期刊
NATURE
卷 501, 期 7467, 页码 412-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature12474
关键词
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资金
- ERC [268897, 322744]
- Swedish Research Council [K2011-62X-21870-01-6, K2012-62X-03185-42-4]
- Swedish Brain Foundation
- Swedish Brain Power
- Swedish Parkinson Foundation
- Karolinska Distinguished Professor Award
- Swedish Alzheimer Foundation
- National Institutes of Health [AG04418, NS070825]
- National Institute on Drug Abuse
- National Institutes of Health/Karolinska Institutet Graduate Partnerships Program
- Swedish Society for Medical Research
- United Mitochondrial Disease Foundation
- European Research Council (ERC) [268897] Funding Source: European Research Council (ERC)
Ageing is due to an accumulation of various types of damage(1,2), and mitochondrial dysfunction has long been considered to be important in this process(3-8). There is substantial sequence variation in mammalian mitochondrial DNA (mtDNA)(9), and the high mutation rate is counteracted by different mechanisms that decrease maternal transmission of mutated mtDNA(10-13). Despite these protective mechanisms(14), it is becoming increasingly clear that lowlevel mtDNA heteroplasmy is quite common and often inherited in humans(15,16). We designed a series of mouse mutants to investigate the extent to which inherited mtDNA mutations can contribute to ageing. Here we report that maternally transmitted mtDNA mutations can induce mild ageing phenotypes in mice with a wild-type nuclear genome. Furthermore, maternally transmittedmtDNAmutations lead to anticipation of reduced fertility in mice that are heterozygous for themtDNAmutator allele (PolgAwt/mut) and aggravate premature ageing phenotypes inmtDNAmutatormice (PolgAmut/mut). Unexpectedly, a combination of maternally transmitted and somatic mtDNA mutations also leads to stochastic brain malformations. Our findings show that a pre-existing mutation load will not only allow somatic mutagenesis to create a critically high total mtDNA mutation load sooner but will also increase clonal expansionofmtDNA mutations(17) to enhance the normally occurring mosaic respiratory chain deficiency in ageing tissues(18,19). Our findings suggest that maternally transmitted mtDNA mutations may have a similar role in aggravating aspects of normal human ageing.
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