Human Molecular Genetics Advance Access published online on February 23, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl034
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1 Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, UAS; GRECC, Palo Alto VA Health Care System, 3801 Miranda Ave. Mail Stop 154-I Palo Alto, CA 94304, USA
* To whom correspondence should be addressed. Sod2 -/- mice, which are deficient in the mitochondrial form of superoxide dismutase (MnSOD), have a short survival time that is strongly affected by genetic background. This suggests the existence of genetic modifiers that are capable of modulating the degree of mitochondrial oxidative damage caused by the MnSOD deficiency, thereby altering longevity. To identify these modifier(s), we generated recombinant congenic mice with quantitative trait loci (QTL) containing the putative genetic modifiers on the short-lived C57BL/6J genetic background. MnSOD deficient C57BL/6J mice with a QTL from the distal region of chromosome 13 from DBA/2J were able to survive for as long as those generated on the long-lived DBA/2J background. Within this region, the gene encoding nicotinamide nucleotide transhydrogenase (Nnt) was found to be defective in C57BL/6J mice, and no mature NNT protein could be detected. The forward reaction of NNT, a nuclear-encoded mitochondrial inner membrane protein, couples the generation of NADPH to proton transport and provides NADPH for the regeneration of two important antioxidant compounds, glutathione and thioredoxin, in the mitochondria. This action of NNT could explain its putative protective role in MnSOD-deficient mice.
Received January 5, 2006
Revised February 15, 2006
Accepted February 15, 2006
Article
Genetic modifiers of the phenotype of mice deficient in mitochondrial superoxide dismutase
Ting-Ting Huang 1 *,
Mohammed Naeemuddin 2,
Sailaja Elchuri 2,
Mutsuo Yamaguchi 3,
Heather M. Kozy 4,
Elaine J. Carlson 4,
and
Charles J. Epstein 4
2 Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, UAS
3 Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
4 Department of Pediatrics, University of California, San Francisco, CA 94143, USA
Ting-Ting Huang, E-mail: tthuang{at}stanford.edu
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