Respiratory chain dysfunction and oxidative stress correlate with severity of primary CoQ ₁₀ deficiency

Abstract

Coenzyme Q(10) (CoQ(10)) is essential for electron transport in the mitochondrial respiratory chain and antioxidant defense. Last year, we reported the first mutations in CoQ(10) 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 CoQ(10) deficiency have not been well characterized. In this study, we investigated the consequence of severe CoQ(10) 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 CoQ(10) biosynthetic pathway produce different biochemical alterations. PDSS2 mutant fibroblasts have 12% CoQ(10) 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% CoQ(10) 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 CoQ(10) 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.

COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness

“…of COQ6 mutations is remarkably similar to that of mutations in COQ2 (23) and PDSS2 in humans (34) and Pdss2 in mice (24), all of which respond to CoQ 10 treatment (12,35). Patients with defects in genes required for CoQ 10 biosynthesis - PDSS2, COQ2, and COQ9 - exhibit renal disease, and in some cases there is a dramatic response to CoQ 10 therapy, but this is quite variable (36).…”

Omental adipocyte hypertrophy relates to coenzyme Q10 redox state and lipid peroxidation in obese women

“…We observed a specifi c and signifi cant reduction of the CoQ10 ox content in overweight and obese volunteers, without any variation of CoQ10 red levels or redox state. However, this decrease in CoQ10 ox levels was not patients harboring COQ2 and PDSS2 mutations displayed defects in ATP synthesis and oxidative damage ( 24 ). Otherwise, the CoQ10 red in other cellular membranes displayed antioxidant effects.…”

The submitochondrial distribution of ubiquinone affects respiration in long-livedMclk1+/2mice

“…In these fibroblasts, UQ deficiency is also linked to a partial defect in electron transport and ATP synthesis, as well as significantly increased ROS production and oxidation of lipids and proteins (López-Martin et al, 2007;Quinzii et al, 2008Quinzii et al, , 2010.…”