Defects in multiple complexes of the respiratory chain are present in ageing human colonic crypts.
Mitochondrial DNA (mtDNA) mutations accumulate in a number of ageing tissues and are proposed to play a role in the ageing process. We have previously shown that colonic crypt stem cells accumulate somatic mtDNA point mutations during ageing. These mtDNA mutations result in the loss of the activity of complex IV (cytochrome c oxidase (COX)) of the respiratory chain in the stem cells and their progeny, producing colonic crypts which are entirely COX deficient. However it is not known whether the other complexes of the respiratory chain are similarly affected during ageing. Here we have used antibodies to individual subunits of complexes I-IV to investigate their expression in the colonic epithelium from human subjects aged 18-84. We show that in approximately 50% of crypts with any form of respiratory chain deficiency, decreased expression of subunits of multiple complexes is observed. Furthermore we have sequenced the entire mitochondrial genome of a number of cells with multiple complex defects and have found a wide variety of point mutations in these cells affecting a number of different protein encoding and RNA encoding genes. Finally we discuss the possible mechanisms by which multiple respiratory chain complex defects may occur in these cells.
Greaves
Laura C
LC
Mitochondrial Research Group, Institute for Ageing and Health, Medical School, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne, UK.
Barron
Martin J
MJ
Plusa
Stefan
S
Kirkwood
Thomas B
TB
Mathers
John C
JC
Taylor
Robert W
RW
Turnbull
Doug M
DM
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019943:Amino Acid Substitution; D001483:Base Sequence; D003106:Colon / Q000033:anatomy & histology / Q000378:metabolism*; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics; D004579:Electron Transport / Q000235:genetics / Q000502:physiology*; D042967:Electron Transport Complex I / Q000378:metabolism; D042963:Electron Transport Complex II / Q000378:metabolism; D014450:Electron Transport Complex III / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D054629:Genome, Mitochondrial; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000033:anatomy & histology / Q000378:metabolism; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D055815:Young Adult
D004272:DNA, Mitochondrial; D042963:Electron Transport Complex II; D003576:Electron Transport Complex IV; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III