Mitochondrial repair of 8-oxoguanine and changes with aging.
Reactive oxygen species (ROS) are formed in all living organisms as a by-product of normal metabolism (endogenous sources) and as a consequence of exposure to environmental compounds (exogenous sources). Endogenous ROS are largely formed during oxidative phosphorylation in the mitochondria and, therefore, mitochondrial DNA (mtDNA) is at particularly high risk of ROS-induced damage. Mitochondria are essential for cell viability, and oxidative damage to mtDNA has been implicated as a causative factor in a wide variety of degenerative diseases, and in cancer and aging. One of the most common oxidative DNA lesions is 7,8-dihydro-8-oxoguanine (8-oxoG), which can introduce G/C to T/A transversions after DNA replication. Oxidative DNA base lesions, including 8-oxoG, are repaired primarily by the base excision repair (BER) pathway. While we know much about how this pathway functions in processing the nuclear DNA lesions, little is yet known about BER in mitochondria. We have used a number of different approaches to explore the mechanisms of DNA damage processing in the mtDNA. We have been able to demonstrate that mammalian mitochondria efficiently remove 8-oxoG from their genome, and that the efficiency of 8-oxoG incision increases with age in rats and mice. Yet 8-oxoG accumulates in mtDNA during aging. Changes in mitochondrial function with age have been observed in several organisms and accumulation of DNA lesions in mtDNA with age may be an underlying cause for numerous age-associated diseases including cancer.
Stevnsner
Tinna
T
Department of Molecular Biology, Danish Center for Molecular Gerontology, C.F. Mollers alle bldg 130, University of Aarhus, DK 8000 Aarhus, Denmark. tvs@mb.au.dk
Thorslund
Tina
T
de Souza-Pinto
Nadja C
NC
Bohr
Vilhelm A
VA
D000375:Aging / Q000235:genetics*; D000818:Animals; D002467:Cell Nucleus; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics*; D043382:DNA-Formamidopyrimidine Glycosylase; D006147:Guanine / Q000031:analogs & derivatives* / Q000502:physiology*; D008322:Mammals; D009699:N-Glycosyl Hydrolases / Q000502:physiology; D017382:Reactive Oxygen Species / Q000009:adverse effects
D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; C024829:8-hydroxyguanine; D006147:Guanine; D009699:N-Glycosyl Hydrolases; D043382:DNA-Formamidopyrimidine Glycosylase