Clonal expansion of early to mid-life mitochondrial DNA point mutations drives mitochondrial dysfunction during human ageing.
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. Ho...
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| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-09-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1004620 |
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| author | Laura C Greaves Marco Nooteboom Joanna L Elson Helen A L Tuppen Geoffrey A Taylor Daniel M Commane Ramesh P Arasaradnam Konstantin Khrapko Robert W Taylor Thomas B L Kirkwood John C Mathers Douglass M Turnbull |
| author_facet | Laura C Greaves Marco Nooteboom Joanna L Elson Helen A L Tuppen Geoffrey A Taylor Daniel M Commane Ramesh P Arasaradnam Konstantin Khrapko Robert W Taylor Thomas B L Kirkwood John C Mathers Douglass M Turnbull |
| author_sort | Laura C Greaves |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-bc764e33a1204f2fbee613cf25efce7f |
| institution | OA Journals |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2014-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-bc764e33a1204f2fbee613cf25efce7f2025-08-20T02:22:45ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042014-09-01109e100462010.1371/journal.pgen.1004620Clonal expansion of early to mid-life mitochondrial DNA point mutations drives mitochondrial dysfunction during human ageing.Laura C GreavesMarco NooteboomJoanna L ElsonHelen A L TuppenGeoffrey A TaylorDaniel M CommaneRamesh P ArasaradnamKonstantin KhrapkoRobert W TaylorThomas B L KirkwoodJohn C MathersDouglass M TurnbullAge-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.https://doi.org/10.1371/journal.pgen.1004620 |
| spellingShingle | Laura C Greaves Marco Nooteboom Joanna L Elson Helen A L Tuppen Geoffrey A Taylor Daniel M Commane Ramesh P Arasaradnam Konstantin Khrapko Robert W Taylor Thomas B L Kirkwood John C Mathers Douglass M Turnbull Clonal expansion of early to mid-life mitochondrial DNA point mutations drives mitochondrial dysfunction during human ageing. PLoS Genetics |
| title | Clonal expansion of early to mid-life mitochondrial DNA point mutations drives mitochondrial dysfunction during human ageing. |
| title_full | Clonal expansion of early to mid-life mitochondrial DNA point mutations drives mitochondrial dysfunction during human ageing. |
| title_fullStr | Clonal expansion of early to mid-life mitochondrial DNA point mutations drives mitochondrial dysfunction during human ageing. |
| title_full_unstemmed | Clonal expansion of early to mid-life mitochondrial DNA point mutations drives mitochondrial dysfunction during human ageing. |
| title_short | Clonal expansion of early to mid-life mitochondrial DNA point mutations drives mitochondrial dysfunction during human ageing. |
| title_sort | clonal expansion of early to mid life mitochondrial dna point mutations drives mitochondrial dysfunction during human ageing |
| url | https://doi.org/10.1371/journal.pgen.1004620 |
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