Mitochondrial point mutations do not limit the natural lifespan of mice

University of Washington Seattle, Seattle, Washington, United States
Nature Genetics (Impact Factor: 29.35). 05/2007; 39(4):540-3. DOI: 10.1038/ng1988
Source: PubMed


Whether mitochondrial mutations cause mammalian aging, or are merely correlated with it, is an area of intense debate. Here, we use a new, highly sensitive assay to redefine the relationship between mitochondrial mutations and age. We measured the in vivo rate of change of the mitochondrial genome at a single-base pair level in mice, and we demonstrate that the mutation frequency in mouse mitochondria is more than ten times lower than previously reported. Although we observed an 11-fold increase in mitochondrial point mutations with age, we report that a mitochondrial mutator mouse was able to sustain a 500-fold higher mutation burden than normal mice, without any obvious features of rapidly accelerated aging. Thus, our results strongly indicate that mitochondrial mutations do not limit the lifespan of wild-type mice.


Available from: Warren C Ladiges, Mar 17, 2014
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    • "Accumulation of mitochondrial mutations has been linked to individual lifespan (Feng et al. 2001; Trifunovic et al. 2004; Yang et al. 2013), though not consistently (Speakman et al. 2004; Vermulst et al. 2007; Joyner-Matos et al. 2011). The causal links between metabolism, mitochondrial mutation, and individual ageing are a matter of debate (e.g., Martin et al. 1992; Partridge 2001; Jacobs 2003; Loeb et al. 2005). "
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    ABSTRACT: The mitochondrial theory of ageing proposes that the cumulative effect of biochemical damage in mitochondria causes mitochondrial mutations and plays a key role in ageing. Numerous studies have applied comparative approaches to test one of the predictions of the theory: that the rate of mitochondrial mutations is negatively correlated with longevity. Comparative studies face three challenges in detecting correlates of mutation rate: covariation of mutation rates between species due to ancestry, covariation between life history traits, and difficulty obtaining accurate estimates of mutation rate. We address these challenges using a novel Poisson regression method to examine the link between mutation rate and lifespan in rockfish (Sebastes). This method has better performance than traditional sister-species comparisons when sister species are too recently diverged to give reliable estimates of mutation rate. Rockfish are an ideal model system: they have long life spans with indeterminate growth and little evidence of senescence, which minimizes the confounding tradeoffs between lifespan and fecundity. We show that lifespan in rockfish is negatively correlated to rate of mitochondrial mutation, but not the rate of nuclear mutation. The life history of rockfish allows us to conclude that this relationship is unlikely to be driven by the tradeoffs between longevity and fecundity, or by the frequency of DNA replications in the germline. Instead the relationship is compatible with the hypothesis that mutation rates are reduced by selection in long-lived taxa to reduce the chance of mitochondrial damage over its lifespan, consistent with the mitochondrial theory of ageing. © The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail:
    Molecular Biology and Evolution 06/2015; 32(10). DOI:10.1093/molbev/msv137 · 9.11 Impact Factor
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    • "Data were analyzed by one-way ANOVA followed by Bonferroni test. were higher than those reached during normal aging in WT mice, heterozygous POLG mice initially were reported to have no " overt " phenotype (Vermulst et al, 2007). This was interpreted as evidence against a role for somatic mtDNA mutations during normal aging. "
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    ABSTRACT: Mitochondrial DNA (mtDNA) mutations are hypothesized to play a pathogenic role in aging and age-related neurodegenerative diseases such as Parkinson's disease (PD). In support of this, high levels of somatic mtDNA mutations in "POLG mutator" mice carrying a proofreading-deficient form of mtDNA polymerase γ (Polg(D257A)) lead to a premature aging phenotype. However, the relevance of this finding to the normal aging process has been questioned as the number of mutations is greater even in young POLG mutator mice, which shows no overt phenotype, than levels achieved during normal aging in mice. Vulnerability of dopaminergic neurons to 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) increases with age, and we hypothesized that this may result in part from the accumulation with age of somatic mtDNA mutations. If correct, then levels of mutations in young (2-3month old) POLG mutator mice should be sufficient to increase vulnerability to MPTP. In contrast, we find that susceptibility to MPTP in both heterozygous and homozygous POLG mutator mice at this young age is not different from that of wild type littermate controls as measured by levels of tyrosine hydroxylase positive (TH+) striatal terminals, striatal dopamine and its metabolites, a marker of oxidative damage, or stereological counts of TH+ and total substantia nigra neurons. These unexpected results do not support the hypothesis that somatic mtDNA mutations contribute to the age-related vulnerability of dopaminergic neurons to MPTP. It remains possible that somatic mtDNA mutations influence vulnerability to other stressors, or require additional time for the deleterious consequences to manifest. Furthermore, the impact of the higher levels of mutations present at older ages in these mice was not assessed in our study, although a prior study also failed to detect an increase in vulnerability to MPTP in older mice. With these caveats, the current data do not provide evidence for a role of somatic mtDNA mutations in determining the vulnerability to MPTP. Copyright © 2014 Elsevier Inc. All rights reserved.
    Neurotoxicology and Teratology 10/2014; 46C:62-67. DOI:10.1016/ · 2.76 Impact Factor
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    • "Although this model has been used to demonstrate the correlation between mtDNA mutations, mitochondrial dysfunction and premature aging, it is questionable to what extent this genetic mitochondrial mutator model represents the molecular mechanisms that underlie mitochondrial dysfunction during normal aging. For instance, the level of mtDNA substitution mutations in old individuals with a corresponding mitochondrial dysfunction does not produce a mitochondrial dysfunction when present in young mutator mice [9]. Rather, mtDNA deletions were suggested to be responsible for age-mediated dysfunction. "
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    ABSTRACT: Mitochondrial DNA (mtDNA) mutations can result in mitochondrial dysfunction, but emerging experimental data question the fundamental role of mtDNA mutagenesis in age-associated mitochondrial impairment. The multicopy nature of mtDNA renders the impact of a given mtDNA mutation unpredictable. In this study, we compared mtDNA stability and mtRNA integrity during normal aging. Seven distinct sites in mouse brain mtDNA and corresponding mtRNA were analyzed. Accumulation of mtDNA mutations during aging was highly site-specific. The variation in mutation frequencies overrode the age-mediated increase by more than 100-fold and aging generally did not influence mtDNA mutagenesis. Errors introduced by mtRNA polymerase were also site-dependent and up to two hundred-fold more frequent than mtDNA mutations, and independent of mtDNA mutation frequency. We therefore conclude that mitochondrial transcription fidelity limits the impact of mtDNA mutations.
    PLoS ONE 05/2014; 9(5):e96940. DOI:10.1371/journal.pone.0096940 · 3.23 Impact Factor
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