Overexpression of copper/zinc superoxide dismutase does not prevent neonatal lethality in mutant mice that lack manganese superoxide dismutase

There are two types of intracellular superoxide dismutases: the mitochondri al manganese SOD (MnSOD) and the cytoplasmic copper/zinc SOD (CuZnSOD). Mut ant mice that lack MnSOD die shortly after birth because of cardiomyopathy and mitochondrial injury. In order to verify if CuZnSOD could compensate fo r MnSOD deficiency, a new mutant mouse that overexpresses CuZnSOD but is de ficient in MnSOD was generated by crossing MnSOD knockout mice with CuZnSOD transgenic mice. CuZnSOD activity was significantly increased in the blood brain, liver, and heart of MnSOD knockout, CuZnSOD transgenic mice when co mpared with nontransgenic mice. However, overexpression of CuZnSOD did not prevent neonatal lethality in mice that lack MnSOD, nor did it prevent oxid ative aconitase inactivation, nor did it rescue MnSOD-deficient astrocytes in culture. Based on our findings, which emphasize the strong enzymatic com partmentalization of CuZnSOD and MnSOD, therapeutic antioxidant strategies should consider the final intracellular localization of the antioxidant use d, especially when those strategies are directed against mitochondrial dise ases. (C) 2000 Elsevier Science Inc.