Mitochondrial DNA repair of oxidative damage in mammalian cells.
Nuclear and mitochondrial DNA are constantly being exposed to damaging agents, from endogenous and exogenous sources. In particular, reactive oxygen species (ROS) are formed at high levels as by-products of the normal metabolism. Upon oxidative attack of DNA many DNA lesions are formed and oxidized bases are generated with high frequency. Mitochondrial DNA has been shown to accumulate high levels of 8-hydroxy-2'-deoxyguanosine, the product of hydroxylation of guanine at carbon 8, which is a mutagenic lesion. Most of these small base modifications are repaired by the base excision repair (BER) pathway. Despite the initial concept that mitochondria lack DNA repair, experimental evidences now show that mitochondria are very proficient in BER of oxidative DNA damage, and proteins necessary for this pathway have been isolated from mammalian mitochondria. Here, we examine the BER pathway with an emphasis on mtDNA repair. The molecular mechanisms involved in the formation and removal of oxidative damage from mitochondria are discussed. The pivotal role of the OGG1 glycosylase in removal of oxidized guanines from mtDNA will also be examined. Lastly, changes in mtDNA repair during the aging process and possible biological implications are discussed.
Bohr
Vilhelm A
VA
Laboratory of Molecular Gerontology, Box 1, National Institute on Aging, NIH, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA. vbohr@nih.gov
Stevnsner
Tinna
T
de Souza-Pinto
Nadja C
NC
D000225:Adenine / Q000031:analogs & derivatives* / Q000378:metabolism; D000375:Aging; D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D045647:DNA Glycosylases; D011088:DNA Ligases / Q000378:metabolism; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D043382:DNA-Formamidopyrimidine Glycosylase; D006151:Guanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D019271:Hypoxanthine / Q000378:metabolism; D051379:Mice; D008929:Mitochondria, Heart / Q000201:enzymology; D008930:Mitochondria, Liver / Q000201:enzymology; D009699:N-Glycosyl Hydrolases / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D000076105:X-ray Repair Cross Complementing Protein 1
D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D017382:Reactive Oxygen Species; D000076105:X-ray Repair Cross Complementing Protein 1; D006151:Guanosine; C004981:1,N(6)-ethenoadenine; D019271:Hypoxanthine; C046215:8-hydroxyguanosine; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; D043382:DNA-Formamidopyrimidine Glycosylase; D011088:DNA Ligases; D000225:Adenine