Respiratory chain dysfunction and oxidative stress correlate with severity of primary CoQ10 deficiency

Coenzyme Q10 (CoQ10) is essential for electron transport in the mitochondrial respiratory chain and antioxidant defense. Last year, we re ported the first mutations in CoQ10 biosynthetic genes, COQ2, which encodes 4‐parahydroxybenzoate: polyprenyl transferase;and PDSS2, which encodes subunit 2 of decaprenyl diphosphate synthase. How ever, the pathogenic mechanisms of primary CoQ10deficiency have not been well characterized. In this study, we investigated the consequence of severe CoQ10 deficiency on bioenergetics, oxidative stress, and antioxidant defenses in cultured skin fibroblasts harboring COQ2 and PDSS2 mutations. Defects in the first two committed steps of the CoQ10 biosynthetic pathway produce different biochemical alterations. PDSS2 mutant fibroblasts have 12% CoQ10 relative to control cells and markedly reduced ATP synthesis, but do not show increased reactive oxygen species (ROS) production, signs of oxidative stress, or in creased antioxidant defense markers. In contrast, COQ2 mutant fibroblasts have 30% CoQ10 with par tial defect in ATP synthesis, as well as significantly increased ROS production and oxidation of lipids and proteins. On the basis of a small number of cell lines, our results suggest that primary CoQ10 defi ciencies cause variable defects of ATP synthesis and oxidative stress, which may explain the different clinical features and may lead to more rational therapeutic strategies.— Quinzii, C. M., López, L. C., Von‐Moltke, J., Naini, A., Krishna, S., Schuelke, M., Salviati, L., Navas, P., DiMauro, S., Hirano, M. Respiratory chain dysfunction and oxidative stress correlate with severity of primary CoQ10 deficiency. FASEB J. 22, 1874–1885 (2008)