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

Ting-Ting Huang1, Mohammed Naeemuddin, Sailaja Elchuri

  • 1Department of Neurology and Neurological Sciences, Stanford University, CA 94305, USA. tthuang@stanford.edu

Human Molecular Genetics
|February 25, 2006
PubMed

Insights

Genetic background significantly impacts survival in mice lacking mitochondrial superoxide dismutase (MnSOD). A specific QTL on chromosome 13, containing the nicotinamide nucleotide transhydrogenase (Nnt) gene, was identified as a key longevity modifier.

Area of Science:

  • Mitochondrial biology
  • Genetics
  • Aging research

Background:

  • Mice deficient in mitochondrial superoxide dismutase (Sod2-/-) exhibit reduced lifespan, influenced by genetic background.
  • This suggests genetic modifiers regulate oxidative stress and longevity in MnSOD-deficient states.

Purpose of the Study:

  • To identify genetic modifiers influencing survival in MnSOD-deficient mice.
  • To investigate the role of specific quantitative trait loci (QTL) in modulating mitochondrial oxidative damage and lifespan.

Main Methods:

  • Generation of recombinant congenic mice carrying QTLs from DBA/2J on a C57BL/6J background.
  • Analysis of survival rates in MnSOD-deficient mice with specific QTLs.
  • Investigating gene function within identified QTL regions, focusing on nicotinamide nucleotide transhydrogenase (Nnt).

Main Results:

  • MnSOD-deficient mice with a QTL from chromosome 13 of DBA/2J origin showed significantly extended survival, comparable to long-lived DBA/2J backgrounds.
  • The nicotinamide nucleotide transhydrogenase (Nnt) gene was found to be defective in the short-lived C57BL/6J strain, with no detectable mature NNT protein.
  • NNT's role in generating NADPH, essential for mitochondrial antioxidant regeneration, was highlighted.

Conclusions:

  • A QTL on chromosome 13, containing the Nnt gene, acts as a major genetic modifier of longevity in MnSOD-deficient mice.
  • Deficiency in NNT contributes to increased mitochondrial oxidative damage and reduced lifespan in C57BL/6J mice.
  • NNT's antioxidant-supporting function is crucial for survival under conditions of MnSOD deficiency.

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