The treatment of primary CoQ deficiency requires the targeting of multiple pathogenic mechanisms.

BACKGROUND: Primary coenzyme Q (CoQ) deficiency is a severe mitochondrial disorder characterized by diverse clinical manifestations due to multiple pathomechanisms. Although CoQ(10) supplementation remains the standard treatment, its therapeutic efficacy is limited by poor bioavailability and restricted tissue distribution, especially to the central nervous system. METHODS: In this study, we investigated the therapeutic potential of combining CoQ(10) with vanillic acid (VA), a structural analog of 4-hydroxybenzoic acid, in both murine and human models of primary CoQ deficiency, through phenotypic, biochemical, and molecular analyses. RESULTS: In Coq9(R239X) mice, we demonstrate that co-administration of CoQ(10) and VA significantly extends lifespan and improves motor function beyond the effects observed with either compound alone. Mechanistically, this enhanced therapeutic efficacy results from the complementary actions of both compounds, i.e., CoQ(10) increases quinone pools in peripheral tissues and modulates one-carbon metabolism, particularly in the liver, while VA reduces DMQ accumulation in the kidney and liver and exhibits potent anti-neuroinflammatory properties, leading to a reduction in gliosis. The co-treatment shows remarkable tissue-specific responses, with the liver displaying the most pronounced metabolic adaptations. In this tissue, the combined therapy restores the expression of genes involved in sulfide oxidation and one-carbon metabolism pathways. We further validate these findings in human COQ7-deficient fibroblasts, where the co-treatment normalizes key metabolic pathways more effectively than individual treatments. CONCLUSIONS: Our findings demonstrate that combining CoQ(10) with VA effectively addresses multiple pathogenic mechanisms in CoQ deficiency, resulting in enhanced therapeutic outcomes. This therapeutic strategy could represent a more effective and feasible treatment approach for mitochondrial disorders, particularly those involving CoQ deficiency and neurological manifestations.