Mitochondria, oxidative DNA damage, and aging
Protection from reactive oxygen species (ROS) and from mitochondrial oxidative damage is well known to be necessary to longevity. The relevance of mitochondrial DNA (mtDNA) to aging is suggested by the fact that the two most commonly measured forms of mtDNA damage, deletions and the oxidatively induced lesion 8-oxo-dG, increase with age. The rate of increase is species-specific and correlates with maximum lifespan.
It is less clear that failure or inadequacies in the protection from reactive oxygen species (ROS) and from mitochondrial oxidative damage are sufficient to explain senescence. DNA containing 8-oxo-dG is repaired by mitochondria, and the high ratio of mitochondrial to nuclear levels of 8-oxo-dG previously reported are now suspected to be due to methodological difficulties. Furthermore, MnSOD −/+ mice incur higher than wild type levels of oxidative damage, but do not display an aging phenotype. Together, these findings suggest that oxidative damage to mitochondria is lower than previously thought, and that higher levels can be tolerated without physiological consequence.
A great deal of work remains before it will be known whether mitochondrial oxidative damage is a “clock” which controls the rate of aging. The increased level of 8-oxo-dG seen with age in isolated mitochondria needs explanation. It could be that a subset of cells lose the ability to protect or repair mitochondria, resulting in their incurring disproportionate levels of damage. Such an uneven distribution could exceed the reserve capacity of these cells and have serious physiological consequences. Measurements of damage need to focus more on distribution, both within tissues and within cells. In addition, study must be given to the incidence and repair of other DNA lesions, and to the possibility that repair varies from species to species, tissue to tissue, and young to old.
KeywordsOxygen Reactive Oxygen Species Oxidative Damage High Ratio Physiological Consequence
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
Harman D. Aging: A theory based on free radical and radiation chemistry. Journal of Gerontology
. 1956;11:298–300.PubMedGoogle Scholar
Szilard L. On the nature of the aging process. Proceedings of the National Academy of Sciences of the United States of America
. 1959;45:30–45.PubMedGoogle Scholar
Stein G, Weiss J. Chemical effects of ionizing radiations. Nature
. 1948;161:650.PubMedGoogle Scholar
Commoner B, Townsend J, Pakke GE. Free radicals in biological materials. Nature
. 1954;174: 689–691.PubMedCrossRefGoogle Scholar
Grollman AP, Moriya M. Mutagenesis by 8-oxoguanine: an enemy within. Trends in Genetics
. 1993;9: 246–249.PubMedCrossRefGoogle Scholar
Purmal AA, Kow YW, Wallace SS. Major oxidative products of cytosine, 5-hydroxycytosine and 5-hydroxyuracil, exhibit sequence context-dependent mispairing in vitro. Nucleic Acids Research
. 1994;22:72–78.PubMedGoogle Scholar
Collins AR. Oxidative DNA damage, antioxidants, and cancer. BioEssays.
Stuart GR, Oda Y, de Boer JG, Glickman BW. Mutation frequency and specificity with age in liver, bladder and brain of lacl transgenic mice. Genetics
. 2000; 154(3):1291–1300.PubMedGoogle Scholar
Jones OT. The mechanism of the production of superoxide by phagocytes. Mol Chem Neuropathol.
1993; 19(1–2):177–184.PubMedCrossRefGoogle Scholar
Rodeberg DA, Chaet MS, Bass RC, Arkovitz MS, Garcia VF. Nitric oxide: an overview. Am J Surg.
May JM, de Haen C. The insulin-like effect of hydrogen peroxide on pathways of lipid synthesis in rat adipocytes. J Biol Chem.
May JM, de Haen C. Insulin-stimulated intracellular hydrogen peroxide production in rat epididymal fat cells. J Biol Chem.
Krieger-Brauer HI, Kather H. Human fat cells possess a plasma membrane-bound H202-generating system that is activated by insulin via a mechanism bypassing the receptor kinase. J Clin Invest.
1992;89(3): 1006–1013.PubMedGoogle Scholar
Krieger-Brauer HI, Medda PK, Kather H. Insulin-induced activation of NADPH-dependent H202 generation in human adipocyte plasma membranes is mediated by Galphai2. J Biol Chem.
1997; 272(15):10135–10143.Google Scholar
Sasaki H, Kodama K, Yamada M. A review of forty-five years study of Hiroshima and Nagasaki atomic bomb survivors. Aging. J Radiat Res (Tokyo)
. 1991;32 Suppl:310–326.CrossRefGoogle Scholar
Beckman KB, Ames BN. The free radical theory of aging matures. Physiol Rev.
1998;78(2): 547–581.PubMedGoogle Scholar
Harman D. The biologic clock: the mitochondria? J Am Geriatr Soc.
Miquel J, Economos AC, Fleming J, Johnson JE, Jr. Mitochondrial role in cell aging. Exp Gerontol.
Shearman CW, Kalf GF. DNA replication by a membrane-DNA complex from rat liver mitochondria. Arch Biochem Biophys.
Singh G, Sharkey SM, Moorehead R. Mitochondrial DNA damage by anticancer agents. Pharmacology and Therapeutics
. 1992;54:217–230.PubMedCrossRefGoogle Scholar
Davis AF, Clayton DA. In situ localization of mitochondrial DNA replication in intact mammalian cells. J Cell Biol.
Bandy B, Davison AJ. Mitochondrial mutations may increase oxidative stress: implications for carcinogenesis and aging?. Free Radical Biology and Medicine.
Kasai H, Nishimura S. Hydroxylation of the C-8 position of deoxyguanosine by reducing agents in the presence of oxygen. Nucleic Acids Symp Ser.
Kasai H, Nishimura S. Hydroxylation of deoxy guanosine at the C-8 position by polyphenols and aminophenols in the presence of hydrogen peroxide and ferric ion. Gann.
Kasai H, Nishimura S. Hydroxylation of deoxyguanosine at the C-8 position by ascorbic acid and other reducing agents. Nucleic Acids Res.
1984; 12(4):2137–2145.PubMedGoogle Scholar
Kasai H, Nishimura S. DNA damage induced by asbestos in the presence of hydrogen peroxide. Gann.
Kasai H, Tanooka H, Nishimura S. Formation of 8-hydroxyguanine residues in DNA by X-irradiation. Gann.
1984;75(12): 1037–1039.PubMedGoogle Scholar
Floyd RA, Watson JJ, Wong PK, Altmiller DH, Rickard RC. Hydroxyl free radical adduct of deoxyguanosine: sensitive detection and mechanisms of formation. Free Radical Research Communications
. 1986;1(3): 163–172.PubMedGoogle Scholar
Kouchakdjian M, Bodepudi V, Shibutani S, et al. NMR structural studies of the ionizing radiation adduct 7-hydro-8-oxodeoxyguanosine (8-oxo-7H-dG) opposite deoxyadenosine in a DNA duplex. 8-Oxo-7H-dG(syn).dA(anti) alignment at lesion site. Biochemistry
. 1991;30:1403–1412.PubMedCrossRefGoogle Scholar
McAuley-Hecht KE, Leonard GA, Gibson NJ, et al. Crystal structure of a DNA duplex containing 8-hydroxydeoxyguanine-adenine base pairs. Biochemistry
. 1994;33(34):10266–10270.Google Scholar
Shibutani S, Takeshita M, Grollman AP. Insertion of specific bases during DNA synthesis past the oxidation-damaged base 8-oxodG. Nature
. 1991;349:431–434.PubMedCrossRefGoogle Scholar
Pinz KG, Shibutani S, Bogenhagen DF. Action of mitochondrial DNA polymerase gamma at sites of base loss or oxidative damage. Journal of Biological Chemistry
. 1995;270(16):9202–9206.PubMedCrossRefGoogle Scholar
Moraes EC, Keyse SM, Tyrrell RM. Mutagenesis by hydrogen peroxide treatment of mammalian cells: a molecular analysis. Carcinogenesis
. 1990;11:283–293.PubMedGoogle Scholar
Tkeshelashvili LK, McBride T, Spence K, Loeb LA. Mutation spectrum of copper-induced DNA damage [published erratum appears in J Biol Chem 1992 Jul 5;267(19):13778]. J Biol Chem.
Michaels ML, Pham L, Cruz C, Miller JH. MutM, a protein that prevents G.C—T.A transversions, is formamidopyrimidine-DNA glycosylase. Nucleic Acids Research
. 1991;19:3629–3632.PubMedGoogle Scholar
Radicella JP, Dherin C, Desmaze C, Fox MS, Boiteux S. Cloning and characterization of hOGG1, a human homolog of the OGG1 gene of Saccharomyces cerevisiae. Proc Natl Acad Sci USA
. 1997;94(15):8010–8015.PubMedCrossRefGoogle Scholar
Suter M, Richter C. Fragmented mitochondrial DNA is the predominant carrier of oxidized DNA bases. Biochemistry
. 1999;38(1):459–464.PubMedCrossRefGoogle Scholar
Helbock HJ, Beckman KB, Shigenaga MK, et al. DNA oxidation matters: the HPLC-electrochemical detection assay of 8-oxo-deoxyguanosine and 8-oxo-guanine. Proc Natl Acad Sci USA
. 1998;95(1):288–293.PubMedCrossRefGoogle Scholar
Hayakawa M, Ogawa T, Sugiyama S, Tanaka M, Ozawa T. Massive conversion of guanosine to 8-hydroxy-guanosine in mouse liver mitochondrial DNA by administration of azidothymidine. Biochemical and Biophysical Research Communications
. 1991;176:87–93.PubMedCrossRefGoogle Scholar
Dizdaroglu M. Chemical determination of oxidative DNA damage by gas chromatography-mass spectrometry. Methods Enzymol.
Wassermann K, Kohn KW, Bohr VA. Heterogeneity of nitrogen mustard-induced DNA damage and repair at the level of the gene in Chinese hamster ovary cells. Journal of Biological Chemistry
. 1990;265:13906–13913.Google Scholar
Epe B, Hegler J, Wild D. Singlet oxygen as an ultimately reactive species in Salmonella typhimurium DNA damage induced by methylene blue/visible light. Carcinogenesis
. 1989;10:2019–2024.PubMedGoogle Scholar
Hegler J, Bittner D, Boiteux S, Epe B. Quantification of oxidative DNA modifications in mitochondria. Carcinogenesis
. 1993;14:2309–2312.PubMedGoogle Scholar
Bohr VA, Smith CA, Okumoto DS, Hanawalt PC. DNA repair in an active gene: removal of pyrimidine dimers from the DHFR gene of CHO cells is much more efficient than in the genome overall. Cell.
Bohr VA, Okumoto DS. Analysis of pyrimidine dimers in defined genes. In: Friedberg EC, Hanawalt PC, eds. DNA Repair: A laboratory manual of research procedures, VoL III
. 0 ed. New York and Basel: Marcel Dekker, Inc.; 1988:347–366.Google Scholar
Kalinowski DP, Illenye S, Van Houten B. Analysis of DNA damage and repair in murine leukemia L1210 cells using a quantitative polymerase chain reaction assay. Nucleic Acids Research
. 1992;20(13): 3485–3494.PubMedGoogle Scholar
Yakes FM, Van Houten B. Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress. Proc Natl Acad Sci USA.
1997; 94(2):514–519.PubMedCrossRefGoogle Scholar
Drouin R, Rodriguez H, Holmquist GP, Akman SA. In vivo Cu-H202-and H202-induced DNA damage maps show the same oxidative damage frequency for each nucleotide position. Proceedings of the National Academy of Sciences of the United States of America.
Vol. 36; 1995:550.Google Scholar
Rodriguez H, Drouin R, Holmquist GP, et al. Mapping of copper hydrogen peroxide-induced DNA damage at nucleotide resolution in human genomic DNA by ligation-mediated polymerase chain reaction. Journal of Biological Chemistry
. 1995;270:17633–17640.Google Scholar
Driggers WJ, Holmquist GP, LeDoux SP, Wilson GL. Mapping frequencies of endogenous oxidative damage and the kinetic response to oxidative stress in a region of rat mtDNA. Nucleic Acids Res.
1997;25(21): 4362–4369.PubMedCrossRefGoogle Scholar
Mueller PR, Wold B. In vivo footprinting of a muscle specific enhancer by Ligation Mediated PCR. Science
. 1989;246:780–786.PubMedGoogle Scholar
Pfeifer GP, Drouin R, Riggs AD, Holmquist GP. Binding of transcription factors creates hot spots for UV photoproducts in vivo. Mol Cell Biol.
Soultanakis RP, Melamede RJ, Bespalov IA, et al. Fluorescence detection of 8-oxoguanine in nuclear and mitochondrial DNA of cultured cells using a recombinant fab and confocal scanning laser microscopy. Free Radic Biol Med.
Beckman KB, Ames BN. Oxidative decay of DNA. J Biol Chem.
Collins A, Cadet J, Epe B, Gedik C. Problems in the measurement of 8-oxoguanine in human DNA. Report of a workshop, DNA oxidation, held in Aberdeen, UK, 19–21 January, 1997. Carcinogenesis
. 1997; 18(9):1833–1836.PubMedCrossRefGoogle Scholar
ESCODD. Comparison of different methods of measuring 8-oxoguanine as a marker of oxidative DNA damage. ESCODD (European Standards Committee on Oxidative DNA Damage). Free Radic Res.
Hudson EK, Hogue BA, Souza-Pinto NC, et al. Age-associated change in mitochondrial DNA damage. Free Radical Research
. 1998;29(6):573–579.PubMedGoogle Scholar
Anson RM, Hudson E, Bohr VA. Mitochondrial endogenous oxidative damage has been overestimated. Faseb J.
Richter C, Park JW, Ames BN. Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proceedings of the National Academy of Sciences of the United States of America
. 1988;85(17): 6465–6467.PubMedGoogle Scholar
Higuchi Y, Linn S. Purification of all forms of HeLa cell mitochondrial DNA and assessment of damage to it caused by hydrogen peroxide treatment of mitochondria or cells. Journal of Biological Chemistry
. 1995; 270(14):7950–7956.PubMedCrossRefGoogle Scholar
Takasawa M, Hayakawa M, Sugiyama S, Hattori K, Ito T, Ozawa T. Age-associated damage in mitochondrial function in rat hearts. Exp Gerontol.
Beckman KB, Ames BN. Detection and quantification of oxidative adducts of mitochondrial DNA Methods in Enzymology
. 1996;264:442–453.PubMedGoogle Scholar
Beckman KB, Ames BN. Endogenous oxidative damage of mtDNA. Mutat Res.
1999;424(1–2): 51–58.PubMedGoogle Scholar
Hayakawa M, Sugiyama S, Hattori K, Takasawa M, Ozawa T. Age-associated damage in mitochondrial DNA in human hearts. Mol Cell Biochem.
1993; 119:95–103.PubMedCrossRefGoogle Scholar
Zastawny TH, Dabrowska M, Jaskolski T, et al. Comparison of oxidative base damage in mitochondria and nuclear DNA. Free Radic Biol Med.
Anson RM, Senturker S, Dizdaroglu M, Bohr VA. Measurement of oxidatively induced base lesions in liver from Wistar rats of different ages. Free Radic Biol Med.
Chung MH, Kasai H, Nishimura S, Yu BP. Protection of DNA damage by dietary restriction. Free Radical Biology and Medicine
. 1992;12(6):523–525.PubMedCrossRefGoogle Scholar
Sohal RS, Agarwal S, Candas M, Forster MJ, Lal H. Effect of age and caloric restriction on DNA oxidative damage in different tissues of C57BL/6 mice. Mechanisms of Ageing and Development
. 1994;76:215–224.PubMedCrossRefGoogle Scholar
Lass A, Sohal BH, Weindruch R, Forster MJ, Sohal RS. Caloric restriction prevents age-associated accrual of oxidative damage to mouse skeletal muscle mitochondria. Free Radic Biol Med.
1998;25(9): 1089–1097.PubMedCrossRefGoogle Scholar
Masoro EJ. Dietary restriction. Exp Gerontol.
Cortopassi GA, Arnheim N. Detection of a specific mitochondrial DNA deletion in tissues of older humans. Nucleic Acids Res.
Linnane AW, Baumer A, Maxwell RJ, Preston H, Zhang CF, Marzuki S. Mitochondrial gene mutation: the ageing process and degenerative diseases. Biochemistry International
. 1990;22:1067–1076.PubMedGoogle Scholar
Cortopassi GA, Shibata D, Soong NW, Arnheim N. A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues. Proceedings of the National Academy of Science USA
. 1992;89:7370–7374.Google Scholar
Simonetti S, Chen X, DiMauro S, Schon EA. Accumulation of deletions in human mitochondrial DNA during normal aging: analysis by quantitative PCR. Biochim Biophys Acta.
Lee HC, Pang CY, Hsu HS, Wei YH. Differential accumulations of 4,977 bp deletion in mitochondrial DNA of various tissues in human ageing. Biochim Biophys Acta.
Filser N, Margue C, Richter C. Quantification of wild-type mitochondrial DNA and its 4.8-kb deletion in rat organs. Biochem Biophys Res Commun.
1997;233(1): 102–107.PubMedCrossRefGoogle Scholar
Liu VW, Zhang C, Pang CY, et al. Independent occurrence of somatic mutations in mitochondrial DNA of human skin from subjects of various ages. Hum Mutat.
Soong NW, Hinton DR, Cortopassi G, Arnheim N. Mosaicism for a specific somatic mitochondrial DNA mutation in adult human brain. Nat Genet.
Corral-Debdnski M, Horton T, Lott MT, Shoffner JM, Beal MF, Wallace DC. Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nat Genet.
Filburn CR, Edris W, Tamatani M, Hogue B, Kudryashova I, Hansford RG. Mitochondrial electron transport chain activities and DNA deletions in regions of the rat brain. Mech Ageing Dev.
Luo Y, Roth GS. The roles of dopamine oxidative stress and dopamine receptor signaling in aging and age-related neurodegeneration. Antioxidants and Redox Signaling
. 2000;In Press.Google Scholar
de Grey AD. A proposed refinement of the mitochondrial free radical theory of aging. Bioessays.
Gershon D. The mitochondrial theory of aging: is the culprit a faulty disposal system rather than indigenous mitochondrial alterations? [comment]. Exp Gerontol.
Kowald A. The mitochondrial theory of aging: do damaged mitochondria accumulate by delayed degradation?. Exp Gerontol.
Wang E, Wong A, Cortopassi G. The rate of mitochondrial mutagenesis is faster in mice than humans. Mutat Res.
Hattori K, Tanaka M, Sugiyama S, et al. Age-dependent increase in deleted mitochondrial DNA in the human heart: possible contributory factor to presbycardia. American Heart Journal.
Katayama M, Tanaka M, Yamamoto H, Ohbayashi T, Nimura Y, Ozawa T. Deleted mitochondrial DNA in the skeletal muscle of aged individuals. Biochem Int.
Zhang C, Baumer A, Maxwell RJ, Linnane AW, Nagley P. Multiple mitochondrial DNA deletions in an eldedy human individual. FEBS Lett.
Lee CM, Chung SS, Kaczkowski JM, Weindruch R, Aiken JM. Multiple mitochondrial DNA deletions associated with age in skeletal muscle of rhesus monkeys. Journal of Gerontology
. 1993;48:B201–B205.PubMedGoogle Scholar
Melov S, Shoffner JM, Kaufman A, Wallace DC. Marked increase in the number and variety of mitochondrial DNA rearrangements in aging human skeletal muscle [published erratum appears in Nucleic Acids Res 1995 Dec 11;23(23): 4938]. Nucleic Acids Res.
Reynier P, Malthiery Y. Accumulation of deletions in MtDNA during tissue aging: analysis by long PCR. Biochem Biophys Res Commun.
Eimon PM, Chung SS, Lee CM, Weindruch R, Aiken JM. Age-associated mitochondrial DNA deletions in mouse skeletal muscle: comparison of different regions of the mitochondrial genome. Dev Genet.
1996;18(2): 107–113.PubMedCrossRefGoogle Scholar
Tengan CH, Moraes CT. Detection and analysis of mitochondrial DNA deletions by whole genome PCR. Biochem Mol Med.
Zhang C, Liu VW, Addessi CL, Sheffield DA, Linnane AW, Nagley P. Differential occurrence of mutations in mitochondrial DNA of human skeletal muscle during aging [published erratum appears in Hum Mutat 1998;12(1):69]. Hum Mutat.
Lee HC, Pang CY, Hsu HS, Wei YH. Ageing-associated tandem duplications in the D-loop of mitochondrial DNA of human muscle. FEBS Lett.
Wei YH, Pang CY, You BJ, Lee HC. Tandem duplications and large-scale deletions of mitochondrial DNA are early molecular events of human aging process. Ann N Y Acad Sci.
Schwarze SR, Lee CM, Chung SS, Roecker EB, Weindruch R, Aiken JM. High levels of mitochondrial DNA deletions in skeletal muscle of old rhesus monkeys. Mech Ageing Dev.
Muller-Hocker J, Seibel P, Schneiderbanger K, Kadenbach B. Different in situ hybridization patterns of mitochondrial DNA in cytochrome c oxidase-deficient extraocular muscle fibres in the elderly. Virchows Arch A Pathol Anat Histopathol.
Moslemi AR, Melberg A, Holme E, Oldfors A. Clonal expansion of mitochondrial DNA with multiple deletions in autosomal dominant progressive external ophthalmoplegia. Ann Neurol.
Muller-Hocker J, Jacob U, Seibel P. Hashimoto thyroiditis is associated with defects of cytochrome-c oxidase in oxyphil Askanazy cells and with the common deletion (4,977) of mitochondrial DNA. Ultrastruct Pathol.
1998; 22(1):91–100.PubMedCrossRefGoogle Scholar
Prelle A, Fagiolari G, Checcarelli N, et al. Mitochondrial myopathy: correlation between oxidative defect and mitochondrial DNA deletions at single fiber level. Acta Neuropathol (Berl)
. 1994;87(4):371–376.Google Scholar
Lee CM, Lopez ME, Weindruch R, Aiken JM. Association of age-related mitochondrial abnormalities with skeletal muscle fiber atrophy. Free Radic Biol Med.
Hayakawa M, Torii K, Sugiyama S, Tanaka M, Ozawa T. Age-associated accumulation of 8-hydroxydeoxyguanosine in mitochondrial DNA of human diaphragm. Biochem Biophys Res Commun.
Hayakawa M, Hattori K, Sugiyama S, Ozawa T. Age-associated oxygen damage and mutations in mitochondrial DNA in human hearts. Biochemical and Biophysical Research Communications
. 1992;189:979–985.PubMedCrossRefGoogle Scholar
Yen TC, King KL, Lee HC, Yeh SH, Wei YH. Age-dependent increase of mitochondrial DNA deletions together with lipid peroxides and superoxide dismutase in human liver mitochondria. Free Radic Biol Med.
1994;16(2): 207–214.PubMedCrossRefGoogle Scholar
Wei YH, Kao SH, Lee HC. Simultaneous increase of mitochondrial DNA deletions and lipid peroxidation in human aging. Ann N Y Acad Sci.
Lezza AM, Mecocci P, Cormio A, et al. Mitochondrial DNA 4977 bp deletion and OH8dG levels correlate in the brain of aged subjects but not Alzheimer’s disease patients. Faseb J.
Muscari C, Giaccari A, Stefanelli C, et al. Presence of a DNA-4236 bp deletion and 8-hydroxy-deoxyguanosine in mouse cardiac mitochondrial DNA during aging. Aging (Milano)
. 1996;8(6):429–433.Google Scholar
Aruoma OI, Halliwell B, Gajewski E, Dizdaroglu M. Copper-ion-dependent damage to the bases in DNA in the presence of hydrogen peroxide. Biochemical Journal
. 1991;273:601–604.PubMedGoogle Scholar
Yamamoto F, Kasai H, Togashi Y, Takeichi N, Hori T, Nishimura S. Elevated level of 8-hydroxydeoxyguanosine in DNA of liver, kidneys, and brain of Long-Evans Cinnamon rats. Japanese Joumal of Cancer Research
. 1993; 84(5):508–511.Google Scholar
Mansouri A, Gaou I, Fromenty B, et al. Premature oxidative aging of hepatic mitochondrial DNA in Wilson’s disease. Gastroenterology
. 1997;113(2):599–605.PubMedCrossRefGoogle Scholar
Kubota N, Hayashi J, Inada T, Iwamura Y. Induction of a particular deletion in mitochondrial DNA by X rays depends on the inherent radiosensitivity of the cells. Radiat Res.
Lezza AM, Boffoli D, Scacco S, Cantatore P, Gadaleta MN. Correlation between mitochondrial DNA 4977-bp deletion and respiratory chain enzyme activities in aging human skeletal muscles. Biochem Biophys Res Commun.
Tengan CH, Gabbai AA, Shanske S, Zeviani M, Moraes CT. Oxidative phosphorylation dysfunction does not increase the rate of accumulation of age-related mtDNA deletions in skeletal muscle. Mutat Res.
1997; 379(1):1–11.PubMedGoogle Scholar
Pacifici RE, Davies KJ. Protein, lipid and DNA repair systems in oxidative stress: the free-radical theory of aging revisited. Gerontology
. 1991;37:166–180.PubMedCrossRefGoogle Scholar
McCord JM, Fridovich I. Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J Biol Chem.
Reaume AG, Elliott JL, Hoffman EK, et al. Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. NatGenet.
Kondo T, Reaume AG, Huang TT, et al. Reduction of CuZn-superoxide dismutase activity exacerbates neuronal cell injury and edema formation after transient focal cerebral ischemia. J Neurosci.
1997;17(11): 4180–4189.PubMedGoogle Scholar
Li Y, Huang TT, Carlson EJ, et al. Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nat Genet.
Melov S, Schneider JA, Day BJ, et al. A novel neurological phenotype in mice lacking mitochondrial manganese superoxide dismutase. Nat Genet.
Ishii N, Fujii M, Hartman PS, et al. A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes. Nature
. 1998;394(6694):694–697.PubMedCrossRefGoogle Scholar
Guidot DM, Repine JE, Kitlowski AD, et al. Mitochondrial respiration scavenges extramitochondrial superoxide anion via a nonenzymatic mechanism. J Clin Invest.
Clayton DA, Doda JN, Friedberg EC. The absence of a pyrimidine dimer repair mechanismin mammalian mitochondria. Proceedings of the National Academy of Sciences of the United States of America
. 1974; 71(7):2777–2781.PubMedGoogle Scholar
Ryoji M, Katayama H, Fusamae H, Matsuda A, Sakai F, Utano H. Repair of DNA damage in a mitochondrial lysate of Xenopus laevis oocytes. Nucleic Acids Research
. 1996;24(20):4057–4062.PubMedCrossRefGoogle Scholar
Lansman RA, Clayton DA. Selective nicking of mammalian mitochondrial DNA in vivo: photosensitization by incorporation of 5-bromodeoxyuridine. Journal of Molecular Biology
. 1975;99:761–776.PubMedGoogle Scholar
Pascucci B, Versteegh A, van Hoffen A, van Zeeland AA, Mullenders LH, Dogliotti E. DNA repair of UV photoproducts and mutagenesis in human mitochondrial DNA. J Mol Biol.
LeDoux SP, Wilson GL, Beecham EJ, Stevnsner T, Wassermann K, Bohr VA. Repair of mitochondrial DNA after various types of DNA damage in Chinese hamster ovary cells. Carcinogenesis
. 1992;13:1967–1973.PubMedGoogle Scholar
Bohr VA. Gene specific DNA repair. Carcinogenesis
. 1991;12:1983–1992.PubMedGoogle Scholar
Mellon I, Spivak G, Hanawalt PC. Selective removal of transcription-blocking DNA damage from the transcribed strand of the mammalian DHFR gene. Cell
. 1987;51(2):241–249.PubMedCrossRefGoogle Scholar
Pfeifer GP, Drouin R, Holmquist GP. Detection of DNA adducts at the DNA sequence level by ligation-mediated PCR. Mutation Research
. 1993;288:39–46.PubMedGoogle Scholar
Hanawalt PC, Gee P, Ho L, Hsu RK, Kane CJ. Genomic heterogeneity of DNA repair. Role in aging? Annals of the New York Academy of Sciences
. 1992;663:17–25.PubMedGoogle Scholar
Holmes GE, Bernstein C, Bernstein H. Oxidative and other DNA damages as the basis of aging: a review. Mutation Research
. 1992;275:305–315.PubMedCrossRefGoogle Scholar
Bohr VA, Anson RM. DNA damage, mutation and fine structure DNA repair in aging. Mutation Research
. 1995;338(1–6):25–34.PubMedGoogle Scholar
Myers KA, Saffhill R, O’Connor PJ. Repair of alkylated purines in the hepatic DNA of mitochondria and nuclei in the rat. Carcinogenesis
. 1988;9(2):285–292.PubMedGoogle Scholar
Satoh MS, Huh N, Rajewsky MF, Kuroki T. Enzymatic removal of O6-ethylguanine from mitochondrial DNA in rat tissues exposed to N-ethyl-N-nitrosourea in vivo. Journal of Biological Chemistry
. 1988;263(14): 6854–6856.PubMedGoogle Scholar
Pettepher CC, LeDoux SP, Bohr VA, Wilson GL. Repair of alkali-labile sites within the mitochondrial DNA of RINr 38 cells after exposure to the nitrosourea streptozotocin. Journal of Biological Chemistry
. 1991; 266:3113–3117.PubMedGoogle Scholar
Pirsel M, Bohr VA. Methyl methanesulfonate adduct formation and repair in the DHFR gene and in mitochondrial DNA in hamster cells. Carcinogenesis
. 1993;14:2105–2108.PubMedGoogle Scholar
Cullinane C, Bohr VA. DNA interstrand cross-links induced by psoralen are not repaired in mammalian mitochondria. Cancer Res.
Snyderwine EG, Bohr VA. Gene-and strand-specific damage and repair in Chinese hamster ovary cells treated with 4-nitroquinoline 1-oxide. Cancer Research
. 1992;52:4183–4189.PubMedGoogle Scholar
Thyagarajan B, Padua RA, Campbell C. Mammalian mitochondria possess homologous DNA recombination activity. Journal of Biological Chemistry
. 1996;271(44):27536–27543.Google Scholar
Richter C. Reactive oxygen and DNA damage in mitochondria. Mutation Research
. 1992;275: 249–255.PubMedCrossRefGoogle Scholar
Driggers WJ, LeDoux SP, Wilson GL. Repair of oxidative damage within the mitochondrial DNA of RINr 38 cells. Journal of Biological Chemistry
. 1993;268:22042–22045.Google Scholar
Chung MH, Kiyosawa H, Ohtsuka E, Nishimura S, Kasai H. DNA strand cleavage at 8-hydroxyguanine residues by hot piperidine treatment. Biochemical and Biophysical Research Communications
. 1992;188:1–7.PubMedCrossRefGoogle Scholar
Driggers WJ, Grishko VI, LeDoux SP, Wilson GL. Defective repair of oxidative damage in the mitochondrial DNA of a xeroderma pigmentosum group A cell line. Cancer Research
. 1996;56(6):1262–1266.PubMedGoogle Scholar
Shen CC, Wertelecki W, Driggers WJ, LeDoux SP, Wilson GL. Repair of mitochondrial DNA damage induced by bleomycin in human cells. Mutation Research
. 1995;337(1):19–23.PubMedGoogle Scholar
Anson RM, Croteau DL, Stierum RH, Filburn F, Parsell R, Bohr VA. Homogenous repair of singlet oxygen-induced DNA damage in differentially transcribed regions and strands of human mitochondrial DNA. Nucleic Acids Research
. 1998;26(2):662–668.PubMedCrossRefGoogle Scholar
Taffe BG, Larminat F, Laval J, Croteau DL, Anson RM, Bohr VA. Gene-specific nuclear and mitochondrial repair of formamidopyrimidine DNA glycosylase-sensitive sites in Chinese hamster ovary cells. Mutation Research
. 1996;364(3):183–192.PubMedGoogle Scholar
Epe B, Pflaum M, Boiteux S. DNA damage induced by photosensitizers in cellular and cell-free systems. Mutation Research
. 1993;299:135–145.PubMedCrossRefGoogle Scholar
Epe B, Pflaum M, Haring M, Hegler J, Rudiger H. Use of repair endonucleases to characterize DNA damage induced by reactive oxygen species in cellular and cell-free systems. Toxicol Lett.
Horai S, Hayasaka K. Intraspecific nucleotide sequence differences in the major noncoding region of human mitochondrial DNA. American Journal of Human Genetics
. 1990;46:828–842.PubMedGoogle Scholar
Crawford DR, Wang Y, Schools GP, Kochheiser J, Davies KJ. Down-regulation of mammalian mitochondrial RNAs during oxidative stress. Free Radic Biol Med.
Abramova NE, Davies KJA, Crawford DR. Polynucleotide degradation during early stage response to oxidative stress is specific to mitochondria. Free Radical Biology and Medicine
. 2000;28(2):281–288.PubMedCrossRefGoogle Scholar
Tang JT, Yamazaki H, Inoue T, et al. Mitochondrial DNA influences radiation sensitivity and induction of apoptosis in human fibroblasts. Anticancer Research
. 1999;19(6B):4959–4964.PubMedGoogle Scholar
Fung H, Kow YW, Van Houten B, et al. Asbestos increases mammalian AP-endonuclease gene expression, protein levels, and enzyme activity in mesothelial cells. Cancer Res.
Souza-Pinto NC, Croteau DL, Hudson EK, Hansford RG, Bohr VA. Age-associated increase in 8-oxo-deoxyguanosine glycosylase/AP lyase activity in rat mitochondria. Nucleic Acids Research
. 1999;27(8):1935–1942.PubMedCrossRefGoogle Scholar
Anderson CT, Friedberg EC. The presence of nuclear and mitochondrial uracil-DNA glycosylase in extracts of human KB cells. Nucleic Acids Research
. 1980;8(4):875–888.PubMedGoogle Scholar
Caradonna S, Ladner R, Hansbury M, Kosciuk M, Lynch F, Muller S. Affinity purification and comparative analysis of two distinct human uracil DNA glycosylases. Exp Cell Res.
Nilsen H, Otterlei M, Haug T, et al. Nuclear and mitochondrial uracil-DNA glycosylases are generated by alternative splicing and transcription from different positions in the UNG gene. Nucleic Acids Research
. 1997;25(4):750–755.PubMedCrossRefGoogle Scholar
Tomkinson AE, Bonk RT, Linn S. Mitochondrial endonuclease activities specific for apurinic/apyrimidinic sites in DNA from mouse cells. Journal of Biological Chemistry
. 1988;263(25):12532–12537.Google Scholar
Croteau DL, ap Rhys CM, Hudson EK, Dianov GL, Hansford RG, Bohr VA. An oxidative damage-specific endonuclease from rat liver mitochondria. J Biol Chem.
Rosenquist TA, Zharkov DO, Grollman AP. Cloning and characterization of a mammalian 8-oxoguanine DNA glycosylase. Proc Natl Acad Sci U S A
. 1997;94(14):7429–7434.PubMedCrossRefGoogle Scholar
Takao M, Aburatani H, Kobayashi K, Yasui A. Mitochondrial targeting of human DNA glycosylases for repair of oxidative DNA damage. Nucleic Acids Res.
Vanderstraeten S, Van den Brule S, Hu J, Foury F. The role of 3′-5′ exonucleolytic proofreading and mismatch repair in yeast mitochondrial DNA error avoidance. J Biol Chem.
1998; 273(37):23690–23697.Google Scholar
Pinz KG, Bogenhagen DF. Efficient repair of abasic sites in DNA by mitochondrial enzymes. Mol Cell Biol.
Reenan RA, Kolodner RD. Characterization of insertion mutations in the Saccharomyces cerevisiae MSH1 and MSH2 genes: evidence for separate mitochondrial and nuclear functions. Genetics
. 1992;132:975–985.PubMedGoogle Scholar
Shadel GS, Clayton DA. Mitochondrial DNA maintenance in vertebrates. Annu Rev Biochem.
1997; 66:409–435.PubMedCrossRefGoogle Scholar
Awadalla P, Eyre-Walker A, Smith JM. Linkage disequilibrium and recombination in hominid mitochondrial DNA. Science
. 1999;286(5449):2524–2525.PubMedCrossRefGoogle Scholar
Hagelberg E, Goldman N, Lio P, et al. Evidence for mitochondrial DNA recombination in a human population of island Melanesia. Proc R Soc Lond B Biol Sci.
Ikeda S, Ozaki K. Action of mitochondrial endonuclease G on DNA damaged by L-ascorbic acid, peplomycin, and cis-diamminedichloroplatinum (II). Biochem Biophys Res Commun.
Le XC, Xing JZ, Lee J, Leadon SA, Weinfeld M. Inducible repair of thymine glycol detected by an ultrasensitive assay for DNA damage. Science
. 1998;280(5366):1066–1069.PubMedCrossRefGoogle Scholar
Ku HH, Sohal RS. Comparison of mitochondrial pro-oxidant generation and anti-oxidant defenses between rat and pigeon: possible basis of variation in longevity and metabolic potential. Mechanisms of Ageing and Development
. 1993;72:67–76.PubMedCrossRefGoogle Scholar
Barja G, Cadenas S, Rojas C, Perez-Campo R, Lopez-Torres M. Low mitochondrial free radical production per unit O2 consumption can explain the simultaneous presence of high longevity and high aerobic metabolic rate in birds. Free Radic Res.
Ogburn CE, Austad SN, Holmes DJ, et al. Cultured renal epithelial cells from birds and mice: Enhanced resistance of avian cells to oxidative stress and DNA damage. Journals of Gerontology Series A-Biological Sciences and Medical Sciences
. 1998;53(4):B287–B292.Google Scholar
Herrero A, Barja G. 8-oxo-deoxyguanosine levels in heart and brain mitochondrial and nuclear DNA of two mammals and three birds in relation to their different rates of aging. Aging-Clinical And Experimental Research
. 1999;11(5):294–300.Google Scholar
Barja G, Herrero A. Oxidative damage to mitochondrial DNA is inversely related to maximum life span in the heart and brain of mammals. FASEB Journal
Williams MD, Van Remmen H, Conrad CC, Huang TT, Epstein CJ, Richardson A. Increased oxidative damage is correlated to altered mitochondrial function in heterozygous manganese superoxide dismutase knockout mice. J Biol Chem.
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