Decreased complex II respiration and HNE-modified SDH subunit in diabetic heart

Several lines of research suggest that mitochondria play a role in the etiopathogenesis of diabetic cardiomyopathy, although the mechanisms involved are still debated. In the present study, we report that State 3 oxygen consumption decreases by similar to 35% with glutamate and by similar to 30% with succinate in mitochondria from diabetic rat hearts compared to controls. In these mitochondria the enzymatic activities of complex 1 and complex If are also decreased to a comparable extent. Western blot analysis of mitochondrial protein pattern using antibodies recognizing proteins modified by the lipid peroxidation product 4-hydroxynonenal indicates the EAD-containing subunit of succinate dehydrogenase as one of the targets of this highly reactive aldehyde. In rats diabetic for 6 or 12 weeks, insulin supplementation for 2 weeks decreases the level of protein modified by 4-hydroxynonenal and restores mitochondrial respiration and enzyme activity to control level. Taken together, these results: (1) indicate that 4-hydroxynonenal is endogenously produced within diabetic mitochondria and forms an adduct with selective mitochondrial proteins, (2) identify one of these proteins as a subunit of succinate dehydrogenase, and (3) provide strong evidence that insulin treatment can reverse and ameliorate free radical damage and mitochondrial function under diabetic conditions. (c) 2005 Elsevier Inc. All rights reserved.