Mice with duplications and deletions at the Tme locus have altered MnSOD activity.
Superoxide radicals that result from normal cellular metabolism have been implicated as a cause of multiple age-related degenerative diseases (Halliwell, B., and Gutteridge, J. M. (1990) Methods Enzymol. 186, 1-85; Harman, D. (1988) Mol. Cell. Biochem. 84, 155-161; Ames, B. N., Shigenaga, M. K., and Hagen, T. M. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 7915-7922). Manganese superoxide dismutase (MnSOD) is thought to be the sole enzymic scavenger of superoxide in mammalian mitochondria. We have investigated MnSOD activity and gene dose in mice with deletions and a duplication of the Tme (t-associated maternal effect) locus on chromosome 17. We find that MnSOD activity is significantly correlated with gene dose in these animals; animals with heterozygous deletions of Tme have 50% of normal activity, and animals with a heterozygous duplication of Tme have 150% of normal activity. These ratios of activity appear to be systemic, as they were observed in brain, heart, skeletal muscle and liver. The results support the model that basal MnSOD activity is regulated solely by cis elements, in that variation in MnSOD activity caused by altered gene dose on one chromosome is not compensated by gene activity on the other. Since gene knockouts of MnSOD have not yet been generated, the tlub2 and Thp animals may become useful models for those studying the role of mitochondrial superoxide in pathophysiological processes. A model for the maternal-lethal effect of Tme deletions is proposed.
Wang
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Department of Molecular Pharmacology and Toxicology, University of Southern California, Los Angeles 90033.
Cortopassi
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D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000201:enzymology; D002874:Chromosome Mapping; D017931:DNA Primers; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D006579:Heterozygote; D008099:Liver / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains / Q000235:genetics*; D008969:Molecular Sequence Data; D005810:Multigene Family; D009132:Muscles / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology; D016133:Polymerase Chain Reaction / Q000379:methods; D013045:Species Specificity; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism*
D017931:DNA Primers; D013482:Superoxide Dismutase