ArticleMechanisms of ageing and development2014
Similar patterns of clonally expanded somatic mtDNA mutations in the colon of heterozygous mtDNA mutator mice and ageing humans.
Article in Mechanisms of ageing and development, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 44 citations in OpenAlex.
- Review
- Accumulated mtDNA mutations are linked to specific impairments in NADH-linked respiration.iScience · 2026Article
- The CHCHD2-CHCHD10 protein complex is modulated by mitochondrial dysfunction and alters lipid homeostasis in the mouse brain.Cell death & disease · 2025Article
- Cryptic mitochondrial DNA mutations coincide with mid-late life and are pathophysiologically informative in single cells across tissues and species.Nature communications · 2025Article
- Nanobiopsy investigation of the subcellular mtDNA heteroplasmy in human tissues.Scientific reports · 2024Article
- Mechanisms and pathologies of human mitochondrial DNA replication and deletion formation.The Biochemical journal · 2024Review
- NADNature communications · 2024Article
- Interactions of mitochondrial and skeletal muscle biology in mitochondrial myopathy.The Biochemical journal · 2023Review
- Biomarkers of aging.Science China. Life sciences · 2023Review
- Mitochondrial DNA mutations in ageing and cancer.Molecular oncology · 2022Review
- Mitigation of age-dependent accumulation of defective mitochondrial genomes.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- The Role of Mitochondrial Genes in Neurodegenerative Disorders.Current neuropharmacology · 2022Review
- mtDNA Heteroplasmy: Origin, Detection, Significance, and Evolutionary Consequences.Life (Basel, Switzerland) · 2021Review
- Age-associated mitochondrial complex I deficiency is linked to increased stem cell proliferation rates in the mouse colon.Aging cell · 2021Article
- Age-associated mitochondrial DNA mutations cause metabolic remodelling that contributes to accelerated intestinal tumorigenesis.Nature cancer · 2020Article
- Age-related accumulation of de novo mitochondrial mutations in mammalian oocytes and somatic tissues.PLoS biology · 2020Article
- Modulation of mtDNA copy number ameliorates the pathological consequences of a heteroplasmic mtDNA mutation in the mouse.Science advances · 2019Article
- Deleterious mitochondrial DNA point mutations are overrepresented in Drosophila expressing a proofreading-defective DNA polymerase γ.PLoS genetics · 2018Article
- Mutations of mitochondrial DNA are not major contributors to aging of fruit flies.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Base-excision repair deficiency alone or combined with increased oxidative stress does not increase mtDNA point mutations in mice.Nucleic acids research · 2018Article
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
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.
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