title: Association of mitochondrial DNA damage with aging and coronary atherosclerotic heart disease.
abstract: The role of somatic mitochondrial DNA (mtDNA) damage in human aging and progressive diseases of oxidative phosphorylation (OXPHOS) was examined by quantitating the accumulation of mtDNA deletions in normal hearts and hearts with coronary atherosclerotic disease. In normal hearts, mtDNA deletions appeared after 40 and subsequently accumulated with age. The common 4977 nucleotide pair (np) deletion (mtDNA4977) reached a maximum of 0.007%, with the mtDNA7436 and mtDNA10,422 deletions appearing at the same time. In hearts deprived of mitochondrial substrates due to coronary artery disease, the level of the mtDNA4977 deletion was elevated 7-220-fold over age-matched controls, with the mtDNA7436 and mtDNA10,422 deletions increasing in parallel. This cumulative mtDNA damage was associated with a compensatory 3.5-fold induction of nuclear OXPHOS gene mRNA and regions of ischemic hearts subjected to the greatest work load (left ventricle) showed the greatest accumulation of mtDNA damage and OXPHOS gene induction. These observations support the hypothesis that mtDNA damage does accumulate with age and indicates that respiratory stress greatly elevates mitochondrial damage.
authors.affiliation: Department of Genetics and Molecular Medicine, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: M
authors.initials: M
authors.lastname: Corral-Debrinski
authors.forename: J M
authors.initials: JM
authors.lastname: Shoffner
authors.forename: M T
authors.initials: MT
authors.lastname: Lott
authors.forename: D C
authors.initials: DC
authors.lastname: Wallace
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000235:genetics / Q000502:physiology*; D001161:Arteriosclerosis / Q000235:genetics* / Q000473:pathology; D003327:Coronary Disease / Q000235:genetics* / Q000473:pathology; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009206:Myocardium / Q000473:pathology; D010085:Oxidative Phosphorylation; D017384:Sequence Deletion
chemical_list: D004272:DNA, Mitochondrial