Modelling the effects of age-related mtDNA mutation accumulation; complex I deficiency, superoxide and cell death.
Deleterious mitochondrial mutations accumulate during normal human aging in postmitotic tissues. How these mutations affect aging cells is currently unknown. This issue has been addressed in two ways. The first is to determine the likeliest effect of random mutations in the mitochondrial genome, and of the 4977 bp deletion and MELAS point mutation that rise in frequency with age. The results indicate that Complex I is statistically much more likely to be affected than any other product of the mitochondrial genome. We have also attempted to model Complex I deficiency in animals with the drug MPTP, a specific inhibitor of Complex I. We find that MPTP causes massive damage in brains of mice with a genetic deficiency in the mitochondrial superoxide dismutase, MnSOD, but less in mice that overexpress the enzyme. We conclude from these data that MPTP-induced cell death must be mediated through an increase in the steady-state concentration of superoxide anion in mitochondria. Since the likeliest target of mitochondrial mutation is Complex I, deficiency of which causes MnSOD-inhibitable lethality, we propose that rising mtDNA mutations with age will cause an increase in superoxide-mediated cell death. Such a mechanism for age-related cell death has the potential to explain several age-related phenotypes.
Cortopassi
G
G
Department of Molecular Pharmacology and Toxicology, University of Southern California, Los Angeles 90033, USA.
Wang
E
E
D000375:Aging / Q000235:genetics*; D000818:Animals; D016923:Cell Death; D004272:DNA, Mitochondrial / Q000235:genetics*; D016678:Genome; D006801:Humans; D017241:MELAS Syndrome / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D009154:Mutation; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000172:deficiency* / Q000235:genetics*; D017354:Point Mutation; D013481:Superoxides / Q000378:metabolism*
D004272:DNA, Mitochondrial; D013481:Superoxides; D016660:NAD(P)H Dehydrogenase (Quinone)