The protein encoded by COQ7 is required for CoQ10 synthesis in humans, hydroxylating 3-demethoxyubiquinol (DMQ10) in the second to last steps of the pathway. COQ7 mutations lead to a primary CoQ10 deficiency syndrome associated with a pleiotropic neurological disorder. This study shows the clinical, physiological, and molecular characterization of four new cases of CoQ10 primary deficiency caused by five mutations in COQ7, three of which have not yet been described, inducing mitochondrial dysfunction in all patients. However, the specific combination of the identified variants in each patient generated precise pathophysiological and molecular alterations in fibroblasts, which would explain the differential in vitro response to supplementation therapy. Our results suggest that COQ7 dysfunction could be caused by specific structural changes that affect the interaction with COQ9 required for the DMQ10 presentation to COQ7, the substrate access to the active site, and the maintenance of the active site structure. Remarkably, patients\' fibroblasts share transcriptional remodeling, supporting a modification of energy metabolism towards glycolysis, which could be an adaptive mechanism against CoQ10 deficiency. However, transcriptional analysis of mitochondria-associated pathways showed distinct and dramatic differences between patient fibroblasts, which correlated with the extent of pathophysiological and neurological alterations observed in the probands. Overall, this study suggests that the combination of precise genetic diagnostics and the availability of new structural models of human proteins could help explain the origin of phenotypic pleiotropy observed in some genetic diseases and the different responses to available therapies.

Distal hereditary motor neuropathy represents a group of motor inherited neuropathies leading to distal weakness. We report a family of two brothers and a sister affected by distal hereditary motor neuropathy in whom a homozygous variant c.3G>T (p.1Met?) was identified in the COQ7 gene. This gene encodes a protein required for coenzyme Q10 biosynthesis, a component of the respiratory chain in mitochondria. Mutations of COQ7 were previously associated with severe multi-organ disorders characterized by early childhood onset and developmental delay. Using patient blood samples and fibroblasts derived from a skin biopsy, we investigated the pathogenicity of the variant of unknown significance c.3G>T (p.1Met?) in the COQ7 gene and the effect of coenzyme Q10 supplementation in vitro. We showed that this variation leads to a severe decrease in COQ7 protein levels in the patient\'s fibroblasts, resulting in a decrease in coenzyme Q10 production and in the accumulation of 6-demethoxycoenzyme Q10, the COQ7 substrate. Interestingly, such accumulation was also found in the patient\'s plasma. Normal coenzyme Q10 and 6-demethoxycoenzyme Q10 levels were restored in vitro by using the coenzyme Q10 precursor 2,4-dihydroxybenzoic acid, thus bypassing the COQ7 requirement. Coenzyme Q10 biosynthesis deficiency is known to impair the mitochondrial respiratory chain. Seahorse experiments showed that the patient\'s cells mainly rely on glycolysis to maintain sufficient ATP production. Consistently, the replacement of glucose by galactose in the culture medium of these cells reduced their proliferation rate. Interestingly, normal proliferation was restored by coenzyme Q10 supplementation of the culture medium, suggesting a therapeutic avenue for these patients. Altogether, we have identified the first example of recessive distal hereditary motor neuropathy caused by a homozygous variation in the COQ7 gene, which should thus be included in the gene panels used to diagnose peripheral inherited neuropathies. Furthermore, 6-demethoxycoenzyme Q10 accumulation in the blood can be used to confirm the pathogenic nature of the mutation. Finally, supplementation with coenzyme Q10 or derivatives should be considered to prevent the progression of COQ7-related peripheral inherited neuropathy in diagnosed patients.

Coenzyme Q (CoQ) is a redox-active lipid essential for core metabolic pathways and antioxidant defense. CoQ is synthesized upon the mitochondrial inner membrane by an ill-defined \"complex Q\" metabolon. Here, we present structure-function analyses of a lipid-, substrate-, and NADH-bound complex comprising two complex Q subunits: the hydroxylase COQ7 and the lipid-binding protein COQ9. We reveal that COQ7 adopts a ferritin-like fold with a hydrophobic channel whose substrate-binding capacity is enhanced by COQ9. Using molecular dynamics, we further show that two COQ7:COQ9 heterodimers form a curved tetramer that deforms the membrane, potentially opening a pathway for the CoQ intermediates to translocate from the bilayer to the proteins\' lipid-binding sites. Two such tetramers assemble into a soluble octamer with a pseudo-bilayer of lipids captured within. Together, these observations indicate that COQ7 and COQ9 cooperate to access hydrophobic precursors within the membrane and coordinate subsequent synthesis steps toward producing CoQ.

Coenzyme Q10 (CoQ10) is necessary as electron transporter in mitochondrial respiration and other cellular functions. CoQ10 is synthesized by all cells and defects in the synthesis pathway result in primary CoQ10 deficiency that frequently leads to severe mitochondrial disease syndrome. CoQ10 is exceedingly hydrophobic, insoluble, and poorly bioavailable, with the result that dietary CoQ10 supplementation produces no or only minimal relief for patients. We studied a patient from Turkey and identified and characterized a new mutation in the CoQ10 biosynthetic gene COQ7 (c.161G > A; p.Arg54Gln). We find that unexpected neuromuscular pathology can accompany CoQ10 deficiency caused by a COQ7 mutation. We also show that by-passing the need for COQ7 by providing the unnatural precursor 2,4-dihydroxybenzoic acid, as has been proposed, is unlikely to be an effective and safe therapeutic option. In contrast, we show for the first time in human patient cells that the respiratory defect resulting from CoQ10 deficiency is rescued by providing CoQ10 formulated with caspofungin (CF/CoQ). Caspofungin is a clinically approved intravenous fungicide whose surfactant properties lead to CoQ10 micellization, complete water solubilization, and efficient uptake by cells and organs in animal studies. These findings reinforce the possibility of using CF/CoQ in the clinical treatment of CoQ10-deficient patients.

OBJECTIVE: Genetic and environmental factors play significant roles in the pathogenesis of Parkinson\'s disease (PD). Recently, 17 novel risk loci of PD were identified in a meta-analysis of genome-wide association study (GWAS) in the European populations. In order to clarify if these risk loci are associated with PD in Taiwanese population, we conducted a case-control study including 14 of the novel risk loci and analyzed the genetic distribution and allele frequency.
METHODS: A total of 2798 subjects were recruited in this study. Genotyping was performed in 672 PD patients and 609 healthy controls by using Mass ARRAY, and data of another 1517 healthy controls from Taiwan Biobank were also examined.
RESULTS: Our results show that the dominant models of ITPKB rs4653767 (OR (95% CI) = 0.832 (0.699, 0.990), p = 0.038), IL1R2 rs34043159 (OR (95% CI) = 0.812 (0.665, 0.992), p = 0.041) and COQ7 rs11343 (OR (95% CI) = 0.304 (0.180, 0.512), p < 0.001) were associated with PD. In allelic analysis, the T allele of IL1R2 rs34043159 (OR (95% CI) = 0.873 (0.772, 0.987), p = 0.03) and T allele of COQ7 rs11343 (OR (95% CI) = 0.098 (0.040, 0.238), p < 0.001) showed lower risk of PD. After Bonferroni correction, only dominant model and T allele of COQ7 rs11343 showed significantly reduced the risk of PD.
CONCLUSIONS: This study suggests that ITPKB, IL1R2 and COQ7 have influence on the risk of PD in Taiwan.

Mutations of many PDSS and COQ genes are associated with primary coenzyme Q10 (CoQ10) deficiency, whereas mitochondrial DNA (mtDNA) mutations might cause secondary CoQ10 deficiency. Previously, we found that COQ5 and COQ9 proteins are present in different protein complexes in the mitochondria in human 143B cells and demonstrated that COQ5 and COQ9 knockdown suppresses CoQ10 levels. In the present study, we characterized other PDSS and COQ proteins and examined possible crosstalk among various PDSS and COQ proteins. Specific antibodies and mitochondrial localization of mature proteins for these proteins, except PDSS1 and COQ2, were identified. Multiple isoforms of PDSS2 and COQ3 were observed. Moreover, PDSS1, PDSS2, and COQ3 played more important roles in maintaining the stability of the other proteins. Protein complexes containing PDSS2, COQ3, COQ4, COQ6, or COQ7 protein in the mitochondria were detected. Two distinct PDSS2-containing protein complexes could be identified. Transient knockdown of these genes, except COQ6 and COQ8, decreased CoQ10 levels, but only COQ7 knockdown hampered mitochondrial respiration and caused increased ubiquinol:ubiquinone ratios and accumulation of a putative biosynthetic intermediate with reversible redox property as CoQ10. Furthermore, suppressed levels of PDSS2 and various COQ proteins (except COQ3 and COQ8A) were found in cybrids containing the pathogenic mtDNA A8344G mutation or in FCCP-treated 143B cells, which was similar to our previous findings for COQ5. These novel findings may prompt the elucidation of the putative CoQ synthome in human cells and the understanding of these PDSS and COQ protein under physiological and pathological conditions.

Given that the associated clinical manifestations of ubiquinone (UQ, or coenzyme Q) deficiency diseases are highly heterogeneous and complicated, effective new research tools for UQ homeostasis studies are awaited. We set out to develop human COQ7 inhibitors that interfere with UQ synthesis. Systematic structure-activity relationship development starting from a screening hit compound led to the identification of highly potent COQ7 inhibitors that did not disturb physiological cell growth of human normal culture cells. These new COQ7 inhibitors may serve as useful tools for studying the balance between UQ supplementation pathways: de novo UQ synthesis and extracellular UQ uptake.

Multiple system atrophy (MSA) is a progressive neurodegenerative disease clinically characterized by parkinsonism and cerebellar ataxia, and pathologically by oligodendrocyte α-synuclein inclusions. Genetic variants of COQ2 are associated with an increased risk for MSA in certain populations. Also, deficits in the level of coenzyme Q10 and its biosynthetic enzymes are associated with MSA. Here, we measured ATP levels and expression of biosynthetic enzymes for coenzyme Q10, including COQ2, in multiple regions of MSA and control brains. We found a reduction in ATP levels in disease-affected regions of MSA brain that associated with reduced expression of COQ2 and COQ7, supporting the concept that abnormalities in the biosynthesis of coenzyme Q10 play an important role in the pathogenesis of MSA.

BACKGROUND: Primary coenzyme Q10 (CoQ10) deficiencies are clinically and genetically heterogeneous group of disorders associated with defects of genes involved in the CoQ10 biosynthesis pathway. COQ7-associated CoQ10 deficiency is very rare and only two cases have been reported.
RESULTS: We report a patient with encephalo-myo-nephro-cardiopathy, persistent lactic acidosis, and basal ganglia lesions resulting in early infantile death. Using whole exome sequencing, we identified compound heterozygous variants in the COQ7 gene consisting of a deletion insertion resulting in frameshift [c.599_600delinsTAATGCATC, p.(Lys200Ilefs*56)] and a missense substitution [c.319C>T, p.(Arg107Trp), NM_016138.4]. Skin fibroblast studies showed decreased combined complex II + III activity and reduction in CoQ10 level.
CONCLUSIONS: This third patient presenting with lethal encephalo-myo-nephro-cardiopathy represents the severe end of this ultra-rare mitochondrial disease caused by biallelic COQ7 mutations. The response to CoQ10 supplement is poor and alternative treatment strategies should be developed for a more effective management of this disorder.

Coenzyme Q (CoQ) is a key component of the mitochondrial respiratory chain carrying electrons from complexes I and II to complex III and it is an intrinsic component of the respirasome. CoQ concentration is highly regulated in cells in order to adapt the metabolism of the cell to challenges of nutrient availability and stress stimuli. At least 10 proteins have been shown to be required for CoQ biosynthesis in a multi-peptide complex and COQ7 is a central regulatory factor of this pathway. We found that the first 765 bp of the 3\'-untranslated region (UTR) of COQ7 mRNA contains cis-acting elements of interaction with RNA-binding proteins (RBPs) HuR and hnRNP C1/C2. Binding of hnRNP C1/C2 to COQ7 mRNA was found to require the presence of HuR, and hnRNP C1/C2 silencing appeared to stabilize COQ7 mRNA modestly. By contrast, lowering HuR levels by silencing or depriving cells of serum destabilized and reduced the half-life of COQ7 mRNA, thereby reducing COQ7 protein and CoQ biosynthesis rate. Accordingly, HuR knockdown decreased oxygen consumption rate and mitochondrial production of ATP, and increased lactate levels. Taken together, our results indicate that a reduction in COQ7 mRNA levels by HuR depletion causes mitochondrial dysfunction and a switch toward an enhanced aerobic glycolysis, the characteristic phenotype exhibited by primary deficiency of CoQ10. Thus HuR contributes to efficient oxidative phosphorylation by regulating of CoQ10 biosynthesis.