RARE DISEASE
Coenzyme Q10 deficiency
Coenzyme Q10 deficiency
Coenzyme Q10 deficiency
Synonyms: CoQ10 deficiency
Synonyms: CoQ10 deficiency
Synonyms: CoQ10 deficiency
Drug discovery
6
drugs
With orphan designations
Overview
Coenzyme Q10 Deficiency Overview
Primary coenzyme Q10 (CoQ10) deficiency is a rare genetic disorder caused by mutations in COQ genes, disrupting CoQ10 biosynthesis. Clinical manifestations range from severe infantile-onset encephalomyopathy and nephrotic syndrome to adult-onset cerebellar ataxia, cardiomyopathy, and progressive neurological decline. Early CoQ10 supplementation (5–30 mg/kg/day) may stabilize symptoms, particularly renal and muscular involvement, though neurological responses are variable [1][7][9].
Key Clinical Insights
Therapies
CoQ10 replacement: High-dose oral supplementation (5–30 mg/kg/day), with early initiation critical to prevent irreversible organ damage [3][7][13]. Renal and muscle symptoms often respond, but neurological improvements are less predictable [8][12].
Multidisciplinary care: Monitoring/treatment for cardiomyopathy, nephrotic syndrome, and neurological complications [10][16].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
522 drug discovery papers about Coenzyme Q10 deficiency, with 1 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
522 drug discovery papers about Coenzyme Q10 deficiency, with 1 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-30 | Expanding the epilepsy spectrum in primary coenzyme Q10 deficiency with COQ4 variants - Case series and literature review.
To characterize the epileptic spectrum associated with COQ4 variants through three newly identified patients and literature review. We retrospectively collected clinical data from three patients with COQ4 variants diagnosed at Chang Gung Memorial Hospital, Linkou Branch, between November 2021 and December 2023. A literature review identified 66 previously reported patients with COQ4 variants. Clinical presentation, genotype, seizure characteristics, epilepsy syndromes, electroencephalographic findings, and treatment information were extracted when available. Among the 69 cases with COQ4 variants in this study and previously reported cases, 48 (70%) had seizure presentations, including generalized-onset seizures, focal-onset seizures, epileptic spasms, and seizures of unknown onset. Here, we report three patients with COQ4 variants presenting with early infantile developmental and epileptic encephalopathy (EIDEE), the first reported case of epilepsy of infancy with migrating focal seizures (EIMFS) in a patient with COQ4 variants, and infantile epileptic spasms syndrome (IESS) with a favorable documented response to corticosteroid therapy, further expanding the epileptic phenotypic spectrum of COQ4 variants. Our findings broaden the epileptic spectrum associated with COQ4 variants and highlight the importance of early genetic testing in infants with developmental and epileptic encephalopathies, EIMFS, or IESS. The favorable corticosteroid response observed in our patient with IESS and COQ4 variants may have therapeutic implications and warrants further investigation.
2026-09-22 | Vps1 and select autophagic machinery are required for coenzyme Q uptake and trafficking to mitochondria.
Coenzyme Q (CoQ) is an important lipid found in nearly all cellular membranes in eukaryotes. Biosynthesis of CoQ occurs within mitochondria, where it functions as an electron carrier in oxidative phosphorylation and participates in key metabolic pathways. In both mitochondrial and non-mitochondrial membranes, the hydroquinone form of CoQ (CoQH2) also functions as a radical-scavenging antioxidant and participates in other processes required for cell maintenance and survival. Individuals with CoQ deficiency may benefit from high-dose CoQ supplementation; however, its bioavailability is limited, and treatment responses can vary. Here, we sought to gain mechanistic insight into how exogenous CoQ is trafficked to mitochondria. We used the yeast model system Saccharomyces cerevisiae, that produce CoQ6 with a polyisoprenyl tail containing six isoprene units. A CoQ6-deficient (coq2Δ) yeast mutant is used to investigate genes and corresponding pathways required for the cellular uptake and trafficking of exogenous CoQ6 to mitochondrial respiratory complexes. Specifically, we identify essential residues in the dynamin-like protein Vps1 that are required for CoQ6 trafficking and show that yeast vps1 mutants with known defects in autophagy are incapable of trafficking exogenously supplemented CoQ6 to mitochondria. Importantly, we identify a non-canonical role for several autophagic proteins in CoQ6 trafficking. Taken together, our data suggest that uptake of exogenous CoQ6 and its delivery to the mitochondria relies on a novel, specialized lipid trafficking pathway comprised of select autophagic and endosomal membrane trafficking proteins, and the lytic compartment which serves as a transport hub.
2026-08-24 | Time-dependent and partially reversible mitochondrial remodeling induced by coenzyme Q10 depletion in HepG2 cells.
Aging and age related pathological conditions are long-term processes in which cellular states gradually change over extended periods. However, many experimental studies of oxidative stress in cultured cells rely on short-term exposure to exogenous oxidative agents, which may not adequately reflect chronic oxidative conditions. To address this limitation, we established a cellular model of long-term oxidative stress by reducing endogenous antioxidant capacity through inhibition of coenzyme Q10 (CoQ10) biosynthesis rather than applying acute oxidative insults. Using HepG2 cells treated with 4-nitrobenzoic acid, we compared mitochondrial responses to acute and chronic CoQ10 depletion. CoQ10 levels were reduced under both acute and chronic conditions and were restored by co- treatment with 4-hydroxybenzoic acid. Acute CoQ10 depletion resulted in a reduced number of mitochondria and mitochondrial enlargement, accompanied by an increase in mitochondrial DNA copy number (mtDNAcn). In contrast, long-term culture under continuous CoQ10 depletion restored mitochondrial number, size, and mtDNAcn to levels comparable to those of control cells, despite persistently reduced CoQ10 content. However, cell proliferation remained impaired, and mitochondrial ultrastructural properties differed from those of control cells, indicating incomplete recovery under chronic conditions. Furthermore, 4-hydroxybenzoic acid reversed the mitochondrial alterations observed under acute conditions. Together, these findings demonstrate that mitochondrial responses to CoQ10 deficiency are strongly time dependent and involve reversible yet incomplete adaptive remodeling, highlighting the importance of modeling chronic oxidative stress when interpreting mitochondrial phenotypes.
2026-08-04 | Structure-Based Identification and Binding Mode Analysis of Potential COQ8A (ADCK3) Inhibitors Using AutoDock Vina and AlphaFold3
ADCK3 (COQ8A) is a key regulatory protein required for maintaining the stability and activity of the coenzyme Q (CoQ) biosynthetic machinery. Deficiency or dysfunction of ADCK3 can impair CoQ10 biosynthesis, resulting in reduced mitochondrial electron transport efficiency and cellular energy production. In this study, we investigated the binding affinity and binding modes of multiple experimentally validated ligands within the ADCK3 binding pocket. Comparative analyses were performed using both AlphaFold 3 (AF3)-predicted protein–ligand complexes and AutoDock Vina docking simulations. The binding scores and predicted interaction patterns obtained from these approaches were evaluated to identify common structural and physicochemical characteristics associated with favorable ligand binding. In addition, structure-based pharmacophore analysis was conducted to characterize the key molecular features required for ADCK3 recognition. Among the sixteen selected active ligands, six compounds were prioritized for detailed analysis based on their predicted binding performance. Binding mode analysis revealed that ligand stabilization within the ADCK3 pocket was primarily mediated through a combination of hydrogen-bonding interactions, hydrophobic contacts, π-π stacking interactions, and, in some cases, halogen bonding interactions with residues lining the binding cavity. Collectively, these findings provide insight into the molecular determinants governing ligand recognition by ADCK3 and highlight key binding features that may serve as valuable considerations in future ADCK3-targeted drug discovery and lead optimization efforts.
2026-06-03 | Targeting the Mitochondrial Phenotype in Cockayne Syndrome Patient Cells: From Bioenergetic Fragility to Pharmacologic Rescue.
Cockayne syndrome (CS), primarily caused by autosomal recessive pathogenic variants in ERCC6 (CSB) or ERCC8 (CSA), is a transcription-coupled nucleotide excision repair disorder. CS frequently presents with features similar to primary mitochondrial disease (PMD), including leukodystrophy, lactic acidemia, and skeletal muscle mitochondrial DNA (mtDNA) depletion. How this mitochondrial phenotype arises at the cellular level, and whether it can be pharmacologically targeted, is not yet clear. We characterized mtDNA content, respiratory chain (RC) protein abundance, mitochondrial biogenesis signaling pathways, and oxidative phosphorylation capacity in primary fibroblasts from two siblings with identical compound heterozygous ERCC6 pathogenic variants (c.1526+1G>T; c.2800C>A, p.Pro934Thr) despite marked intrafamilial phenotypic divergence. A combined metabolic stress exposure (galactose, reduced glutamine, and buthionine sulfoximine, (BSO)) which reduced CS cell survival was used to screen for therapeutic leads among twenty-three candidate mitochondrial disease therapeutic compounds. Lead compounds were mechanistically validated at the level of mitochondrial superoxide, total cellular oxidative stress, glutathione, and autophagic flux. Patient fibroblasts exhibited several hallmarks of PMD, including reduced mtDNA content, decreased expression of complex I subunit NDUFB8, elevated expression of TOM20 with paradoxically decreased PGC1α suggestive of impaired mitophagic clearance, and decreased mitochondrial respiratory capacity. Under combined metabolic stress, ATP-levels indicative of survival in CS patient fibroblasts selectively collapsed to ~20% of controls. Five dual-rescue compounds, defined as agents that reproducibly restored ATP-based cell survival in both patient fibroblast lines under stress, were identified, including N-acetylcysteine (NAC), coenzyme Q10 (CoQ10), rapamycin, taurine, and (-)-epicatechin. Mechanistic profiling resolved three functional classes of therapeutic effects in CS cells: (1) upstream mitochondrial reactive oxygen species reduction (NAC, CoQ10); (2) mTORC1 inhibition bypassing defective stress-induced autophagic induction (rapamycin); and (3) extra-mitochondrial improvement in cellular stress resilience ((-)- epicatechin, taurine). ERCC6-based CSB deficiency produced a stress-sensitive and physiologically complex mitochondrial phenotype in patient fibroblasts that was pharmacologically treatable by targeting three mechanistically distinct pathways. Oxidative and broader stress buffering, autophagy modulation via mTORC1 inhibition, and enhanced cellular resilience highlight novel therapeutic opportunities to be advanced to clinical trials in CSB patients.
gene therapies
2026-07-13 | Melas Syndrome - Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like Episodes (MELAS): Pathophysiology, Clinical Manifestations, Diagnostic Approaches, and Therapeutic Strategies
Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome represents one of the most prevalent and clinically significant mitochondrial disorders, characterized by a distinctive constellation of neurological and systemic manifestations that profoundly impact patient quality of life and long-term outcomes. This comprehensive review examines the current understanding of MELAS syndrome, encompassing its molecular etiology, pathogenic mechanisms, epidemiological patterns, clinical presentation, diagnostic evaluation, and therapeutic approaches. The syndrome arises primarily from pathogenic variants in mitochondrial DNA, with the m.3243A>G transition in the MTTL1 gene accounting for approximately 80% of cases. The resultant impairment of oxidative phosphorylation leads to deficient adenosine triphosphate production, increased anaerobic glycolysis, and excessive lactate accumulation, particularly affecting tissues with high metabolic demands. The hallmark stroke-like episodes, which are not vascular in origin, reflect the vulnerability of metabolically active brain regions to energy failure and may be mediated by both cytopathic and angiopathic mechanisms. Diagnosis requires integration of clinical findings, biochemical markers, neuroimaging features, and genetic confirmation, with muscle biopsy reserved for select cases. Despite advances in understanding the pathophysiology, no disease-modifying therapy currently exists, and management remains primarily supportive, emphasizing symptom control, prevention of metabolic decompensation, and multidisciplinary care. L-arginine and citrulline supplementation show promise in mitigating acute stroke-like episodes by addressing nitric oxide deficiency, while coenzyme Q10 and other mitochondrial cofactors are commonly employed despite limited evidence. This review highlights the critical need for continued research into novel therapeutic strategies, including gene therapy, mitochondrial replacement, and pharmacological agents targeting mitochondrial function, while emphasizing the importance of early diagnosis and comprehensive multidisciplinary management in optimizing patient outcomes.
2025-02-05 | Mitochondrial-ER Contact Sites and Tethers Influence the Biosynthesis and Function of Coenzyme Q.
Coenzyme Q (CoQ) is an essential redox-active lipid that plays a major role in the electron transport chain, driving mitochondrial ATP synthesis. In Saccharomyces cerevisiae (yeast), CoQ biosynthesis occurs exclusively in the mitochondrial matrix via a large protein-lipid complex, the CoQ synthome, comprised of CoQ itself, late-stage CoQ-intermediates, and the polypeptides Coq3-Coq9 and Coq11. Coq11 is suggested to act as a negative modulator of CoQ synthome assembly and CoQ synthesis, as its deletion enhances Coq polypeptide content, produces an enlarged CoQ synthome, and restores respiration in mutants lacking the CoQ chaperone polypeptide, Coq10. The CoQ synthome resides in specific niches within the inner mitochondrial membrane, termed CoQ domains, that are often located adjacent to the endoplasmic reticulum-mitochondria encounter structure (ERMES). Loss of ERMES destabilizes the CoQ synthome and renders CoQ biosynthesis less efficient. Here we show that deletion of COQ11 suppresses the respiratory deficient phenotype of select ERMES mutants, results in repair and reorganization of the CoQ synthome, and enhances mitochondrial CoQ domains. Given that ER-mitochondrial contact sites coordinate CoQ biosynthesis, we used a Split-MAM (Mitochondrial Associated Membrane) artificial tether consisting of an ER-mitochondrial contact site reporter, to evaluate the effects of artificial membrane tethers on CoQ biosynthesis in both wild-type and ERMES mutant yeast strains. Overall, this work identifies the deletion of COQ11 as a novel suppressor of phenotypes associated with ERMES deletion mutants and indicates that ER-mitochondria tethers influence CoQ content and turnover, highlighting the role of membrane contact sites in regulating mitochondrial respiratory homeostasis.
2020-12-23 | COQ11 deletion mitigates respiratory deficiency caused by mutations in the gene encoding the coenzyme Q chaperone protein Coq10.
Coenzyme Q (Q n ) is a vital lipid component of the electron transport chain that functions in cellular energy metabolism and as a membrane antioxidant. In the yeast Saccharomyces cerevisiae, coq1-coq9 deletion mutants are respiratory-incompetent, sensitive to lipid peroxidation stress, and unable to synthesize Q6 The yeast coq10 deletion mutant is also respiratory-deficient and sensitive to lipid peroxidation, yet it continues to produce Q6 at an impaired rate. Thus, Coq10 is required for the function of Q6 in respiration and as an antioxidant and is believed to chaperone Q6 from its site of synthesis to the respiratory complexes. In several fungi, Coq10 is encoded as a fusion polypeptide with Coq11, a recently identified protein of unknown function required for efficient Q6 biosynthesis. Because "fused" proteins are often involved in similar biochemical pathways, here we examined the putative functional relationship between Coq10 and Coq11 in yeast. We used plate growth and Seahorse assays and LC-MS/MS analysis to show that COQ11 deletion rescues respiratory deficiency, sensitivity to lipid peroxidation, and decreased Q6 biosynthesis of the coq10Δ mutant. Additionally, immunoblotting indicated that yeast coq11Δ mutants accumulate increased amounts of certain Coq polypeptides and display a stabilized CoQ synthome. These effects suggest that Coq11 modulates Q6 biosynthesis and that its absence increases mitochondrial Q6 content in the coq10Δcoq11Δ double mutant. This augmented mitochondrial Q6 content counteracts the respiratory deficiency and lipid peroxidation sensitivity phenotypes of the coq10Δ mutant. This study further clarifies the intricate connection between Q6 biosynthesis, trafficking, and function in mitochondrial metabolism.
2020-08-24 | Intragenic suppressor mutations of the COQ8 protein kinase homolog restore coenzyme Q biosynthesis and function in Saccharomyces cerevisiae.
Saccharomyces cerevisiae Coq8 is a member of the ancient UbiB atypical protein kinase family. Coq8, and its orthologs UbiB, ABC1, ADCK3, and ADCK4, are required for the biosynthesis of coenzyme Q in yeast, E. coli, A. thaliana, and humans. Each Coq8 ortholog retains nine highly conserved protein kinase-like motifs, yet its functional role in coenzyme Q biosynthesis remains mysterious. Coq8 may function as an ATPase whose activity is stimulated by coenzyme Q intermediates and phospholipids. A key yeast point mutant expressing Coq8-A197V was previously shown to result in a coenzyme Q-less, respiratory deficient phenotype. The A197V substitution occurs in the crucial Ala-rich protein kinase-like motif I of yeast Coq8. Here we show that long-term cultures of mutants expressing Coq8-A197V produce spontaneous revertants with the ability to grow on medium containing a non-fermentable carbon source. Each revertant is shown to harbor a secondary intragenic suppressor mutation within the COQ8 gene. The intragenic suppressors restore the synthesis of coenzyme Q. One class of the suppressors fully restores the levels of coenzyme Q and key Coq polypeptides necessary for the maintenance and integrity of the high-molecular mass CoQ synthome (also termed complex Q), while the other class provides only a partial rescue. Mutants harboring the first class of suppressors grow robustly under respiratory conditions, while mutants containing the second class grow more slowly under these conditions. Our work provides insight into the function of this important yet still enigmatic Coq8 family.
2018-10-24 | Suppression of respiratory growth defect of mutant deficient in mitochondrial phospholipase A1 by overexpression of genes involved in coenzyme Q synthesis in Saccharomyces cerevisiae.
DDL1 encodes a mitochondrial phospholipase A1 involved in acyl chain remodeling of mitochondrial phospholipids and degradation of cardiolipin in Saccharomyces cerevisiae. The deletion of DDL1 leads to respiratory growth defects. To elucidate the physiological role of DDL1, we screened for genes that, when overexpressed, suppress the respiratory growth defect of the DDL1 deletion mutant. Introduction of COQ8, COQ9, or COQ5, which are involved in coenzyme Q (CoQ) synthesis, using a multicopy vector suppressed the respiratory growth defect of the DDL1 deletion mutant. In contrast, introduction of COQ8 using a multicopy vector did not accelerate the growth of the deletion mutants of TAZ1 or CLD1, which encode an acyltransferase or phospholipase A2, respectively, involved in the remodeling of cardiolipin. These results suggest genetic interactions between the mitochondrial phospholipase A1 gene and the genes involved in CoQ synthesis.
proteins
2023-11-07 | Prosaposin is a novel coenzyme Q10–binding protein
Coenzyme Q10 (CoQ10) is essential for mitochondrial ATP production and functions as an important antioxidant in every biomembrane and lipoprotein. Due to its hydrophobicity, a binding and transfer protein for CoQ10 is plausible, and we previously described saposin B as a CoQ10-binding and transfer protein. Here, we report that prosaposin, the precursor of saposin B, also binds CoQ10. As prosaposin is both a secretory protein and integral membrane protein, it is ubiquitous in the body. Prosaposin was isolated from human seminal plasma, and CoQ10 was extracted from hexane solution into the water phase. It was additionally found that immunoprecipitates of mouse brain cytosol generated using two different anti-prosaposin antibodies contained coenzyme Q9. Furthermore, mouse liver cytosol and mouse kidney cytosol also contained prosaposin–coenzyme Q9 complex. These results suggest that prosaposin binds CoQ10 in human cells and body fluids. The significance and role of the Psap-CoQ10 complex in vivo is also discussed.
2023-03-17 | Transferrin, insulin, and progesterone modulate intracellular concentrations of coenzyme Q and cholesterol, products of the mevalonate pathway, in undifferentiated PC12 cells
Coenzyme Q (CoQ) is important not only as an essential lipid for the mitochondrial electron transport system, but also as an antioxidant. CoQ levels decrease during aging and in various diseases. Orally administered CoQ is not readily taken up in the brain, so it is necessary to develop a method to increase the amount of CoQ in neurons. CoQ is synthesized via mevalonate pathway, like cholesterol. Transferrin, insulin, and progesterone are factors used in the culture of neurons. In this study, we determined the effect of these reagents on cellular CoQ and cholesterol levels. The administration of transferrin, insulin, and progesterone increased cellular CoQ levels in undifferentiated PC12 cells. When serum was removed and only insulin was administered, intracellular CoQ levels increased. This increase was even more pronounced with concurrent administration of transferrin, insulin, and progesterone. Cholesterol level decreased by the administration of transferrin, insulin, and progesterone. Progesterone treatment lowered intracellular cholesterol levels in a concentration-dependent manner. Our findings suggest that transferrin, insulin, and progesterone may be useful in regulating CoQ levels and cholesterol levels, which are products of the mevalonate pathway.
2019-09-03 | Loss of a novel striated muscle-enriched mitochondrial protein Coq10a enhances postnatal cardiac hypertrophic growth
Abstract Postnatal mammalian cardiomyocytes undergo a major transition from hyperplasia (increases in cell numbers) to hypertrophy (expansion in cell size). This process is accompanied by rapid mitochondrial biogenesis and metabolic switches to meet the demand of increased cardiac output. Although most mitochondrial components express ubiquitously, recent transcriptomic and proteomic analyses have discovered numerous tissue-specific mitochondrial proteins whose physiological functions are largely unknown. Here we report that a highly evolutionarily conserved mitochondrial protein Coq10a is predominantly expressed in mammalian cardiac and skeletal muscles, and is highly up-regulated around birth in a thyroid hormone-dependent manner. Deletion of Coq10a by CRISPR/Cas9 leads to enhanced cardiac growth after birth. Surprisingly, adult Coq10a mutant mice maintain the hypertrophic heart phenotype with increased levels of coenzyme Q (CoQ) per cardiomyocyte, preserved cardiac contractile function and mitochondrial respiration, which contrasts with reported mice and humans with mutations in other Coq family genes. Further RNA-seq analysis and mitochondrial characterization suggest an increase of mitochondrial biogenesis in the Coq10a mutant heart as a possible consequence of Peroxisome proliferator-activated receptor Gamma Coactivator 1-alpha (PGC1α) activation, consistent with a recent intriguing report that CoQ may function as a natural ligand and partial agonist of Peroxisome Proliferator-Activated Receptor (PPAR) α/γ. Taken together, our study reveals a previously unknown function of a novel striated muscle-enriched mitochondrial protein Coq10a in regulating postnatal heart growth.
2009-01-05 | Restoration of electron transport without proton pumping in mammalian mitochondria.
We have restored the CoQ oxidative capacity of mouse mtDNA-less cells (rho degrees cells) by transforming them with the alternative oxidase Aox of Emericella nidulans. Cotransforming rho degrees cells with the NADH dehydrogenase of Saccharomyces cerevisiae, Ndi1 and Aox recovered the NADH DH/CoQ reductase and the CoQ oxidase activities. CoQ oxidation by AOX reduces the dependence of rho degrees cells on pyruvate and uridine. Coexpression of AOX and NDI1 further improves the recycling of NAD(+). Therefore, 2 single-protein enzymes restore the electron transport in mammalian mitochondria substituting >80 nuclear DNA-encoded and 11 mtDNA-encoded proteins. Because those enzymes do not pump protons, we were able to split electron transport and proton pumping (ATP synthesis) and inquire which of the metabolic deficiencies associated with the loss of oxidative phosphorylation should be attributed to each of the 2 processes.
2004-01-01 | Therapeutic strategies in Friedreich’s ataxia
Friedreich's ataxia is caused by a pronounced lack of frataxin, a mitochondrial protein of not fully understood function. Lack of frataxin homologues in yeast and mice leads to increased sensitivity to oxidative stress, depletion of proteins with iron-sulfur clusters like respiratory chain complexes I–III and aconitase, and to iron accumulation in mitochondria. Similar effects have been demonstrated in human disease with increased markers of oxidative DNA damage in urine and impaired oxidative phosphorylation in in vivo exercise studies using 31 Phosphorus magnetic resonance spectroscopy (31P-MRS). Therapeutical trials mainly focus on antioxidative treatment with coenzyme Ql0 or its short-chain variant idebenone. Promising effects on cardiac hypertrophy in uncontrolled preliminary studies contrast with minor effects in controlled trials and no effect of antioxidants on neurological deficits has been established. Preliminary encouraging 31P-MRS data exist for the treatment with L-carnitine but not with creatine. However, all these interventions may take effect too late in the pathogenic process. Alternative strategies aiming at an enhancement of frataxin by stem cell transplantation, gene transfer or frataxin supplementation are desirable. Additionally, more efficient biomarkers are needed to monitor treatment effects.
oligonucleotides
2021-10-25 | Genetic screening reveals phospholipid metabolism as a key regulator of the biosynthesis of the redox-active lipid coenzyme Q.
Mitochondrial energy production and function rely on optimal concentrations of the essential redox-active lipid, coenzyme Q (CoQ). CoQ deficiency results in mitochondrial dysfunction associated with increased mitochondrial oxidative stress and a range of pathologies. What drives CoQ deficiency in many of these pathologies is unknown, just as there currently is no effective therapeutic strategy to overcome CoQ deficiency in humans. To date, large-scale studies aimed at systematically interrogating endogenous systems that control CoQ biosynthesis and their potential utility to treat disease have not been carried out. Therefore, we developed a quantitative high-throughput method to determine CoQ concentrations in yeast cells. Applying this method to the Yeast Deletion Collection as a genome-wide screen, 30 genes not known previously to regulate cellular concentrations of CoQ were discovered. In combination with untargeted lipidomics and metabolomics, phosphatidylethanolamine N-methyltransferase (PEMT) deficiency was confirmed as a positive regulator of CoQ synthesis, the first identified to date. Mechanistically, PEMT deficiency alters mitochondrial concentrations of one-carbon metabolites, characterized by an increase in the S-adenosylmethionine to S-adenosylhomocysteine (SAM-to-SAH) ratio that reflects mitochondrial methylation capacity, drives CoQ synthesis, and is associated with a decrease in mitochondrial oxidative stress. The newly described regulatory pathway appears evolutionary conserved, as ablation of PEMT using antisense oligonucleotides increases mitochondrial CoQ in mouse-derived adipocytes that translates to improved glucose utilization by these cells, and protection of mice from high-fat diet-induced insulin resistance. Our studies reveal a previously unrecognized relationship between two spatially distinct lipid pathways with potential implications for the treatment of CoQ deficiencies, mitochondrial oxidative stress/dysfunction, and associated diseases.
other
2025-12-18 | Successful Living Kidney Donation from Heterozygous Carrier Parents to Siblings with Coenzyme Q8B Nephropathy: Two Case Series.
Introduction: Coenzyme Q8B (COQ8B) nephropathy is an autosomal recessive hereditary disorder caused by primary coenzyme Q10 (CoQ10) deficiency. It manifests as a genetic steroid-resistant nephrotic syndrome (SRNS), typically of childhood-onset. CoQ10 supplementation is a treatment option; however, it is not always effective in an entire patient population, leading to end-stage kidney disease. Kidney transplantation (KTx) is an effective treatment option for genetic SRNS; however, living KTx within biologically related members is associated with increased risk of allograft failure in recipients and future kidney dysfunction in donors. Here, we present two successful cases of living kidney donations from heterozygous carrier parents to their siblings with COQ8B nephropathy. Case Presentation: The family comprised two parents and three siblings. Two of the daughters were diagnosed with proteinuria at 11 and 8 years of age, respectively. COQ8B nephropathy diagnosis was confirmed by next-generation and Sanger sequencing analysis, which revealed a novel compound heterozygous mutation in the COQ8B gene (c.737G>A and c.1468C>T). An older sister missed an opportunity for CoQ10 supplementation due to late diagnosis, whereas a younger sister did not respond to CoQ10 supplementation. Living kidney donation from father to the older sister and from mother to the younger sister was successfully performed without post-transplant recurrence in recipients or kidney dysfunction in donors within 5 and 2 years of follow-up. Conclusion: Parent-to-child KTx may be an effective treatment option within family members affected with COQ8B nephropathy.
.
small molecules
2026-09-30 | Expanding the epilepsy spectrum in primary coenzyme Q10 deficiency with COQ4 variants - Case series and literature review.
To characterize the epileptic spectrum associated with COQ4 variants through three newly identified patients and literature review. We retrospectively collected clinical data from three patients with COQ4 variants diagnosed at Chang Gung Memorial Hospital, Linkou Branch, between November 2021 and December 2023. A literature review identified 66 previously reported patients with COQ4 variants. Clinical presentation, genotype, seizure characteristics, epilepsy syndromes, electroencephalographic findings, and treatment information were extracted when available. Among the 69 cases with COQ4 variants in this study and previously reported cases, 48 (70%) had seizure presentations, including generalized-onset seizures, focal-onset seizures, epileptic spasms, and seizures of unknown onset. Here, we report three patients with COQ4 variants presenting with early infantile developmental and epileptic encephalopathy (EIDEE), the first reported case of epilepsy of infancy with migrating focal seizures (EIMFS) in a patient with COQ4 variants, and infantile epileptic spasms syndrome (IESS) with a favorable documented response to corticosteroid therapy, further expanding the epileptic phenotypic spectrum of COQ4 variants. Our findings broaden the epileptic spectrum associated with COQ4 variants and highlight the importance of early genetic testing in infants with developmental and epileptic encephalopathies, EIMFS, or IESS. The favorable corticosteroid response observed in our patient with IESS and COQ4 variants may have therapeutic implications and warrants further investigation.
2026-09-22 | Vps1 and select autophagic machinery are required for coenzyme Q uptake and trafficking to mitochondria.
Coenzyme Q (CoQ) is an important lipid found in nearly all cellular membranes in eukaryotes. Biosynthesis of CoQ occurs within mitochondria, where it functions as an electron carrier in oxidative phosphorylation and participates in key metabolic pathways. In both mitochondrial and non-mitochondrial membranes, the hydroquinone form of CoQ (CoQH2) also functions as a radical-scavenging antioxidant and participates in other processes required for cell maintenance and survival. Individuals with CoQ deficiency may benefit from high-dose CoQ supplementation; however, its bioavailability is limited, and treatment responses can vary. Here, we sought to gain mechanistic insight into how exogenous CoQ is trafficked to mitochondria. We used the yeast model system Saccharomyces cerevisiae, that produce CoQ6 with a polyisoprenyl tail containing six isoprene units. A CoQ6-deficient (coq2Δ) yeast mutant is used to investigate genes and corresponding pathways required for the cellular uptake and trafficking of exogenous CoQ6 to mitochondrial respiratory complexes. Specifically, we identify essential residues in the dynamin-like protein Vps1 that are required for CoQ6 trafficking and show that yeast vps1 mutants with known defects in autophagy are incapable of trafficking exogenously supplemented CoQ6 to mitochondria. Importantly, we identify a non-canonical role for several autophagic proteins in CoQ6 trafficking. Taken together, our data suggest that uptake of exogenous CoQ6 and its delivery to the mitochondria relies on a novel, specialized lipid trafficking pathway comprised of select autophagic and endosomal membrane trafficking proteins, and the lytic compartment which serves as a transport hub.
2026-08-24 | Time-dependent and partially reversible mitochondrial remodeling induced by coenzyme Q10 depletion in HepG2 cells.
Aging and age related pathological conditions are long-term processes in which cellular states gradually change over extended periods. However, many experimental studies of oxidative stress in cultured cells rely on short-term exposure to exogenous oxidative agents, which may not adequately reflect chronic oxidative conditions. To address this limitation, we established a cellular model of long-term oxidative stress by reducing endogenous antioxidant capacity through inhibition of coenzyme Q10 (CoQ10) biosynthesis rather than applying acute oxidative insults. Using HepG2 cells treated with 4-nitrobenzoic acid, we compared mitochondrial responses to acute and chronic CoQ10 depletion. CoQ10 levels were reduced under both acute and chronic conditions and were restored by co- treatment with 4-hydroxybenzoic acid. Acute CoQ10 depletion resulted in a reduced number of mitochondria and mitochondrial enlargement, accompanied by an increase in mitochondrial DNA copy number (mtDNAcn). In contrast, long-term culture under continuous CoQ10 depletion restored mitochondrial number, size, and mtDNAcn to levels comparable to those of control cells, despite persistently reduced CoQ10 content. However, cell proliferation remained impaired, and mitochondrial ultrastructural properties differed from those of control cells, indicating incomplete recovery under chronic conditions. Furthermore, 4-hydroxybenzoic acid reversed the mitochondrial alterations observed under acute conditions. Together, these findings demonstrate that mitochondrial responses to CoQ10 deficiency are strongly time dependent and involve reversible yet incomplete adaptive remodeling, highlighting the importance of modeling chronic oxidative stress when interpreting mitochondrial phenotypes.
2026-08-04 | Structure-Based Identification and Binding Mode Analysis of Potential COQ8A (ADCK3) Inhibitors Using AutoDock Vina and AlphaFold3
ADCK3 (COQ8A) is a key regulatory protein required for maintaining the stability and activity of the coenzyme Q (CoQ) biosynthetic machinery. Deficiency or dysfunction of ADCK3 can impair CoQ10 biosynthesis, resulting in reduced mitochondrial electron transport efficiency and cellular energy production. In this study, we investigated the binding affinity and binding modes of multiple experimentally validated ligands within the ADCK3 binding pocket. Comparative analyses were performed using both AlphaFold 3 (AF3)-predicted protein–ligand complexes and AutoDock Vina docking simulations. The binding scores and predicted interaction patterns obtained from these approaches were evaluated to identify common structural and physicochemical characteristics associated with favorable ligand binding. In addition, structure-based pharmacophore analysis was conducted to characterize the key molecular features required for ADCK3 recognition. Among the sixteen selected active ligands, six compounds were prioritized for detailed analysis based on their predicted binding performance. Binding mode analysis revealed that ligand stabilization within the ADCK3 pocket was primarily mediated through a combination of hydrogen-bonding interactions, hydrophobic contacts, π-π stacking interactions, and, in some cases, halogen bonding interactions with residues lining the binding cavity. Collectively, these findings provide insight into the molecular determinants governing ligand recognition by ADCK3 and highlight key binding features that may serve as valuable considerations in future ADCK3-targeted drug discovery and lead optimization efforts.
2026-06-03 | Targeting the Mitochondrial Phenotype in Cockayne Syndrome Patient Cells: From Bioenergetic Fragility to Pharmacologic Rescue.
Cockayne syndrome (CS), primarily caused by autosomal recessive pathogenic variants in ERCC6 (CSB) or ERCC8 (CSA), is a transcription-coupled nucleotide excision repair disorder. CS frequently presents with features similar to primary mitochondrial disease (PMD), including leukodystrophy, lactic acidemia, and skeletal muscle mitochondrial DNA (mtDNA) depletion. How this mitochondrial phenotype arises at the cellular level, and whether it can be pharmacologically targeted, is not yet clear. We characterized mtDNA content, respiratory chain (RC) protein abundance, mitochondrial biogenesis signaling pathways, and oxidative phosphorylation capacity in primary fibroblasts from two siblings with identical compound heterozygous ERCC6 pathogenic variants (c.1526+1G>T; c.2800C>A, p.Pro934Thr) despite marked intrafamilial phenotypic divergence. A combined metabolic stress exposure (galactose, reduced glutamine, and buthionine sulfoximine, (BSO)) which reduced CS cell survival was used to screen for therapeutic leads among twenty-three candidate mitochondrial disease therapeutic compounds. Lead compounds were mechanistically validated at the level of mitochondrial superoxide, total cellular oxidative stress, glutathione, and autophagic flux. Patient fibroblasts exhibited several hallmarks of PMD, including reduced mtDNA content, decreased expression of complex I subunit NDUFB8, elevated expression of TOM20 with paradoxically decreased PGC1α suggestive of impaired mitophagic clearance, and decreased mitochondrial respiratory capacity. Under combined metabolic stress, ATP-levels indicative of survival in CS patient fibroblasts selectively collapsed to ~20% of controls. Five dual-rescue compounds, defined as agents that reproducibly restored ATP-based cell survival in both patient fibroblast lines under stress, were identified, including N-acetylcysteine (NAC), coenzyme Q10 (CoQ10), rapamycin, taurine, and (-)-epicatechin. Mechanistic profiling resolved three functional classes of therapeutic effects in CS cells: (1) upstream mitochondrial reactive oxygen species reduction (NAC, CoQ10); (2) mTORC1 inhibition bypassing defective stress-induced autophagic induction (rapamycin); and (3) extra-mitochondrial improvement in cellular stress resilience ((-)- epicatechin, taurine). ERCC6-based CSB deficiency produced a stress-sensitive and physiologically complex mitochondrial phenotype in patient fibroblasts that was pharmacologically treatable by targeting three mechanistically distinct pathways. Oxidative and broader stress buffering, autophagy modulation via mTORC1 inhibition, and enhanced cellular resilience highlight novel therapeutic opportunities to be advanced to clinical trials in CSB patients.
gene therapies
2026-07-13 | Melas Syndrome - Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like Episodes (MELAS): Pathophysiology, Clinical Manifestations, Diagnostic Approaches, and Therapeutic Strategies
Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome represents one of the most prevalent and clinically significant mitochondrial disorders, characterized by a distinctive constellation of neurological and systemic manifestations that profoundly impact patient quality of life and long-term outcomes. This comprehensive review examines the current understanding of MELAS syndrome, encompassing its molecular etiology, pathogenic mechanisms, epidemiological patterns, clinical presentation, diagnostic evaluation, and therapeutic approaches. The syndrome arises primarily from pathogenic variants in mitochondrial DNA, with the m.3243A>G transition in the MTTL1 gene accounting for approximately 80% of cases. The resultant impairment of oxidative phosphorylation leads to deficient adenosine triphosphate production, increased anaerobic glycolysis, and excessive lactate accumulation, particularly affecting tissues with high metabolic demands. The hallmark stroke-like episodes, which are not vascular in origin, reflect the vulnerability of metabolically active brain regions to energy failure and may be mediated by both cytopathic and angiopathic mechanisms. Diagnosis requires integration of clinical findings, biochemical markers, neuroimaging features, and genetic confirmation, with muscle biopsy reserved for select cases. Despite advances in understanding the pathophysiology, no disease-modifying therapy currently exists, and management remains primarily supportive, emphasizing symptom control, prevention of metabolic decompensation, and multidisciplinary care. L-arginine and citrulline supplementation show promise in mitigating acute stroke-like episodes by addressing nitric oxide deficiency, while coenzyme Q10 and other mitochondrial cofactors are commonly employed despite limited evidence. This review highlights the critical need for continued research into novel therapeutic strategies, including gene therapy, mitochondrial replacement, and pharmacological agents targeting mitochondrial function, while emphasizing the importance of early diagnosis and comprehensive multidisciplinary management in optimizing patient outcomes.
2025-02-05 | Mitochondrial-ER Contact Sites and Tethers Influence the Biosynthesis and Function of Coenzyme Q.
Coenzyme Q (CoQ) is an essential redox-active lipid that plays a major role in the electron transport chain, driving mitochondrial ATP synthesis. In Saccharomyces cerevisiae (yeast), CoQ biosynthesis occurs exclusively in the mitochondrial matrix via a large protein-lipid complex, the CoQ synthome, comprised of CoQ itself, late-stage CoQ-intermediates, and the polypeptides Coq3-Coq9 and Coq11. Coq11 is suggested to act as a negative modulator of CoQ synthome assembly and CoQ synthesis, as its deletion enhances Coq polypeptide content, produces an enlarged CoQ synthome, and restores respiration in mutants lacking the CoQ chaperone polypeptide, Coq10. The CoQ synthome resides in specific niches within the inner mitochondrial membrane, termed CoQ domains, that are often located adjacent to the endoplasmic reticulum-mitochondria encounter structure (ERMES). Loss of ERMES destabilizes the CoQ synthome and renders CoQ biosynthesis less efficient. Here we show that deletion of COQ11 suppresses the respiratory deficient phenotype of select ERMES mutants, results in repair and reorganization of the CoQ synthome, and enhances mitochondrial CoQ domains. Given that ER-mitochondrial contact sites coordinate CoQ biosynthesis, we used a Split-MAM (Mitochondrial Associated Membrane) artificial tether consisting of an ER-mitochondrial contact site reporter, to evaluate the effects of artificial membrane tethers on CoQ biosynthesis in both wild-type and ERMES mutant yeast strains. Overall, this work identifies the deletion of COQ11 as a novel suppressor of phenotypes associated with ERMES deletion mutants and indicates that ER-mitochondria tethers influence CoQ content and turnover, highlighting the role of membrane contact sites in regulating mitochondrial respiratory homeostasis.
2020-12-23 | COQ11 deletion mitigates respiratory deficiency caused by mutations in the gene encoding the coenzyme Q chaperone protein Coq10.
Coenzyme Q (Q n ) is a vital lipid component of the electron transport chain that functions in cellular energy metabolism and as a membrane antioxidant. In the yeast Saccharomyces cerevisiae, coq1-coq9 deletion mutants are respiratory-incompetent, sensitive to lipid peroxidation stress, and unable to synthesize Q6 The yeast coq10 deletion mutant is also respiratory-deficient and sensitive to lipid peroxidation, yet it continues to produce Q6 at an impaired rate. Thus, Coq10 is required for the function of Q6 in respiration and as an antioxidant and is believed to chaperone Q6 from its site of synthesis to the respiratory complexes. In several fungi, Coq10 is encoded as a fusion polypeptide with Coq11, a recently identified protein of unknown function required for efficient Q6 biosynthesis. Because "fused" proteins are often involved in similar biochemical pathways, here we examined the putative functional relationship between Coq10 and Coq11 in yeast. We used plate growth and Seahorse assays and LC-MS/MS analysis to show that COQ11 deletion rescues respiratory deficiency, sensitivity to lipid peroxidation, and decreased Q6 biosynthesis of the coq10Δ mutant. Additionally, immunoblotting indicated that yeast coq11Δ mutants accumulate increased amounts of certain Coq polypeptides and display a stabilized CoQ synthome. These effects suggest that Coq11 modulates Q6 biosynthesis and that its absence increases mitochondrial Q6 content in the coq10Δcoq11Δ double mutant. This augmented mitochondrial Q6 content counteracts the respiratory deficiency and lipid peroxidation sensitivity phenotypes of the coq10Δ mutant. This study further clarifies the intricate connection between Q6 biosynthesis, trafficking, and function in mitochondrial metabolism.
2020-08-24 | Intragenic suppressor mutations of the COQ8 protein kinase homolog restore coenzyme Q biosynthesis and function in Saccharomyces cerevisiae.
Saccharomyces cerevisiae Coq8 is a member of the ancient UbiB atypical protein kinase family. Coq8, and its orthologs UbiB, ABC1, ADCK3, and ADCK4, are required for the biosynthesis of coenzyme Q in yeast, E. coli, A. thaliana, and humans. Each Coq8 ortholog retains nine highly conserved protein kinase-like motifs, yet its functional role in coenzyme Q biosynthesis remains mysterious. Coq8 may function as an ATPase whose activity is stimulated by coenzyme Q intermediates and phospholipids. A key yeast point mutant expressing Coq8-A197V was previously shown to result in a coenzyme Q-less, respiratory deficient phenotype. The A197V substitution occurs in the crucial Ala-rich protein kinase-like motif I of yeast Coq8. Here we show that long-term cultures of mutants expressing Coq8-A197V produce spontaneous revertants with the ability to grow on medium containing a non-fermentable carbon source. Each revertant is shown to harbor a secondary intragenic suppressor mutation within the COQ8 gene. The intragenic suppressors restore the synthesis of coenzyme Q. One class of the suppressors fully restores the levels of coenzyme Q and key Coq polypeptides necessary for the maintenance and integrity of the high-molecular mass CoQ synthome (also termed complex Q), while the other class provides only a partial rescue. Mutants harboring the first class of suppressors grow robustly under respiratory conditions, while mutants containing the second class grow more slowly under these conditions. Our work provides insight into the function of this important yet still enigmatic Coq8 family.
2018-10-24 | Suppression of respiratory growth defect of mutant deficient in mitochondrial phospholipase A1 by overexpression of genes involved in coenzyme Q synthesis in Saccharomyces cerevisiae.
DDL1 encodes a mitochondrial phospholipase A1 involved in acyl chain remodeling of mitochondrial phospholipids and degradation of cardiolipin in Saccharomyces cerevisiae. The deletion of DDL1 leads to respiratory growth defects. To elucidate the physiological role of DDL1, we screened for genes that, when overexpressed, suppress the respiratory growth defect of the DDL1 deletion mutant. Introduction of COQ8, COQ9, or COQ5, which are involved in coenzyme Q (CoQ) synthesis, using a multicopy vector suppressed the respiratory growth defect of the DDL1 deletion mutant. In contrast, introduction of COQ8 using a multicopy vector did not accelerate the growth of the deletion mutants of TAZ1 or CLD1, which encode an acyltransferase or phospholipase A2, respectively, involved in the remodeling of cardiolipin. These results suggest genetic interactions between the mitochondrial phospholipase A1 gene and the genes involved in CoQ synthesis.
proteins
2023-11-07 | Prosaposin is a novel coenzyme Q10–binding protein
Coenzyme Q10 (CoQ10) is essential for mitochondrial ATP production and functions as an important antioxidant in every biomembrane and lipoprotein. Due to its hydrophobicity, a binding and transfer protein for CoQ10 is plausible, and we previously described saposin B as a CoQ10-binding and transfer protein. Here, we report that prosaposin, the precursor of saposin B, also binds CoQ10. As prosaposin is both a secretory protein and integral membrane protein, it is ubiquitous in the body. Prosaposin was isolated from human seminal plasma, and CoQ10 was extracted from hexane solution into the water phase. It was additionally found that immunoprecipitates of mouse brain cytosol generated using two different anti-prosaposin antibodies contained coenzyme Q9. Furthermore, mouse liver cytosol and mouse kidney cytosol also contained prosaposin–coenzyme Q9 complex. These results suggest that prosaposin binds CoQ10 in human cells and body fluids. The significance and role of the Psap-CoQ10 complex in vivo is also discussed.
2023-03-17 | Transferrin, insulin, and progesterone modulate intracellular concentrations of coenzyme Q and cholesterol, products of the mevalonate pathway, in undifferentiated PC12 cells
Coenzyme Q (CoQ) is important not only as an essential lipid for the mitochondrial electron transport system, but also as an antioxidant. CoQ levels decrease during aging and in various diseases. Orally administered CoQ is not readily taken up in the brain, so it is necessary to develop a method to increase the amount of CoQ in neurons. CoQ is synthesized via mevalonate pathway, like cholesterol. Transferrin, insulin, and progesterone are factors used in the culture of neurons. In this study, we determined the effect of these reagents on cellular CoQ and cholesterol levels. The administration of transferrin, insulin, and progesterone increased cellular CoQ levels in undifferentiated PC12 cells. When serum was removed and only insulin was administered, intracellular CoQ levels increased. This increase was even more pronounced with concurrent administration of transferrin, insulin, and progesterone. Cholesterol level decreased by the administration of transferrin, insulin, and progesterone. Progesterone treatment lowered intracellular cholesterol levels in a concentration-dependent manner. Our findings suggest that transferrin, insulin, and progesterone may be useful in regulating CoQ levels and cholesterol levels, which are products of the mevalonate pathway.
2019-09-03 | Loss of a novel striated muscle-enriched mitochondrial protein Coq10a enhances postnatal cardiac hypertrophic growth
Abstract Postnatal mammalian cardiomyocytes undergo a major transition from hyperplasia (increases in cell numbers) to hypertrophy (expansion in cell size). This process is accompanied by rapid mitochondrial biogenesis and metabolic switches to meet the demand of increased cardiac output. Although most mitochondrial components express ubiquitously, recent transcriptomic and proteomic analyses have discovered numerous tissue-specific mitochondrial proteins whose physiological functions are largely unknown. Here we report that a highly evolutionarily conserved mitochondrial protein Coq10a is predominantly expressed in mammalian cardiac and skeletal muscles, and is highly up-regulated around birth in a thyroid hormone-dependent manner. Deletion of Coq10a by CRISPR/Cas9 leads to enhanced cardiac growth after birth. Surprisingly, adult Coq10a mutant mice maintain the hypertrophic heart phenotype with increased levels of coenzyme Q (CoQ) per cardiomyocyte, preserved cardiac contractile function and mitochondrial respiration, which contrasts with reported mice and humans with mutations in other Coq family genes. Further RNA-seq analysis and mitochondrial characterization suggest an increase of mitochondrial biogenesis in the Coq10a mutant heart as a possible consequence of Peroxisome proliferator-activated receptor Gamma Coactivator 1-alpha (PGC1α) activation, consistent with a recent intriguing report that CoQ may function as a natural ligand and partial agonist of Peroxisome Proliferator-Activated Receptor (PPAR) α/γ. Taken together, our study reveals a previously unknown function of a novel striated muscle-enriched mitochondrial protein Coq10a in regulating postnatal heart growth.
2009-01-05 | Restoration of electron transport without proton pumping in mammalian mitochondria.
We have restored the CoQ oxidative capacity of mouse mtDNA-less cells (rho degrees cells) by transforming them with the alternative oxidase Aox of Emericella nidulans. Cotransforming rho degrees cells with the NADH dehydrogenase of Saccharomyces cerevisiae, Ndi1 and Aox recovered the NADH DH/CoQ reductase and the CoQ oxidase activities. CoQ oxidation by AOX reduces the dependence of rho degrees cells on pyruvate and uridine. Coexpression of AOX and NDI1 further improves the recycling of NAD(+). Therefore, 2 single-protein enzymes restore the electron transport in mammalian mitochondria substituting >80 nuclear DNA-encoded and 11 mtDNA-encoded proteins. Because those enzymes do not pump protons, we were able to split electron transport and proton pumping (ATP synthesis) and inquire which of the metabolic deficiencies associated with the loss of oxidative phosphorylation should be attributed to each of the 2 processes.
2004-01-01 | Therapeutic strategies in Friedreich’s ataxia
Friedreich's ataxia is caused by a pronounced lack of frataxin, a mitochondrial protein of not fully understood function. Lack of frataxin homologues in yeast and mice leads to increased sensitivity to oxidative stress, depletion of proteins with iron-sulfur clusters like respiratory chain complexes I–III and aconitase, and to iron accumulation in mitochondria. Similar effects have been demonstrated in human disease with increased markers of oxidative DNA damage in urine and impaired oxidative phosphorylation in in vivo exercise studies using 31 Phosphorus magnetic resonance spectroscopy (31P-MRS). Therapeutical trials mainly focus on antioxidative treatment with coenzyme Ql0 or its short-chain variant idebenone. Promising effects on cardiac hypertrophy in uncontrolled preliminary studies contrast with minor effects in controlled trials and no effect of antioxidants on neurological deficits has been established. Preliminary encouraging 31P-MRS data exist for the treatment with L-carnitine but not with creatine. However, all these interventions may take effect too late in the pathogenic process. Alternative strategies aiming at an enhancement of frataxin by stem cell transplantation, gene transfer or frataxin supplementation are desirable. Additionally, more efficient biomarkers are needed to monitor treatment effects.
oligonucleotides
2021-10-25 | Genetic screening reveals phospholipid metabolism as a key regulator of the biosynthesis of the redox-active lipid coenzyme Q.
Mitochondrial energy production and function rely on optimal concentrations of the essential redox-active lipid, coenzyme Q (CoQ). CoQ deficiency results in mitochondrial dysfunction associated with increased mitochondrial oxidative stress and a range of pathologies. What drives CoQ deficiency in many of these pathologies is unknown, just as there currently is no effective therapeutic strategy to overcome CoQ deficiency in humans. To date, large-scale studies aimed at systematically interrogating endogenous systems that control CoQ biosynthesis and their potential utility to treat disease have not been carried out. Therefore, we developed a quantitative high-throughput method to determine CoQ concentrations in yeast cells. Applying this method to the Yeast Deletion Collection as a genome-wide screen, 30 genes not known previously to regulate cellular concentrations of CoQ were discovered. In combination with untargeted lipidomics and metabolomics, phosphatidylethanolamine N-methyltransferase (PEMT) deficiency was confirmed as a positive regulator of CoQ synthesis, the first identified to date. Mechanistically, PEMT deficiency alters mitochondrial concentrations of one-carbon metabolites, characterized by an increase in the S-adenosylmethionine to S-adenosylhomocysteine (SAM-to-SAH) ratio that reflects mitochondrial methylation capacity, drives CoQ synthesis, and is associated with a decrease in mitochondrial oxidative stress. The newly described regulatory pathway appears evolutionary conserved, as ablation of PEMT using antisense oligonucleotides increases mitochondrial CoQ in mouse-derived adipocytes that translates to improved glucose utilization by these cells, and protection of mice from high-fat diet-induced insulin resistance. Our studies reveal a previously unrecognized relationship between two spatially distinct lipid pathways with potential implications for the treatment of CoQ deficiencies, mitochondrial oxidative stress/dysfunction, and associated diseases.
other
2025-12-18 | Successful Living Kidney Donation from Heterozygous Carrier Parents to Siblings with Coenzyme Q8B Nephropathy: Two Case Series.
Introduction: Coenzyme Q8B (COQ8B) nephropathy is an autosomal recessive hereditary disorder caused by primary coenzyme Q10 (CoQ10) deficiency. It manifests as a genetic steroid-resistant nephrotic syndrome (SRNS), typically of childhood-onset. CoQ10 supplementation is a treatment option; however, it is not always effective in an entire patient population, leading to end-stage kidney disease. Kidney transplantation (KTx) is an effective treatment option for genetic SRNS; however, living KTx within biologically related members is associated with increased risk of allograft failure in recipients and future kidney dysfunction in donors. Here, we present two successful cases of living kidney donations from heterozygous carrier parents to their siblings with COQ8B nephropathy. Case Presentation: The family comprised two parents and three siblings. Two of the daughters were diagnosed with proteinuria at 11 and 8 years of age, respectively. COQ8B nephropathy diagnosis was confirmed by next-generation and Sanger sequencing analysis, which revealed a novel compound heterozygous mutation in the COQ8B gene (c.737G>A and c.1468C>T). An older sister missed an opportunity for CoQ10 supplementation due to late diagnosis, whereas a younger sister did not respond to CoQ10 supplementation. Living kidney donation from father to the older sister and from mother to the younger sister was successfully performed without post-transplant recurrence in recipients or kidney dysfunction in donors within 5 and 2 years of follow-up. Conclusion: Parent-to-child KTx may be an effective treatment option within family members affected with COQ8B nephropathy.
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Drug Discovery Landscape
6 orphan drug designations for Coenzyme Q10 deficiency.
6 orphan drug designations for Coenzyme Q10 deficiency.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
4-hydroxybenzoic acid | small molecules | FDA | — | New York University, on behalf of NYU Grossman School of Medicine |
4-hydroxybenzoic acid | small molecules | FDA | — | University of Granada |
4-hydroxybenzoate | small molecules | FDA | — | Gleeson Lab - UCSD |
coenzyme Q10 (CoQ10) | small molecules | FDA | — | BPGbio Inc. |
Parahydroxybenzoic acid | small molecules | EMA | — | Universidad De Granada |
Ubiquinol | small molecules | EMA | — | Consorcio Centro de Investigación Biomédica en Red |
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