DNA deletions and clonal mutations drive premature aging in mitochondrial mutator mice.
Mitochondrial DNA (mtDNA) mutations are thought to have a causal role in many age-related pathologies. Here we identify mtDNA deletions as a driving force behind the premature aging phenotype of mitochondrial mutator mice, and provide evidence for a homology-directed DNA repair mechanism in mitochondria that is directly linked to the formation of mtDNA deletions. In addition, our results demonstrate that the rate at which mtDNA mutations reach phenotypic expression differs markedly among tissues, which may be an important factor in determining the tolerance of a tissue to random mitochondrial mutagenesis.
Vermulst
Marc
M
Department of Pathology, University of Washington, Seattle, Washington 91895, USA.
Wanagat
Jonathan
J
Kujoth
Gregory C
GC
Bielas
Jason H
JH
Rabinovitch
Peter S
PS
Prolla
Tomas A
TA
Loeb
Lawrence A
LA
D019588:Aging, Premature / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D002374:Catalase / Q000235:genetics / Q000502:physiology; D000074002:DNA Polymerase gamma; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000502:physiology*; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016296:Mutagenesis; D018384:Oxidative Stress; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics*; D017384:Sequence Deletion; D012689:Sequence Homology, Nucleic Acid; D014018:Tissue Distribution
D004272:DNA, Mitochondrial; D002374:Catalase; D003576:Electron Transport Complex IV; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C498803:Polg protein, mouse