title: Similar patterns of clonally expanded somatic mtDNA mutations in the colon of heterozygous mtDNA mutator mice and ageing humans.
abstract: Clonally expanded mitochondrial DNA (mtDNA) mutations resulting in focal respiratory chain deficiency in individual cells are proposed to contribute to the ageing of human tissues that depend on adult stem cells for self-renewal; however, the consequences of these mutations remain unclear. A good animal model is required to investigate this further; but it is unknown whether mechanisms for clonal expansion of mtDNA mutations, and the mutational spectra, are similar between species. Here we show that mice, heterozygous for a mutation disrupting the proof-reading activity of mtDNA polymerase (PolgA(+/mut)) resulting in an increased mtDNA mutation rate, accumulate clonally expanded mtDNA point mutations in their colonic crypts with age. This results in focal respiratory chain deficiency, and by 81 weeks of age these animals exhibit a similar level and pattern of respiratory chain deficiency to 70-year-old human subjects. Furthermore, like in humans, the mtDNA mutation spectrum appears random and there is an absence of selective constraints. Computer simulations show that a random genetic drift model of mtDNA clonal expansion can accurately model the data from the colonic crypts of wild-type, PolgA(+/mut) animals, and humans, providing evidence for a similar mechanism for clonal expansion of mtDNA point mutations between these mice and humans.
authors.affiliation: Centre for Brain Ageing and Vitality, Institute for Ageing and Health, The Medical School, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Holly L
authors.initials: HL
authors.lastname: Baines
authors.affiliation: Max Planck Institute for Biology of Ageing, Cologne, Germany.
authors.forename: James B
authors.initials: JB
authors.lastname: Stewart
authors.affiliation: Centre for Brain Ageing and Vitality, Institute for Ageing and Health, The Medical School, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Craig
authors.initials: C
authors.lastname: Stamp
authors.affiliation: Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle Upon Tyne NE4 5PL, UK.
authors.forename: Anze
authors.initials: A
authors.lastname: Zupanic
authors.affiliation: Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle Upon Tyne NE4 5PL, UK.
authors.forename: Thomas B L
authors.initials: TB
authors.lastname: Kirkwood
authors.affiliation: Max Planck Institute for Biology of Ageing, Cologne, Germany.
authors.forename: Nils-Göran
authors.initials: NG
authors.lastname: Larsson
authors.affiliation: Centre for Brain Ageing and Vitality, Institute for Ageing and Health, The Medical School, Newcastle upon Tyne NE2 4HH, UK; Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Douglass M
authors.initials: DM
authors.lastname: Turnbull
authors.affiliation: Centre for Brain Ageing and Vitality, Institute for Ageing and Health, The Medical School, Newcastle upon Tyne NE2 4HH, UK. Electronic address: laura.greaves@ncl.ac.uk.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Greaves
mesh_terms: D000368:Aged; D000375:Aging / Q000235:genetics / Q000378:metabolism; D000818:Animals; D003198:Computer Simulation; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008957:Models, Genetic; D017354:Point Mutation
chemical_list: D004272:DNA, Mitochondrial; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human; C498803:Polg protein, mouse
keywords: Ageing; Colon; Mitochondria; Mouse; MtDNA