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Mice with duplications and deletions at the Tme locus have altered MnSOD activity
1Department of Molecular Pharmacology and Toxicology, University of Southern California, Los Angeles 90033.
Abstract:
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.
Insights
Manganese superoxide dismutase (MnSOD) activity in mice directly correlates with gene dose. Altered gene copy numbers at the Tme locus result in proportional changes in MnSOD levels, supporting cis-element regulation.
Area of Science:
- Biochemistry
- Genetics
- Mitochondrial Biology
Background:
- Superoxide radicals from metabolism contribute to age-related diseases.
- Manganese superoxide dismutase (MnSOD) is the primary mitochondrial scavenger of superoxide.
- The Tme locus on chromosome 17 influences MnSOD activity.
Purpose of the Study:
- To investigate the relationship between MnSOD activity and gene dose.
- To determine if MnSOD regulation is influenced by cis-acting elements.
Main Methods:
- Studied MnSOD activity in mice with chromosomal deletions and duplications at the Tme locus.
- Measured MnSOD activity across various tissues including brain, heart, skeletal muscle, and liver.
Main Results:
- MnSOD activity showed a direct correlation with the gene dose of the Tme locus.
- Heterozygous deletions resulted in 50% of normal MnSOD activity.
- Heterozygous duplications resulted in 150% of normal MnSOD activity.
- These activity ratios were consistent across all tested tissues.
Conclusions:
- Basal MnSOD activity is regulated by cis elements.
- Gene dosage at the Tme locus directly impacts systemic MnSOD activity.
- Mice with altered Tme gene doses serve as potential models for studying mitochondrial superoxide's role in disease.