Genetic modifiers of the phenotype of mice deficient in mitochondrial superoxide dismutase.
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.
Department of Neurology and Neurological Sciences, Stanford University, CA 94305, USA. tthuang@stanford.edu
Ting-Ting
TT
Huang
Mohammed
M
Naeemuddin
Sailaja
S
Elchuri
Mutsuo
M
Yamaguchi
Heather M
HM
Kozy
Elaine J
EJ
Carlson
Charles J
CJ
Epstein
D000483:Alleles; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D005260:Female; D015810:Linkage Disequilibrium; D008297:Male; D051379:Mice; D020297:Mice, Congenic / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D009250:NADP Transhydrogenases / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D040641:Quantitative Trait Loci; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism
D013482:Superoxide Dismutase; D009250:NADP Transhydrogenases