Mitochondrial point mutations do not limit the natural lifespan of mice

University of Washington Seattle, Seattle, Washington, United States
Nature Genetics (Impact Factor: 29.65). 05/2007; 39(4):540-3. DOI: 10.1038/ng1988
Source: PubMed

ABSTRACT 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.

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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; DOI:10.1093/molbev/msv137 · 14.31 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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    • "However, while a plethora of data suggests that mtDNA mutations accumulate with age, it is still a matter of debate whether such an accumulation is a cause of aging. It has been reported that mtDNA deletions, but not point mutations, are associated with premature aging and lifespan in mice with defective polγ (Vermulst et al., 2007, 2008). However, a recent report suggests that germline-transmitted mtDNA mutations may aggravate the aging phenotype of adult animals (Ross et al., 2013). "
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    ABSTRACT: The last 30years of research greatly contributed to shed light on the role of mitochondrial DNA (mtDNA) variability in aging, although contrasting results have been reported, mainly due to bias regarding the population size and stratification, and to the use of analysis methods (haplogroup classification) that resulted to be not sufficiently adequate to grasp the complexity of the phenomenon. A 5-years European study (the GEHA EU project) collected and analysed data on mtDNA variability on an unprecedented number of long-living subjects (enriched for longevity genes) and a comparable number of controls (matched for gender and ethnicity) in Europe. This very large study allowed a reappraisal of the role of both the inherited and the somatic mtDNA variability in aging, as an association with longevity emerged only when mtDNA variants in OXPHOS complexes co-occurred. Moreover, the availability of data from both nuclear and mitochondrial genomes on a large number of subjects paves the way for an evaluation at a very large scale of the epistatic interactions at a higher level of complexity. This scenario is expected to be even more clarified in the next future with the use of next generation sequencing (NGS) techniques, which are becoming applicable to evaluate mtDNA variability and, then, new mathematical/bioinformatic analysis methods are urgently needed. Recent advances of association studies on age-related diseases and mtDNA variability will be also discussed in this review, taking into account the bias hidden by population stratification. Finally very recent findings in terms of mtDNA heteroplasmy (i.e. the coexistence of wild type and mutated copies of mtDNA) and aging as well as mitochondrial epigenetic mechanisms will be also discussed.
    Experimental gerontology 04/2014; 56. DOI:10.1016/j.exger.2014.03.022 · 3.53 Impact Factor
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