12 páginas, 8 figuras, 2 tablas.

Coenzyme Q10 (CoQ10) is essential for electron transport in the mitochondrial respiratory chain and antioxidant defense. Last year, we reported the first mutations in CoQ10 biosynthetic genes, COQ2, which encodes 4-parahydroxybenzoate: polyprenyl transferase; and PDSS2, which encodes subunit 2 of decaprenyl diphosphate synthase. However, the pathogenic mechanisms of primary CoQ10 deficiency 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 increased antioxidant defense markers. In contrast, COQ2 mutant fibroblasts have 30% CoQ10 with partial 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 deficiencies 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.

This work was supported by U.S. National Institutes of Health (NIH) grants NS-11766 and HD-32062, by grants from the Muscular Dystrophy Association, and by the Marriott Mitochondrial Disorder Clinical Research Fund. L.C.L. is a postdoctoral fellow of the Ministerio de Educacion y Ciencia, Spain. C.M.Q. is supported by the Muscular Dystrophy Association.