EXCESSIVE FORMATION OF HYDROXYL RADICALS AND ALDEHYDIC LIPID-PEROXIDATION PRODUCTS IN CULTURED SKIN FIBROBLASTS FROM PATIENTS WITH COMPLEX-I DEFICIENCY

Previous studies suggest oxygen free radicals' involvement in the etio logy of cardiomyopathy with cataracts. To investigate the role of free radicals in the pathogenesis of the cardiomyopathy with cataracts and complex I deficiency, fibroblasts from patients were assessed for hyd roxyl radical formation and aldehydic lipid peroxidation products with and without redox active agents that increase free radicals. The rate of hydroxyl radical formation in patient cells was increased over 2-1 0-fold under basal conditions, and up to 20-fold after menadione or do xorubicin treatment compared with normal cells. We also found an overp roduction of aldehydes in patient cells both under basal conditions an d after treatment. Both hydroxyl radicals and toxic aldehydes such as hexanal, 4-hydroxynon-2-enal, and malondialdehyde were elevated in cel ls from patients with three types of complex I deficiency. In contrast , acyloins, the less toxic conjugated products of pyruvate and saturat ed aldehydes, were lower in the patient cells. Our data provide direct evidence for the first time that complex I deficiency is associated w ith excessive production of hydroxyl radicals and lipid peroxidation. The resultant damage may contribute to the early onset of cardiomyopat hy and cataracts and death in early infancy in affected patients with this disease.