Coenzyme Q10 supplementation restores mitochondrial respiration in patients with primary CoQ10 deficiency caused by novel COQ2 and COQ4 variants.

Primary coenzyme Q10 deficiencies (COQ10D) are rare mitochondrial disorders caused by pathogenic variants in genes involved in coenzyme Q10 (CoQ10) biosynthesis, leading to impaired mitochondrial respiration and heterogeneous neurological phenotypes. In this study, we identified and functionally characterized novel recessive variants in COQ2 and COQ4 using whole-exome sequencing. One proband carried a homozygous COQ2 variant (c.1039 A > G; p.Ser347Gly), while the second harbored compound heterozygous COQ4 variants (c.238 C > T; p.Arg80Cys and c.380del; p.Tyr127PhefsTer7). Variant segregation was confirmed by Sanger sequencing, and in silico protein modelling predicted deleterious structural effects. Mitochondrial function was assessed in freshly isolated platelets from probands, family members, and healthy controls using high-resolution respirometry. The COQ2 proband showed increased proton leak and reduced ATP-linked respiration, indicating uncoupled oxidative phosphorylation, whereas the COQ4 proband, already receiving CoQ10, showed near-normal mitochondrial function. Following three months of CoQ10 supplementation, the COQ2 proband showed significant improvement in ATP synthesis and reduced proton leak, accompanied by clinical neurological improvement. mRNA expression analysis revealed feedback regulation, while protein levels of ETC complexes I-V remained unchanged. Importantly, CoQ10 supplementation in healthy individuals did not alter mitochondrial respiration, confirming the specificity of therapeutic benefit in COQ10Ds. Overall, in addition to expanding the genetic spectrum of COQ10Ds, this study also provides functional evidence that defective mitochondrial function in these conditions is, at least in part, reversible with targeted CoQ10 therapy, underscoring the importance of early genetic diagnosis and timely initiation of CoQ10 supplementation.