of CoQ10 from a variety of animal proteins, vegetables, and fruits, especially chicken legs and hearts [19]. Taking CoQ10 supplements is also an effective strategy for increasing plasma CoQ10 levels. The small intestine is the primary site of CoQ10 absorption, where the oxidized form of ubiquinone is absorbed less efficiently than the reduced form. However, ubiquinone absorption is much greater when taken with food, especially lipid-containing food. After being absorbed in the small intestine, CoQ10 enters the circulation, binds to plasma lipoproteins, and is transported to different tissues and organs throughout the body. CoQ10 is mostly found in the heart, kidney, liver, muscle, and other tissues with high metabolic rate and mitochondrial content [20].

CoQ is a lipid-soluble substance found in most cell membranes and serum lipoproteins and is essential for the ETC [18]. CoQ10 plays a crucial role in ETC by transferring electrons to generate an electrochemical gradient in the mitochondria, which in turn produces ATP in the presence of ATP synthase. Notably, besides the oxidative phosphorylation process, CoQ10 receives electrons from the mitochondrial dehydrogenases to supply energy to the ETC in many processes. Therefore, CoQ10 plays a crucial role in carbohydrate and lipid metabolism. It receives electrons from flavoprotein dehydrogenase (ETFDH) and mitochondrial glycerol-3-phosphate dehydrogenase (GAPDH) during fatty acid beta-oxidation process. It participates in sulfide detoxification and assists mitochondria in generating ATP by accepting electrons from sulfide quinone oxidoreductase (SQOR). It also accepts electrons from proline dehydrogenase 1 (PRODH) and proline dehydrogenase 2 (PRODH2) in amino acid catabolism. Additionally, CoQ10 receives electrons from dihydroorotate dehydrogenase (DHODH) and is involved in uridine production [16] (Figs. 2 and 3).

Fig. 2.

Complexes I and II, as well as other dehydrogenases that reduce CoQ at the inner mitochondrial membrane, are shown in the OXPHOS system. ACAD, acyl-CoA dehydrogenase; complexes I: NADH, CoQ oxidoreductase; complexes II, succinate dehydrogenase; complexes III, cytochrome c oxidoreductase; complexes IV, cytochrome c oxidase; complexes V, ATP synthetase; Cyt c, cytochrome c; DHODH, dihidroorotate dehydrogenase; ETF-FAD, electron transfer flavoprotein; ETFDH, electron transfer flavoprotein coenzyme Q reductase; GPDH, glycerol 3 phosphate dehydrogenase; ProDH, proline dehydrogenase; SQOR, sulfide/quinone oxidoreductase; IMS, inter membrane space; MIM, mitochondrial inner membrane

Fig. 3.

Summary of the effects of CoQ10 supplementation in vitro. A Exogenous supplementation of CoQ10 improves sperm quality by improving sperm concentration, activity, and other parameters; B exogenous supplementation of CoQ10 promotes oocyte maturation while also resisting oocyte aging; C exogenous supplementation of CoQ10 promotes erythroid differentiation during defective erythropoiesis; D exogenous supplementation of CoQ10 can affect the nervous system by increasing dendritic spine density; E exogenous supplementation of CoQ10 promotes glomerular filtration rate to improve renal function

In addition to the aforementioned functions, CoQ10 acts as an antioxidant to regulate the amount of mitochondrial reactive oxygen species (ROS), protecting cells from excessive oxidative stress and lipid peroxidation. It has also been suggested that CoQ10 may protect embryonic heart development by inhibiting the opening of the mitochondrial permeability transition pore (mPTP) to maintain mitochondrial membrane potential and oxidative phosphorylation [21, 22].

The Overview of Embryonic Development

Embryogenesis is the process by which a zygote develops into a new individual through a series of intricate transformations. Fertilization is complete when the male pronucleus is fused with the female pronucleus. After fertilization, the zygote divides into a two-cell stage embryo, four-cell stage embryo, and eight-cell stage embryo, gradually forming a morula. Fluid secreted by the blastomere accumulates in the intercellular space and forms a blastocyst cavity in the center of the embryo. As the blastocyst cavity expands, the rate of cell differentiation decreases, and the developmental potential of the cells is restricted in the 16-cell stage embryo, resulting in the formation of two cell lineages, the trophoblastic ectoderm (TE) and the inner cell mass (ICM) [23]. TE is engaged in the formation of the placenta, and through a series of interactions with the uterine wall, the blastocyst attaches to the uterus and forms a bond with the mother. ICM cells divide and differentiate to form the yolk sac, allantoic, and amniotic folds, which separate the embryo and provide a direct route for material exchange between the mother and fetus [24, 25]. ICM cells also develop into organ systems, such as the brain, spinal cord, bones, and skin [26–29].

Adequate energy supply is crucial during embryonic development. Mitochondria can produce ATP via mETC to provide energy for cellular activities during embryonic development. Oocytes require high levels of energy to undergo meiosis and complete fertilization, which is heavily dependent on mitochondria. During oocyte development, mitochondria are clustered around the condensed chromatin and spindle, and migrate into the protoplast after fertilization via the regulation of microtubules. It was found that ATP levels in fertilized zygotes are higher than that in unfertilized ovum, pointing out that aberrant mitochondrial oxidative phosphorylation and reduced ATP synthesis can lead to defective ovum fertilization [30].

Mitochondrial content, such as mtDNA copy number, may be used as an indicator for ovum quality assessment and oocyte fertilization outcomes. Unfertilized oocytes contain approximately 100,000 more copies of mtDNA than fertilized oocytes [31]. Given that aerobic respiration in eukaryotes is fully dependent on mitochondrial function, any mutation in mtDNA or nuclear-encoded mitochondrial genes may cause mitochondrial dysfunction, leading to a variety of pathological results, including embryonic lethality.

Polarity shifts in the mitochondrial membrane potential are important for the respiratory chain system and organelles that regulate the dynamic calcium homeostasis. The electron transfer process in the mitochondrial respiratory chain is also known as proton translocation. Basically, protons are pumped from the mitochondrial matrix and across the inner mitochondrial membrane, forming a proton gradient to store energy for subsequent conversion of ADP to ATP by enzymes in the respiratory chain [32]. Mitochondrial activity in oocytes declines with age and the potential for embryonic development. Previous studies have shown that in immature oocytes, mitochondria are diffusely distributed with decreased activity, while in mature oocytes, mitochondria are highly active and distributed throughout the cytoplasm [33, 34]. It is further demonstrated that mitochondria play a crucial role in embryonic development.

Coenzyme Q10 and embryonic development

Development process of oocytes

It has been suggested that oocyte quality is one of the most critical factors for pregnancy outcomes in vitro fertilization and embryo transfer. Decreased fertility is mostly due to the aging of the ovary during growth and development, which results in a decline in the number and quality of the oocytes. Most females gradually deplete the oocyte pool produced during their lifetime with a concomitant increase in the number of defective oocytes, a process known as physiological ovarian aging, with menopause being the final stage [35, 36]. However, some individuals experience premature decline in fertility, such as menopause and miscarriage, known as premature pathological ovarian aging [37].

After ovulation, the oocyte continues to undergo meiosis I and stays in the second meiosis metaphase (MII) to form the mature oocyte, one of the major factors influencing female fertility. The cytoplasm of the oocyte contains proteins, RNAs, metabolites, and organelles, especially mitochondria, required for ovum fertilization and embryonic development [38, 39]. Perez et al. demonstrated that microinjections of mitochondria into a fertilized ovum prevented apoptosis and improved embryonic growth in mice [40].

Cumulus cells provide growth factors, lipids, and even metabolites to support oocyte growth during oocyte development [41–43]. Lack of nutrients supplied by cumulus cells affects oocyte maturation. Recent research has demonstrated that the composition of follicular fluid significantly plays an important role in oocyte growth. Increased oxidative stress during aging altered the follicular fluid microenvironment [44] and significantly impaired oocyte development. It initiated a number of cascades related to oocyte quality, culminating in the activation of apoptotic pathways [45–49]. On the other hand, the level of CoQ10, a natural antioxidant present in follicular fluid, was strongly correlated with oocyte quality. CoQ10 levels in female mammals declined with age [50]; however, an appropriate supplementation of CoQ10 improved poor oocyte quality, enhanced mitochondrial function, and promoted embryonic development [51–54].

CoQ10 in oocytes maturation

Follicular fluid contains a range of components produced in metabolic pathways, providing over 200 proteins essential for follicle growth. These proteins promote oocyte maturation and protect the follicle from oxidation damage [55]. Studies have shown that CoQ10 is transported in plasma by lipoproteins and has important antioxidant activity in lipoproteins. Elevated levels of lipoproteins in follicular fluid significantly improve the ability to transport CoQ10 and promote its antioxidant activity. Oral supplementation with CoQ10(200 mg/d) for 30 days significantly increased fertilization success in mature oocytes of older (35 +) participants undergoing in vitro fertilization (IVF-ET; 88% vs 74% in the untreated control). The status of zygotes was also improved dramatically (82% in class I, 18% in class II vs. 60% in class I, 25% in class II, and 15% in class III). In addition, supplementation with CoQ10 increased high-density lipoprotein levels and decreased antioxidant content, but increased antioxidative capacity in follicular fluid, contributing to oocyte maturation and reproductive success [52]. LEE et al. found that 50 μM CoQ10 treatment during in vitro culture effectively reduced the ROS levels in the cells; meanwhile, the in vitro maturation capacity of oocytes was increased from 48.9 to 75.7% [56].

Yang et al. reported that supplementation of maturation medium with 50 μM CoQ10 increased nuclear maturation and decreased ROS levels and early apoptosis in porcine oocytes. Further studies on mitochondrial membrane potential and ATP synthesis revealed that CoQ10 altered mitochondrial distribution and promoted ATP synthesis, thereby improving mitochondrial function and, ultimately, meiotic maturation and subsequent development of oocytes, especially those with quality defects. These findings imply that CoQ10 may act directly on oocytes to improve oocyte quality by altering mitochondrial activity to promote nuclear maturation [51, 57]. In line with these findings, Alireza Heydarnejad et al. reported that mature sheep oocytes treated with moderate amounts of CoQ10 exhibited improved mitochondrial mass and distribution. The expression of three major apoptotic markers, BAX, BCL2, and caspase3, was significantly decreased, whereas the expression of the cell quality markers GDF9 and BMP15 was increased in CoQ10-treated oocytes or cumulus cells compared with the control group. These findings indicate that CoQ10 may be an excellent candidate for improving oocyte quality and thus promoting embryo development [58, 59].

Furthermore, it is worth noting that the dosage of CoQ10 supplementation affects the physiological reproductive processes in sheep. Adding 15–30 M CoQ10 to the maturation medium enhanced the developmental ability of oocytes in terms of blastocyst formation, hatching rate, and embryo quality, which were reduced by 50 M CoQ10 [58]. This indicates that excessive CoQ10 supplementation has certain deleterious consequences, and an appropriate amount of CoQ10 is required for its beneficial effect on oocyte development. Gendelman and Roth et al. also found that supplementation of 50 M and 100 M CoQ10 had distinct impacts on blastocyst formation rate in different seasons. 50 M CoQ10 enhanced whereas 100 M CoQ10 decreased the ability of oocytes to fertilize, divide fertilized ovules, and form blastocysts in winter. Furthermore, 50 M CoQ10 supplementation had no effect on oocyte quality grade, but improved highly polarized mitochondria in class I oocytes and increased the expression of mitochondria-related genes, such as MTND2P1, SDHD, CYTB, MT-CO2, and ATP5B. These findings further imply that the dosage of CoQ10 supplementation is critical for oocyte development and maturation and that its beneficial effects may be achieved via monitoring the oxidative status of oocytes [60].

Aging of oocytes

There are two types of oocyte aging: one is post-ovulatory senescence which occurs when an oocyte does not complete fertilization during the optimal time at MII [58], and the second is reproductive or maternal aging, which occurs when an oocyte is in a senescent environment before ovulation [62].

One of the primary assessments of oocyte quality is to evaluate oocyte morphology and integrity. Cell fragmentation and loss of developmental potential are common in aging oocytes, and the rates of fragmentation and mortality increase with age [63]. Oocytes are more likely to undergo spindle disruption during postovulatory meiosis. Actin microfilaments are essential for spindle positioning during meiosis and protect maternal chromosomes from damage during sperm entry [64]. Treatment of in vitro cultured oocytes with 50 μM CoQ10 has been reported to minimize the loss of actin cap in aged oocytes, thereby improving oocyte quality [65]. This suggests that CoQ10 improves postovulatory oocyte quality in aged oocytes, which may be influenced by actin microfilament distribution.

Sirtuin4 (SIRT4), a NAD + -dependent enzyme, regulates mitochondrial function and maintains cellular metabolism [66]. SIRT4 was dramatically elevated during oocyte aging, leading to insufficient mitochondrial redistribution and apoptosis, whereas SIRT4 knockdown significantly reduced the rate of improper mitochondrial distribution and ROS generation [67]. CoQ10 (10 μM) after 12 h of administration restored the abnormal morphology caused by oocyte aging, whereas overexpression of SIRT4 combined with CoQ10 supplementation switched the mitochondrial state to that of aging oocytes [68]. These findings indicate that CoQ10 may maintain mitochondrial function in aging oocytes by altering SIRT4 expression, thereby delaying oocyte senescence and improving embryonic development.

The expression of Pdss2 and Coq6, which are related to the CoQ10 synthesis pathway, was reduced in immature oocytes from aged mice and women. Further research found that the mitochondrial respiratory pool, ROS, and ATP were greatly reduced, and some oocytes even had chromosomal misalignment, which indicates that disrupting the CoQ10 biosynthesis pathway may affect the developmental potential oocytes. Subcutaneous injection of CoQ10 at 22 mg/kg three times per week for 12 weeks reversed these effects, restored mitochondrial activity in oocytes, and improved ovulation and conception rates in females [69]. Furthermore, cumulus cells surrounding oocytes showed reduced expression of proteins involved in the oxidative phosphorylation pathway [70]. The expression of Pdss2 and Coq6, which are involved in CoQ10 synthesis, was reduced with age in both oocytes and cumulus cells, suggesting CoQ10 deficiency in both aged oocytes and cumulus cells. CoQ10 deficiency may result in fewer cumulus cells around each oocyte and decreased glucose absorption in old mice. Weekly injection of 0.084 mg/kg of CoQ10 for 12 weeks improved reproduction and development in elderly mice by reducing oocyte mortality, increasing surrounding cumulus cells, and improving glucose uptake by enhancing the mitochondrial respiratory pool [71]. However, it is unclear whether the increased developmental capability by CoQ10 supplementation is influenced by the combination of cumulus cells and oocytes, or by each cell type individually.

Role of CoQ10 in sperm quality

Approximately 190 million individuals worldwide are affected by infertility, and the amount of people seeking medical assistance is gradually increasing. It is estimated that the male-related infertility accounts for 50% of the pathogenesis of infertility. Unlike unexplained male infertility (UMI), patients with idiopathic male infertility are characterized by abnormal sperm parameters such as sperm concentration, viability, and morphology [72].

Sperm viability is normally used as an important indicator of potential mammalian fertility, and the epididymis, as a site of sperm maturation, plays a key role in sperm development and viability [73]. In particular, specific proteins presented in the epididymal epithelium are likely to provide a unique developmental environment for sperm maturation. Previous studies have reported that sperm-ovum–related proteins undergo proteolytic hydrolysis during epididymal transit and promote sperm maturation through the cAMP-PKA pathway [74]. Mitochondrial quality can influence the progressive motility of sperm cells [75]. Yoo-Jin Park et al. noted that mitochondrial electron transport–associated proteins maintain fertilization capacity by reducing ROS damage during epididymal maturation, suggesting that male infertility may be associated with decreased sperm viability caused by defects in mitochondrial-associated proteins [76]. In addition, spermatozoa maintain viability during capacitation and the acrosome reaction by a high concentration of ATP, which is produced by coordinated oxidative phosphorylation and glycolysis [77]. It was found that mitochondria-related proteins such as UQCRC1 and SDHA were differentially expressed during sperm capacitation. Among them, UQCRC1 was involved in ROS production by regulating mitochondrial electron transport, and overexpression of UQCRC1 caused an increase in ROS, which led to mitochondrial dysfunction in spermatozoa and induced apoptosis [78]. Thus, CoQ10, as an antioxidant and a key cofactor in ETC, could be used in the treatment of male infertility.

Numerous studies have shown that OS plays a crucial role in idiopathic male infertility, also known as male oxidative stress infertility (MOSI) [79, 80]. Excessive ROS causes abnormal sperm parameters and sperm DNA fragmentation (SDF) levels which play a key role in sperm capacitation, acrosome reaction, and sperm-oocyte fusion[81, 82]. Therefore, the use of antioxidants to treat MOSI has emerged as a potential option. Sperm viability, concentration, morphology, pregnancy, and conception rate were improved in patients with idiopathic azoospermia more than 2 years by administering CoQ10 300 mg/days for 6 months or CoQ10 200 mg/days for 3 months. And exogenous supplementation with CoQ10 is more effective among numerous antioxidants that improve OS [83].

Data collection on 65 patients with idiopathic oligoasthenozoospermia was conducted by Alahmar et al. All participants were evaluated for antioxidant levels, CoQ10 concentration, SDF, and baseline analysis as published in WHO2010 guidelines. Routine sperm parameters, total antioxidant capacity (TAC), SDF, and CoQ10 concentration were also continuously monitored in patients who received oral CoQ10 200 mg/day for 3 months. The results revealed that sperm concentration, progressive motility was significantly improved in the patients after 3 months of CoQ10 treatment compared to the control group. Patients had increased total ROS levels, significantly decreased antioxidant status, and decreased SDF percentage. In addition, CoQ10 levels showed a negative correlation with sperm concentration and motility [84]. Consistent with their results, Balercia et al. conducted a randomized controlled trial of 60 patients with idiopathic weak spermatozoa. Treatment with CoQ10 (200 mg/day) for 6 months resulted in an increase in progressive sperm motility in the treatment group [85]. Another randomized controlled trial which received CoQ10 (300 mg/day) treatment indicated an improvement in sperm parameters after 26 weeks of treatment [86]. These results suggested that CoQ10 significantly improves sperm motility in male infertility patients.

Role of CoQ10 in organ system development

In addition to the growth and maturation capacity of germ cells, adequate growth of various organ systems during development substantially impacts embryonic development. Several recent clinical reports have shown that mutations in genes related to CoQ10 synthesis, such as PDSS1, COQ2, COQ4, COQ6, and COQ9, led to CoQ10 deficiency, which in turn resulted in abnormal development of various organs and systems of fetus, or even embryonic dead [87–91]. Here, we discuss the effects of CoQ10 on the development of different organ systems.

Kidney disease

The kidney, one of the most complex organs in mammalians, is a homeostatic organ required for maintaining fluid homeostasis. Organogenesis of the renal system during embryonic development is a relatively complex process, and abnormal nephrogenesis can lead to a variety of diseases [92].

It has been reported that 50% of infants with COQ2 or COQ6 deficiency developed kidney disease within 15 months of life, whereas 50% of individuals with COQ8B deficiency were asymptomatic by age 9. Nephrotic range proteinuria was present in 85.7%, 86.1%, and 71.7% of patients with defects in COQ2, COQ6, and COQ8B, respectively. Forty percent of COQ6-deficient children had moderate chronic kidney disease (CKD), and 20% of these patients had end-stage kidney disease (ESKD) [10]. These findings demonstrate a strong link between CoQ10 and kidney function.

Proteinuria is one of the most common symptoms of nephropathy. A 3-year-old boy with isolated proteinuria was diagnosed with ADCK4 (COQ8B)-associated glomerulopathy (ADCK4-GN) using exome sequencing. Analysis with light microscopy revealed modest glomerular abnormalities in kidney tissue, and data from electron microscopy unmasked mitochondrial hyperplasia and hypertrophy. Proteinuria gradually decreased during 3 months of CoQ10 treatment at a dose of 15 mg per kg body weight per day, and the glomerular filtration rate returned to normal after 5-month treatment. This finding indicates that CoQ10 supplementation may treat patients with mutations in ADCK4. However, the follow-up time needed to be longer to accurately assess the long-term effect [93].

A young patient with glomerular disease was diagnosed with a pathogenic variation in COQ6. CoQ10 treatment improved proteinuria and growth velocity. Interestingly, despite the remission of glomerular disease, plasma CoQ10 concentrations were not increased after daily administration of 30 mg/kg CoQ10, and even decreased after 6 months of treatment. The precise underlying mechanism is unknown; however, this finding provides a potential direction for further research on the mechanism of CoQ10 while providing a treatment for related diseases [94]. Together, these findings indicate reduced CoQ10 in patients, which may cause early onset of abnormal kidney development and dysfunction.

The role of CoQ10 in Nerve generation

Early neural development begins with the thickened cells in front of the primitive streak of the ectoderm, called the neural plate, which fold and gradually unite to form the neural tube and develop into the central nervous system (CNS). This process starts with a sequence of biological activities, such as cell differentiation, proliferation, and migration, followed by the connection of dendrites and axons on the cell surface with neighboring neurons and glial cells. Abnormalities in any of these processes lead to malfunction in the nervous system [95].

Fragile X syndrome (FXS), the most frequent genetic phenomenon of inherited mental retardation and autism, is characterized by impaired language development, seizures, impulsivity, and anxiety. Mitochondria in the forebrain of fmr1 mutant mice exhibited distinct abnormalities during the critical period of neurodevelopment. Modular dynamics analysis showed pathological proton leakage from the mitochondria of fmr1 mutant mice, which caused pathological opening of cyclosporine A (CsA)-sensitive channel revealed by data from screening of specific proton leakage inhibitors. CoQ10 levels in the forebrain of Fmr1 knockout mice were significantly reduced. Peritoneal injection of CoQ10 (160 mg/kg) was given to day 9 postnatal mice. Reduced leakage of CSA-sensitive pathological protons from mitochondria was observed after 24 h, along with increased mitochondrial respiratory efficiency and normalization of dendritic spine density. Repetitive behaviors were also improved in FXS mice [11].

Cerebellar ataxia is a degenerative nervous system disorder characterized by gait problems, dysarthria, vertigo, and dysphagia [96]. Studies on a young patient with ataxia, microcephaly, and generalized epilepsy indicate that CoQ10 is significantly associated with neurological development. Subsequent muscle biopsy revealed a complex III impairment and substantial CoQ10 deficiency in the patient. The authors then analyzed the clinical characteristics of six children with cerebellar ataxia and found that all patients had abnormal electroencephalography (EEG) and cerebellar atrophy, with developmental abnormalities beginning in early childhood. The activity of the ETC complex was defective in four of these patients, despite no significant changes in mitochondrial proliferation. Oral supplementation with CoQ10 (300–3000 mg/day) after 1 to 12 months alleviated muscle atrophy and improved cerebellar function in these children, with motor flexibility improving in five of these children [97, 98].

One clinical example of neurological disorders in infants has also been associated with CoQ10 deficiency. Generalized epilepsy was demonstrated at 7 months of age, mild cerebral atrophy occurred at 1 year of age, and basal ganglia lactate levels were elevated. Visual and auditory deficits were examined at 3 years of age, with occasional seizures, among other phenomena. The ATP level was increased after administration of 50 μM CoQ10 in the cells[99]. In addition, it has been reported that two Turkish brothers suffered from sensorineural deafness and optic nerve atrophy caused by mutations in COQ6. Based on neuroretinal thickness analysis paired with the optical examination, patient 1 presented clinically with bilateral sensorineural deafness, severe hearing impairments at age 6, vision loss at 17, and bilateral papilledema. A pure missense mutation was found in exon 9 of the COQ6 gene based on ethnic background and disease characteristics. After 2 months of supplementation with the 15 mg/kg/day CoQ10 analog idebenone, the visual acuity was improved, and the papilledema disappeared in these patients. However, patient 2, the younger brother of patient 1, who was diagnosed with sensorineural deafness at age 4, had no significant change in hearing at the age of 7 years after 13 months of 10 mg/kg/day of idebenone supplementation but had no new ophthalmologic or neurologic symptoms [100], although both of them suffered from primary CoQ10 insufficiency in childhood due to mutations in COQ6. The mechanism behind this difference is unclear.

The same clinical symptoms as those with COQ6 mutations have also been observed in children with genetic defects in PDSS1, COQ2, and COQ9 [87, 88, 91]. These studies suggest that defective CoQ10 production impairs the development of the embryonic central nervous system and leads to severe clinical symptoms, such as postpartum neurological dysfunction. This discovery provides a new direction for subsequent research on the mechanism of CoQ10 in embryonic development and also indicates a novel strategy for clinicians to treat the disease. In conclusion, CoQ10 is essential for neurodevelopment.

CoQ10 in circulation system

Erythropoiesis is an important physiological process throughout embryonic development [101]. TIF1γ, as a transcriptional mediator, is required for human and zebrafish erythropoiesis [102]. Its absence disrupts hematopoiesis, resulting in the inability of red blood cells to survive efficient oxygen transfer and, ultimately, embryonic death [103]. Marlies P. Rossmann et al. found that leflunomide, a DHODH inhibitor, corrected TIF1γ-dependent abnormalities in erythropoiesis. Knockdown of TIF1γ in embryos altered 95% of mitochondrial gene expression, reducing the ratio of succinate to alpha-ketoglutarate, which reflects abnormal metabolism in the tricarboxylic acid (TCA) cycle, and oxygen consumption rate, which indicates dysfunctional oxidative metabolism. Addition of rotenone, a complex I inhibitor of ETC, reversed leflunomide-induced rescue effect, suggesting that leflunomide could improve erythropoiesis deficiencies by modifying the ETC. Immunochromatin co-precipitation data showed that TIF1γ bound the loci of several CoQ pathway genes, such as PDSS1 and COQ2. mRNA levels of these genes were lower in TIF1γ knockdown group than in the control group. These findings strongly suggest that TIF1γ directly regulates CoQ levels in erythropoiesis, and CoQ may play a key role in human and zebrafish embryonic development, especially in erythropoiesis [7].

The heart is the first functional organ formed during embryonic development and plays a crucial role in delivering nutrients and oxygen to the embryo. The development of the embryonic heart is divided into four stages: crescent creation, linear heart tube development, heart chamber construction, and heart valve development. Each stage is controlled by a complicated and fine-tuned regulatory system, any failure of which may result in heart deformation and, ultimately, embryonic death [104]. During early embryonic heart development, the predominant source of energy for cells gradually shifts from the anaerobic glycolytic pathway to the oxidative phosphorylation pathway, as cardiac performance required for embryonic growth increases. This alteration is mostly determined by the structure and function of mitochondria during development. Closing the mPTP reduces oxidative stress generation and promotes cardiomyocyte differentiation, whereas opening the mPTP results in mitochondrial structural malfunction and apoptosis or necrosis [106]. Previous studies have identified binding sites on mPTP for CoQ10 and another ubiquinone analog, whose expression might restrict or activate channel opening; however, whether CoQ10-regulated mPTP channel opening affects embryonic heart development is unknown [105]. Barajas et al. constructed a Fmr1 deletion mouse model that induced an increase in CoQ10 production and mPTP closure in the developing heart, which is a useful tool for understanding the role of CoQ10 in heart development [22].

COQ7, an enzyme that encodes a critical component of CoQ biosynthesis, is homologous to the longevity gene CLK-1. CLK-1 deficiency caused growth restriction and abnormal heart rhythm during embryonic development, accompanied by aberrant mitochondrial function. On the other hand, addition of exogenous CoQ10 repaired damages caused by CLK-1 deficiency. These findings suggest that CLK-1-deficient animals produce insufficient CoQ10, resulting in mitochondrial malfunction that impedes proper mitochondrial activity and disrupts cardiac function during embryonic development [107].

Several examples of COQ9 deficiency leading to primary CoQ10 deficiency have been reported [91, 108]. One of these children, whose parents were close relatives in Turkey, developed respiratory distress, hypotonia, and widespread cyanosis shortly after birth. The results of the cranial ultrasound revealed neonatal Leigh-like disease, which was gradually improved after a series of treatments. On the other hand, the patient suddenly suffered from seizures on the 10th day after birth, and she died of cardiopulmonary failure on the 18th day. Due to the observed symptoms of mitochondrial disease, a skin biopsy was performed to evaluate oxidative phosphorylase activity, which indicated a defect in CoQ10 metabolism. Examination of mitochondrial enzyme activity revealed a marked decrease in complex II/III activity. Exome sequencing showed a defect in the COQ9 gene. Consistent with the role of COQ9 in CoQ10 biosynthesis, a substantial reduction in total CoQ10 was confirmed by high-performance liquid chromatography. These findings indicate that COQ9 and CoQ10 are important for prenatal development [109]. Together, these results suggest that CoQ10 deficiency caused by different genetic defects in mice and humans may affect the activity of the mitochondrial complex to reduce energy supply capacity, thereby affecting the function of the circulatory system, including the heart and red blood cells and, consequently, exacerbating embryonic developmental disorders.

CoQ10 supplementation

Over the past few years, oral high-dose CoQ10 or ubiquinol orally has become a trend in patients with mitochondrial disease. The bioavailability of different forms of CoQ10 varies, with ubiquinol being better absorbed than ubiquinone. In a neonatal cohort, plasma ubiquinol levels reached 5–10 g/mL after 3–4 weeks of treatment at 10 mg/kg/day [110]. Regarding the effects of oral CoQ10 on embryonic development, Teran et al. reported that CoQ10 reduced the incidence of pre-eclampsia by intervening in placental development [111]. CoQ10 supplementation could also improve oocyte and gamete quality and reduce other developmental abnormalities [112]. Although few evidence that CoQ10 can treat a specific disease, clinical trials have shown that oral CoQ10 supplements are safe and well tolerated. Its negative effects mainly include gastrointestinal problems, nausea, and vomiting. However, excessive CoQ10 supplementation may have the opposite effect; therefore, further clinical studies are required to evaluate the safe dose of CoQ10.

Conclusions and perspective

CoQ10 deficiency increases the risk of poor embryonic development; however, the association between CoQ10 and embryonic development remains unclear. Given that CoQ10 levels are affected by enzymes in its synthesis pathway, it is difficult to tell whether disorders are caused by CoQ10 deficiency or a direct result of defects in the target gene. Finding an accurate way to interfere with CoQ10 levels can thus provide better support for the research on the mechanisms by which CoQ10 regulates embryonic development. Reduced ATP synthesis and increased mitochondrial oxidative stress, two biological processes that affect embryonic development, were shown to occur in the absence of CoQ10. Therefore, further experiments are needed to prove the actual impact of CoQ10 deficiency and provide effective targets for the treatment of CoQ10 deficiency.

More research is also needed to understand the pathophysiological pathways by which abnormalities in CoQ10-related genes cause problems in embryonic development. Collectively, mounting evidence demonstrates that CoQ10 plays an important role in embryonic development, and CoQ10 supplementation improves oocyte quality. On the other hand, while the potential of CoQ10 as an antioxidant to reduce oxidative stress has been reported in the literature, appropriate clinical trials still need to be done.

This review highlights the relevance of CoQ10 as an antioxidant to improve oocyte quality and the crucial role of CoQ10 in embryonic development. It also provides a new idea for studying metabolic changes during embryonic development. Therefore, it is necessary for us further to explore the specific mechanism underlying the role of CoQ10 in embryonic development.

Author contribution

Conceptualization, Xueke He and Miao Jiang; resources, Xueke He and Minjun Liao; writing—original draft preparation, Xueke He; writing—review and editing, Xueke He, Hao Chen, Minjun Liao, Xiaomei Zhao, Miao Jiang, and Da-wei Zhang; supervision, Miao Jiang; funding acquisition, Miao Jiang and Zhisheng Jiang. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by National Key Research and Development Project (2019YFA0801601 to Zhisheng Jiang), National Natural Science Foundation of China (No. 32101018 to Miao Jiang), and Hunan Provincial Natural Science Foundation of China (No. 2023JJ30522 to Miao Jiang).

Data availability

Not applicable.

Declarations

Institutional review board

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Informed consent

Not applicable.

Conflicts of interest

The authors declare no competing interests.