DILATED CARDIOMYOPATHY AND NEONATAL LETHALITY IN MUTANT MICE LACKING MANGANESE SUPEROXIDE-DISMUTASE

The Sod2 gene for Mn-superoxide dismutase (MnSOD), an intramitochondri al free radical scavenging enzyme that is the first line of defense ag ainst superoxide produced as a byproduct of oxidative phosphorylation, was inactivated by homologous recombination. Homozygous mutant mice d ie within the first 10 days of life with a dilated cardiomyopathy, acc umulation of lipid in liver and skeletal muscle, and metabolic acidosi s. Cytochemical analysis revealed a severe reduction in succinate dehy drogenase (complex II) and aconitase (a TCA cycle enzyme) activities i n the heart and, to a lesser extent, in other organs. These findings i ndicate that MnSOD is required for normal biological function of tissu es by maintaining the integrity of mitochondrial enzymes susceptible t o direct inactivation by superoxide.