Endothelial dysfunction and increased oxidative stress in mitochondrial diseases.

MDs (mitochondrial diseases) are a clinically heterogeneous group of disorders characterized by impairment of the respiratory chain function with altered oxidative phosphorylation. We tested the hypothesis that the function of vascular endothelium is affected by increased oxidative stress in MDs. A total of 12 patients with MDs and pair-matched controls were studied. Endothelial function was assessed by measuring FMD (flow-mediated vasodilation) of brachial and common femoral arteries. The test was repeated after vitamin C (500 mg, twice a day) and E (400 mg, once a day) supplementation for 30 days and 90 days after vitamin withdrawal. FMD was reduced in patients compared with controls [AUC/τ (time-averaged area under the curve) for the brachial artery, 1.05±0.24 compared with 4.19±0.59% respectively, P<0.001; AUC/τ for the femoral artery, 0.98±0.19 compared with 2.36±0.29% respectively, P=0.001; values are means±S.E.M.] and correlated (brachial artery) with plasma lactate (r=-0.63, P<0.01). Urinary 8-iso-PGF2α (8-iso-prostaglandin F2α) was higher in patients than controls (505.6±85.9 compared with 302.5±38.7 pg/mg of creatinine; P<0.05) and correlated with plasma lactate (r=0.70, P<0.05). Immunohistochemical analysis showed 8-iso-PGF2α staining in MD-affected striated muscle cells and in blood vessels in muscle biopsies of patients. Antioxidant vitamins transiently restored FMD in patients [ΔAUC/τ (change in AUC/τ) for the brachial artery, +1.38±0.49%, P<0.05; ΔAUC/τ for the femoral artery, +0.98±0.24%, P<0.01] but had no effect on FMD in controls (brachial artery, -1.3±0.63%; and common femoral artery, -0.58±0.30%), thus abolishing the differences between patients and controls. The results of the present study indicate that oxidative stress is increased and is, at least partly, responsible for endothelial dysfunction in MDs.

Coenzyme Q10 is frequently reduced in muscle of patients with mitochondrial myopathy.

Coenzyme Q(10) (CoQ(10)) deficiency has been associated with an increasing number of clinical phenotypes. Whereas primary CoQ(10) defects are related to mutations in ubiquinone biosynthetic genes, which are now being unraveled, and respond well to CoQ(10) supplementation, the etiologies, and clinical phenotypes related to secondary deficiencies are largely unknown. The purpose of this multicenter study was to evaluate the frequency of muscle CoQ(10) deficiency in a cohort of 76 patients presenting with clinically heterogeneous mitochondrial phenotypes which included myopathy among their clinical features. A reliable diagnostic tool based on HPLC quantification was employed to measure muscle CoQ(10) levels. A significant proportion of these patients (28 over 76) displayed CoQ(10) deficiency that was clearly secondary in nine patients, who harbored a pathogenic mutation of mitochondrial DNA. This study provides a rationale for future therapeutic trials on the effect of CoQ(10) supplementation in patients with mitochondrial diseases presenting with myopathy among clinical features.