title: Clonal expansion of early to mid-life mitochondrial DNA point mutations drives mitochondrial dysfunction during human ageing.
abstract: 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.
authors.affiliation: Newcastle University Centre for Brain Ageing and Vitality, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom; Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Greaves
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Marco
authors.initials: M
authors.lastname: Nooteboom
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Centre for Human Metabolomics, North-West University, Potchefstroom, South Africa.
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Elson
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Helen A L
authors.initials: HA
authors.lastname: Tuppen
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Taylor
authors.affiliation: Human Nutrition Research Centre, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Commane
authors.affiliation: Human Nutrition Research Centre, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Ramesh P
authors.initials: RP
authors.lastname: Arasaradnam
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Khrapko
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.affiliation: Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom.
authors.forename: Thomas B L
authors.initials: TB
authors.lastname: Kirkwood
authors.affiliation: Newcastle University Centre for Brain Ageing and Vitality, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom; Human Nutrition Research Centre, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: John C
authors.initials: JC
authors.lastname: Mathers
authors.affiliation: Newcastle University Centre for Brain Ageing and Vitality, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom; Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Douglass M
authors.initials: DM
authors.lastname: Turnbull
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000375:Aging / Q000235:genetics*; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D059645:Mutation Rate; D017354:Point Mutation; D012680:Sensitivity and Specificity; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D045304:Cytochromes c