Oxidative damage in the retinal mitochondria of diabetic mice: Possible protection by superoxide dismutase

PURPOSE. Superoxide levels are elevated in the retina in patients with diabetes, and cytochrome c is released from the mitochondria. The purpose of this study was to elucidate the mechanism involved in the oxidative damage of retinal mitochondria in diabetes and to determine whether mitochondrial superoxide dismutase (MnSOD) provides protection. METHODS. Effects of diabetes were investigated on superoxide and GSH levels, electron transport complexes I and III, and membrane permeability in the isolated mitochondria prepared from the retinas of streptozotocin diabetic mice. To investigate the effect of MnSOD, retinal mitochondrial oxidative stress and electron transport complexes were determined in mice over-expressing MnSOD (MnSOD-Tg). Histopathology was evaluated in trypsin-digested retina. RESULTS. Retinal mitochondria had twofold increase in superoxide levels in nontransgenic (wild-type [WT]) diabetic mice compared with WT nondiabetic mice. In the same retina, diabetes decreased mitochondrial GSH levels by 40% and complex III activity by approximately 20%, and it increased mitochondrial membrane permeability ( swelling) by more than twofold; however, complex I activity was not affected. Overexpression of MnSOD inhibited diabetes-induced increases in mitochondrial superoxide levels and membrane permeability and the decrease in complex III activity. GSH values, however, were not statistically different in WT and MnSOD-Tg diabetic mice. In contrast to the diabetes-induced increase in the number of degenerate ( acellular) capillaries in WT diabetic mice, the numbers of acellular capillaries in MnSOD-Tg nondiabetic and diabetic mice were similar to those in WT nondiabetic mice. CONCLUSIONS. Retinal mitochondria experience increased oxidative damage in diabetes, and complex III is one of the sources of increased superoxide. MnSOD protects the retina from diabetes-induced abnormalities in the mitochondria and prevents vascular histopathology, strongly implicating the role for MnSOD in the pathogenesis of retinopathy in diabetes.