Nature Genetics
11, 376 - 381 (1995)
doi:10.1038/ng1295-376
Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutaseYibing Li1, *, Ting-Ting Huang2, *, Elaine J. Carlson2, Simon Melov5, Philip C. Ursell3, Jean L. Olson3, Linda J. Noble1, Midori P. Yoshimura3, Christoph Berger2, 6, Pak H. Chan1, 4, Douglas C. Wallace5
& Charles J. Epstein2
1Department of Neurosurgery, Box 0748, 533 Parnassus, U585L, University of California, San Francisco, California 94143-0748, USA
2Department of Pediatrics, Box 0748, 533 Parnassus, U585L, University of California, San Francisco, California 94143-0748, USA
3Department of Pathology, Box 0748, 533 Parnassus, U585L, University of California, San Francisco, California 94143-0748, USA
4Department of Neurology, Box 0748, 533 Parnassus, U585L, University of California, San Francisco, California 94143-0748, USA
5Department of Genetics and Molecular Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA
*Y.L. & T.T.H. contributed equally to this work.
6Present address: Children's Medical Research Institute, Wentworthville, NSW 2145, Australia. Correspondence should be addressed to C.J.E. The Sod2 gene for Mn−superoxide dismutase (MnSOD), an intramitochondrial free radical scavenging enzyme that is the first line of defense against superoxide produced as a byproduct of oxidative phosphorylation, was inactivated by homologous recombination. Homozygous mutant mice die within the first 10 days of life with a dilated cardiomyopathy, accumulation of lipid in liver and skeletal muscle, and metabolic acidosis. Cytochemical analysis revealed a severe reduction in succinate dehydrogenase (complex II) and aconitase (a TCA cycle enzyme) activities in the heart and, to a lesser extent, in other organs. These findings indicate that MnSOD is required for normal biological function of tissues by maintaining the integrity of mitochondrial enzymes susceptible to direct inactivation by superoxide.
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