Genetic modifiers of the phenotype of mice deficient in mitochondrial superoxide dismutase

Hum Mol Genet. 2006 Apr 1;15(7):1187-94. doi: 10.1093/hmg/ddl034. Epub 2006 Feb 23.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alleles
  • Animals
  • Cell Nucleus / metabolism
  • Female
  • Linkage Disequilibrium
  • Male
  • Mice
  • Mice, Congenic / genetics
  • Mice, Congenic / metabolism
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Inbred Strains
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Models, Biological
  • Models, Genetic
  • Mutation
  • NADP Transhydrogenases / genetics
  • NADP Transhydrogenases / metabolism
  • Phenotype*
  • Quantitative Trait Loci
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase / metabolism

Substances

  • Superoxide Dismutase
  • NADP Transhydrogenases