MITOCHONDRIAL COMPLEX-I DEFICIENCY LEADS TO INCREASED PRODUCTION OF SUPEROXIDE RADICALS AND INDUCTION OF SUPEROXIDE-DISMUTASE

Mitochondria were isolated from skin fibroblast cultures derived from healthy individuals (controls) and from a group patients with complex I(NADH-CoQ reductase) deficiency of the mitochondrial respiratory chai n. The complex I deficient patients included those with fatal infantil e lactic acidosis (FILA), cardiomyopathy with cataracts (CC), hepatopa thy with tubulopathy (HT), Leigh's disease (LD), cataracts and develop mental delay (CD), and lactic acidemia in the neonatal period followed by mild symptoms (MS). Production of superoxide radicals, on addition of NADH, were measured using the luminometric probe lucigenin with is olated fibroblast mitochondrial membranes. Superoxide production rates were highest with CD and decreased in the order CD much greater than MS > LD > control > HT > FILA = CC. The quantity of Mn-superoxide dism utase (MnSOD), as measured by ELISA techniques, however, was highest i n CC and FILA and lowest in CD. Plots of MnSOD quantity versus superox ide production showed an inverse relationship for most conditions with complex I deficiency. We hypothesize that oxygen radical production i s increased when complex I activity is compromised. However, the obser ved superoxide production rates are modulated by the variant induction of MnSOD which decreases the rates, sometimes below those seen in con trol fibroblast mitochondria. In turn, we show that the variant induct ion of MnSOD is most likely a function of the change in the redox stat e of the cell experienced rather than a result of the complex I defect per se.