Similar patterns of clonally expanded somatic mtDNA mutations in the colon of heterozygous mtDNA mutator mice and ageing humans

• Published in: Mechanisms of ageing and development Vol. 139; pp. 22 - 30
• Main Authors: Baines, Holly L., Stewart, James B., Stamp, Craig, Zupanic, Anze, Kirkwood, Thomas B.L., Larsson, Nils-Göran, Turnbull, Douglass M., Greaves, Laura C.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 01.07.2014; Elsevier Science Ireland
• Subjects: Aged; Ageing; Aging - genetics; Aging - metabolism; Animals; Colon; Computer Simulation; DNA Polymerase gamma; DNA, Mitochondrial - genetics; DNA, Mitochondrial - metabolism; DNA-Directed DNA Polymerase - genetics; DNA-Directed DNA Polymerase - metabolism; Female; Humans; Male; Medicin och hälsovetenskap; Mice; Mice, Mutant Strains; Mitochondria; Models, Genetic; Mouse; MtDNA; Point Mutation; Mitochondria; MtDNA; Colon; Mouse; Ageing
• ISSN: 0047-6374; 1872-6216; 1872-6216
• DOI: 10.1016/j.mad.2014.06.003

•Colonic crypts with mitochondrial dysfunction accumulate with age in PolgA+/mut mice.•Mitochondrial dysfunction is caused by clonally expanded mtDNA point mutations.•The mutations are random and their expansion is not subject to selective constraints.•Colonic crypts of aged humans have a similar mtDNA mutation spectrum and phenotype.•PolgA+/mut mice are a good model to study mitochondrial dysfunction in ageing colon. 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.