Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging.
Mutations in mitochondrial DNA (mtDNA) accumulate in tissues of mammalian species and have been hypothesized to contribute to aging. We show that mice expressing a proofreading-deficient version of the mitochondrial DNA polymerase g (POLG) accumulate mtDNA mutations and display features of accelerated aging. Accumulation of mtDNA mutations was not associated with increased markers of oxidative stress or a defect in cellular proliferation, but was correlated with the induction of apoptotic markers, particularly in tissues characterized by rapid cellular turnover. The levels of apoptotic markers were also found to increase during aging in normal mice. Thus, accumulation of mtDNA mutations that promote apoptosis may be a central mechanism driving mammalian aging.
Kujoth
G C
GC
Departments of Genetics and Medical Genetics, University of Wisconsin, Madison, WI 53706, USA.
Hiona
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A
Pugh
T D
TD
Someya
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S
Panzer
K
K
Wohlgemuth
S E
SE
Hofer
T
T
Seo
A Y
AY
Sullivan
R
R
Jobling
W A
WA
Morrow
J D
JD
Van Remmen
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Sedivy
J M
JM
Yamasoba
T
T
Tanokura
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Weindruch
R
R
Leeuwenburgh
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Prolla
T A
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D000375:Aging / Q000502:physiology*; D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003001:Cloning, Molecular; D004249:DNA Damage; D053938:DNA Fragmentation; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D018390:Gene Targeting; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism; D051379:Mice; D008929:Mitochondria, Heart / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D018384:Oxidative Stress; D010641:Phenotype; D011304:Presbycusis / Q000209:etiology; D017382:Reactive Oxygen Species / Q000378:metabolism
D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human; C498803:Polg protein, mouse; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases