Manganese superoxide dismutase protects mitochondrial complex I against adriamycin-induced cardiomyopathy in transgenic mice

Adriamycin (ADR) is a potent anticancer drug that causes severe cardiomyopa thy, We have previously demonstrated that ADR-induced ultrastructural mitoc hondrial injury in the heart was attenuated in manganese superoxide dismuta se (MnSOD) transgenic mice. To further investigate the biochemical mechanis ms by which MnSOD protected mitochondria against ADR-induced damage, cardia c mitochondrial function and activities were evaluated, The results showed that ADR caused significant decrease in state 3 respiration and respiratory control ratio using both complex I and II substrates in nontransgenic mice . In transgenic mice, state 3 respiration for complex I substrates remained unaffected by ADR, but was reduced for complex II substrate. Complex I act ivity was significantly decreased in nontransgenic, but not in transgenic m ice after ADR treatment, suggesting that mitochondrial complex I is sensiti ve to inactivation by superoxide radicals. The activities of complex II and mitochondrial creatine kinase were decreased by ADR in both nontransgenic and transgenic mice. These results support our previous observations on the protective role of MnSOD on the ultrastructural damage of the heart after ADR treatment and extend the understanding of its mechanisms in mitochondri a. (C) 1999 Academic Press.