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

A novel homozygous COQ2 variant (c.1039 A>G; p.Ser347Gly) was identified in one proband with primary CoQ10 deficiency.

• The variant was identified using whole-exome sequencing.
• Variant segregation was confirmed by Sanger sequencing.
• In silico protein modelling predicted deleterious structural effects of the variant.
• The variant is described as a novel recessive variant expanding the genetic spectrum of COQ10 deficiencies.

A second proband harbored novel compound heterozygous COQ4 variants (c.238 C>T; p.Arg80Cys and c.380del; p.Tyr127PhefsTer7).

• Both variants were identified using whole-exome sequencing.
• Variant segregation was confirmed by Sanger sequencing.
• In silico protein modelling predicted deleterious structural effects.
• These variants represent novel additions to the genetic spectrum of COQ10 deficiencies.

The COQ2 proband showed increased proton leak and reduced ATP-linked respiration, indicating uncoupled oxidative phosphorylation.

• Mitochondrial function was assessed in freshly isolated platelets using high-resolution respirometry.
• Participants included probands, family members, and healthy controls.
• The findings indicate uncoupled oxidative phosphorylation in the COQ2 proband.
• The COQ2 proband was assessed prior to CoQ10 supplementation.

The COQ4 proband, who was already receiving CoQ10 supplementation at the time of assessment, showed near-normal mitochondrial function.

• Mitochondrial function was assessed using high-resolution respirometry in freshly isolated platelets.
• The proband was already on CoQ10 therapy prior to enrollment in the study.
• Near-normal mitochondrial respiration was observed in this treated individual.
• This finding is consistent with therapeutic benefit of CoQ10 in COQ4-related deficiency.

Three months of CoQ10 supplementation in the COQ2 proband produced significant improvement in ATP synthesis and reduced proton leak.

• The supplementation period was three months.
• Improvements were observed in ATP-linked respiration and reduction of proton leak.
• Clinical neurological improvement accompanied the biochemical changes.
• The results provide functional evidence that defective mitochondrial function is 'at least in part, reversible with targeted CoQ10 therapy.'

CoQ10 supplementation in healthy individuals did not alter mitochondrial respiration, confirming specificity of therapeutic benefit to COQ10 deficiency patients.

• Healthy control individuals received CoQ10 supplementation and were assessed by high-resolution respirometry.
• No change in mitochondrial respiration parameters was observed in healthy individuals.
• This finding confirms that observed improvements in probands were disease-specific rather than a general effect of CoQ10.
• The authors describe this as confirming 'the specificity of therapeutic benefit in COQ10Ds.'

mRNA expression analysis revealed feedback regulation of CoQ10 biosynthesis genes, while protein levels of electron transport chain complexes I–V remained unchanged following CoQ10 supplementation.

• mRNA expression analysis was performed alongside respirometry assessments.
• Protein levels of ETC complexes I through V were evaluated and found to be unchanged.
• Feedback regulation at the mRNA level was identified as a mechanistic feature of the response to CoQ10 supplementation.
• The unchanged ETC complex protein levels suggest that functional improvements occurred independently of changes in complex protein abundance.

Primary CoQ10 deficiencies present with heterogeneous neurological phenotypes and are caused by pathogenic variants in genes involved in CoQ10 biosynthesis.

• COQ10 deficiencies are described as 'rare mitochondrial disorders.'
• The disorders lead to impaired mitochondrial respiration.
• Neurological phenotypes are described as heterogeneous.
• The study identified variants in two different biosynthesis genes (COQ2 and COQ4), illustrating genetic heterogeneity.