title: Germline mitochondrial DNA mutations aggravate ageing and can impair brain development.
abstract: Ageing is due to an accumulation of various types of damage, and mitochondrial dysfunction has long been considered to be important in this process. There is substantial sequence variation in mammalian mitochondrial DNA (mtDNA), and the high mutation rate is counteracted by different mechanisms that decrease maternal transmission of mutated mtDNA. Despite these protective mechanisms, it is becoming increasingly clear that low-level mtDNA heteroplasmy is quite common and often inherited in humans. 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 transmitted mtDNA mutations lead to anticipation of reduced fertility in mice that are heterozygous for the mtDNA mutator allele (PolgA(wt/mut)) and aggravate premature ageing phenotypes in mtDNA mutator mice (PolgA(mut/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 expansion of mtDNA mutations to enhance the normally occurring mosaic respiratory chain deficiency in ageing tissues. Our findings suggest that maternally transmitted mtDNA mutations may have a similar role in aggravating aspects of normal human ageing.
authors: Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 171 77 Stockholm, Sweden.
authors: Jaime M
authors: JM
authors: Ross
authors: James B
authors: JB
authors: Stewart
authors: Erik
authors: E
authors: Hagström
authors: Stefan
authors: S
authors: Brené
authors: Arnaud
authors: A
authors: Mourier
authors: Giuseppe
authors: G
authors: Coppotelli
authors: Christoph
authors: C
authors: Freyer
authors: Marie
authors: M
authors: Lagouge
authors: Barry J
authors: BJ
authors: Hoffer
authors: Lars
authors: L
authors: Olson
authors: Nils-Göran
authors: NG
authors: Larsson
mesh_terms: D000375:Aging / Q000235:genetics* / Q000473:pathology; D000483:Alleles; D000818:Animals; D001921:Brain / Q000002:abnormalities* / Q000254:growth & development / Q000378:metabolism*; D002467:Cell Nucleus / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics*; D005111:Extrachromosomal Inheritance / Q000235:genetics*; D005260:Female; D016678:Genome / Q000235:genetics; D006579:Heterozygote; D008098:Litter Size; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000235:genetics*; D016296:Mutagenesis / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D012098:Reproduction / Q000235:genetics / Q000502:physiology; D013269:Stochastic Processes
chemical_list: D004272:DNA, Mitochondrial
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