Clonal expansion of early to mid-life mitochondrial DNA point mutations drives mitochondrial dysfunction during human ageing
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Age-related decline in the integrity of mitochondria is an important contributor to the human ageing process. In a number of ageing stem cell populations, this decline in mitochondrial function is due to clonal expansion of individual mitochondrial DNA (mtDNA) point mutations within single cells. However the dynamics of this process and when these mtDNA mutations occur initially are poorly understood. Using human colorectal epithelium as an exemplar tissue with a well-defined stem cell population, we analysed samples from 207 healthy participants aged 17-78 years using a combination of techniques (Random Mutation Capture, Next Generation Sequencing and mitochondrial enzyme histochemistry), and show that: 1) non-pathogenic mtDNA mutations are present from early embryogenesis or may be transmitted through the germline, whereas pathogenic mtDNA mutations are detected in the somatic cells, providing evidence for purifying selection in humans, 2) pathogenic mtDNA mutations are present from early adulthood (<20 years of age), at both low levels and as clonal expansions, 3) low level mtDNA mutation frequency does not change significantly with age, suggesting that mtDNA mutation rate does not increase significantly with age, and 4) clonally expanded mtDNA mutations increase dramatically with age. These data confirm that clonal expansion of mtDNA mutations, some of which are generated very early in life, is the major driving force behind the mitochondrial dysfunction associated with ageing of the human colorectal epithelium.
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Mitochondrial DNA mutations accumulate with age, secondary to increased ROS and continuous replication, which enables mutations that impair function to potentially expand clonally.
“Mitochondrial DNA mutations also accumulate with age, secondary to increased ROS and continuous replication, which enables mutations that impair function to, potentially, expand clonally (23).”
From Exercise Counters the Age-Related Accumulation of Senescent Cells (2022) · cites this paper as [23]
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- Authors
- Greaves, L. C., Nooteboom, M., Elson, J. L., Tuppen, H. A. L., Taylor, G. A., Commane, D. M., Arasaradnam, R. P., Khrapko, K., Taylor, R. W., Kirkwood, T. B. L., Mathers, J. C., & Turnbull, D. M.
- Affiliations
- Wellcome Centre for Mitochondrial Research (GB)
- North-West University (ZA)
- Newcastle University (GB)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Greaves, Laura C.
- ORCID
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-09-18
- Volume
- 10
- Issue
- 9
- Pages
- e1004620
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC4169240
- OpenAlex
- W2132967521
- Cited by
- 172
- References
- 51
- Citations by year
- 2026: 13 · 2025: 19 · 2024: 19 · 2023: 9 · 2022: 14 · 2021: 8 · 2020: 24 · 2019: 13 · 2018: 12 · 2017: 14 · 2016: 17 · 2015: 8 · 2014: 2
- FWCI
- 5.57
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- CentAUR (University of Reading) (acceptedVersion)
- Northumbria Research Link (Northumbria University) (acceptedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Radboud Repository (Radboud University) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity) (cc-by)
- Funders
- Ellison Medical Foundation
- Wellcome Trust (096919, 096919/Z/11/Z, G0601943)
- National Institute for Health and Care Research (G0601943)
- Food Standards Agency (N12015)
- Newcastle University
- Medical Research Council (G0601943, G0700718)
- Engineering and Physical Sciences Research Council
- Biotechnology and Biological Sciences Research Council (BEP17 042, BB/C008200/1, G0700718)
- Economic and Social Research Council
- NIHR Newcastle Biomedical Research Centre (BH111030)
- Wellcome Trust Centre for Mitochondrial Research (096919Z/11/Z)
- National Institute on Aging (R01AG019787)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- mitochondrial DNA point mutations, clonal expansion, mitochondrial dysfunction, human aging, colorectal epithelium, purifying selection, mtDNA mutation rate, early embryonic development, somatic mtDNA mutations
- MeSH terms
- Adolescent, Adult, Age Factors, Aged, Aging, DNA Mutational Analysis, DNA, Mitochondrial, Humans, Intestinal Mucosa, Middle Aged, Mitochondria, Sensitivity and Specificity, Point Mutation, Mitochondrial Proteins, Cytochromes c, Young Adult, High-Throughput Nucleotide Sequencing, Mutation Rate
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