Mitochondrial DNA oxidative damage and repair in aging and Alzheimer's disease

Antioxidants and Redox Signaling

Volumn 18, Issue 18, 2013, Pages 2444-2457

  Santos, Renato X ^a,b   Correia, Sónia C ^a,b   Zhu, Xiongwei ^c   Smith, Mark A ^c   Moreira, Paula I ^a,d   Castellani, Rudy J ^e   Nunomura, Akihiko ^f   Perry, George ^g  

^a UNIVERSITY OF COIMBRA   (Portugal)

^b UNIVERSITY OF COIMBRA   (Portugal)

^c CASE WESTERN RESERVE UNIVERSITY   (United States)

^d UNIVERSITY OF COIMBRA   (Portugal)

^e UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE   (United States)

^f UNIVERSITY OF YAMANASHI   (Japan)

^g UNIVERSITY OF TEXAS AT SAN ANTONIO   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DNA (APURINIC OR APYRIMIDINIC SITE) LYASE; MANGANESE SUPEROXIDE DISMUTASE; MITOCHONDRIAL DNA; MITOCHONDRIAL PERMEABILITY TRANSITION PORE; NITRIC OXIDE SYNTHASE; REACTIVE OXYGEN METABOLITE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE; XANTHINE OXIDASE;

AGING; ALZHEIMER DISEASE; APOPTOSIS; CALCIUM HOMEOSTASIS; CALCIUM TRANSPORT; CELL COMPARTMENTALIZATION; CELL MATURATION; CELL STRESS; CELL STRUCTURE; CELL SURVIVAL; COGNITION; DISORDERS OF MITOCHONDRIAL FUNCTIONS; DNA DAMAGE; DNA MODIFICATION; DNA REPAIR; EXCISION REPAIR; GENETIC TRANSCRIPTION; HUMAN; MITOCHONDRIAL PERMEABILITY; MITOCHONDRIAL RESPIRATION; MITOCHONDRION; NONHUMAN; OXIDATIVE STRESS; OXYGEN CONSUMPTION; PRIORITY JOURNAL; PROTEIN LOCALIZATION; REVIEW; RISK FACTOR; SINGLE STRANDED DNA BREAK;

AGING; ALZHEIMER DISEASE; ANIMALS; BRAIN; DNA DAMAGE; DNA REPAIR; DNA, MITOCHONDRIAL; HUMANS; MITOCHONDRIA; OXIDATION-REDUCTION; OXIDATIVE STRESS; REACTIVE OXYGEN SPECIES;

ANIMALIA;

EID: 84878619863     PISSN: 15230864     EISSN: 15577716     Source Type: Journal    
DOI: 10.1089/ars.2012.5039     Document Type: Review

References (210)

1. Addabbo F, Montagnani M, and Goligorsky MS. Mitochondria and reactive oxygen species. Hypertens 53: 885-892, 2009.
2. Akbari M, Visnes T, Krokan HE, and Otterlei M. Mi-tochondrial base excision repair of uracil and AP sites takes place by single-nucleotide insertion and long-patch DNA synthesis. DNA Repair (Amst) 7: 605-616, 2008.
3. Akiyama H, Barger S, Barnum S, et al. Inflammation and Alzheimer's disease. Neurobiol Aging 21: 383-421, 2000.
4. Anderson S, Bankier AT, Barrell BG, et al. Sequence and organization of the human mitochondrial genome. Nature 290: 457-465, 1981.
5. Ansari MA and Scheff SW. Oxidative stress in the progression of alzheimer disease in the frontal cortex. J Neu-ropathol Exp Neurol 69: 155-167, 2010.
6. Atamna H and Frey WH, 2nd. A role for heme in Alzheimer's disease: heme binds amyloid beta and has altered metabolism. Proc Natl Acad Sci USA 101: 11153-11158, 2004.
7. Atamna H. Heme binding to Amyloid-beta peptide: mechanistic role in Alzheimer's disease. J Alzheimers Dis 10: 255-266, 2006.
8. Azari NP, Pettigrew KD, Schapiro MB, et al. Early detection of Alzheimer's disease: a statistical approach using positron emission tomographic data. J Cereb Blood Flow Metab 13: 438-447, 1993.
9. Bagh MB, Thakurta IG, Biswas M, Behera P, and Chakra-barti S. Age-related oxidative decline of mitochondrial functions in rat brain is prevented by long term oral antioxidant supplementation. Biogerontology 12:119-131, 2010.
10. Balaban RS, Nemoto S, and Finkel T. Mitochondria, oxi-dants, and aging. Cell 120: 483-495, 2005.
11. Baldeiras I, Santana I, Proença MT, et al. Oxidative damage and progression to Alzheimer's disease in patients with mild cognitive impairment. J Alzheimers Dis 21: 1165-1177, 2010.
12. Barja G and Herrero I. Oxidative damage to mitochondrial DNA is inversely related to maximum life span in the heart and brain of mammals. FASEB J 14: 312-318, 2000.
13. Baughman JM, Perocchi F, Girgis HS, Plovanich M, et al. Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476: 341-345, 2011.
14. Benard, G and Karbowski M. Mitochondrial fusion and division: regulation and role in cell viability. Semin Cell Dev Biol 20: 365-374, 2009.
15. Bender A, Krishnan KJ, Morris CM, et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet 38: 515-517, 2006.
16. Block ML. NADPH oxidase as a therapeutic target in Alzheimer's disease. BMC Neurosci Suppl 2: S8, 2008.
17. Bogenhagen DF. Repair of mtDNA in vertebrates. Am J Hum Genet 64: 1276-1281, 1999.
18. Bohr VA. Defective DNA base excision repair in brain from individuals with Alzheimer's disease and amnestic mild cognitive impairment. Nucleic Acids Res 35: 5545-5555, 2007.
19. Bohr VA. Repair of oxidative DNA damage in nuclear and mitochondrial DNA, and some changes with aging in mammalian cells. Free Radic Biol Med 32: 804-812, 2002.
20. Bokov A, Chaudhuri A, and Richardson A. The role of oxidative damage and stress in aging. Mech Ageing Dev 125: 811-826, 2004.
21. Bosetti F, Brizzi F, Barogi S, et al. Cytochrome c oxidase and mitochondrial F1F0-ATPase (ATP synthase) activities in platelets and brain from patients with Alzheimer's disease. Neurobiol Aging 23: 371-376, 2002.
22. Bowling AC, Mutisya EM, Walker LC, Price DL, Cork LC, and Beal MH. Age-dependent impairment of mitochondrial function in primate brain. J Neurochem 60: 1964-1967, 1993.
23. Brand MD. The sites and topology of mitochondrial superoxide production. Exp Gerontol 45: 466-472, 2010.
24. Brown MR, Sullivan PG, and Geddes JW. Synaptic mitochondria are more susceptible to Ca2+ overload than nonsynaptic mitochondria. J Biol Chem 28: 11658-11668, 2006.
25. Bubber P, Haroutunian V, Fisch G, Blass JP, and Gibson GE. Mitochondrial abnormalities in Alzheimer brain: mechanistic implications. Ann Neurol 57: 695-703, 2005.
26. Buchholz JN, Behringer EJ, Pottorf WJ, Pearce WJ, and Vanterpool CK. Age-dependent changes in Ca2+ homeo-stasis in peripheral neurones: implications for changes in function. Aging Cell 6: 285-296, 2007.
27. Budimir A. Metal ions, Alzheimer's disease and chelation therapy. Acta Pharm 61: 1-14, 2011.
28. Cakatay U, Telci A, Kayal̀i R, Tekeli F, Akçay T, and Sivas A. Relation of oxidative protein damage and nitrotyrosine levels in the aging rat brain. Exp Gerontol 36: 221-229, 2001.
29. Camandola S and Mattson MP. Aberrant subcellular neuronal calcium regulation in aging and Alzheimer's disease. Biochim Biophys Acta 1813: 965-973, 2011.
30. Canevari L, Clark JB, and Bates TE. Beta-Amyloid fragment 25-35 selectively decreases complex IV activity in isolated mitochondria. FEBS Lett 457: 131-134, 1999.
31. Caradonna S, Ladner R, Hansbury M, Kosciuk M, Lynch F, and Muller S. Affinity purification and comparative analysis of two distinct human uracil-DNA glycosylases. Exp Cell Res 222: 345-359, 1996.
32. Cardoso SM, Proenca MT, Santos S, Santana I, and Oliveira CR. Cytochrome c oxidase is decreased in Alzheimer's disease platelets. Neurobiol Aging 25: 105-110, 2004.
33. Carreras MC, Franco MC, Peralta JG, and Poderoso JJ. Nitric oxide, complex I, and the modulation of mitochon-drial reactive species in biology and disease. Mol Aspects Med 25: 125-139, 2004.
34. Castellani RJ, Rolston RK, and Smith MA. Alzheimer disease. Dis Mon 56: 484-546, 2010.
35. Celsi F, Pizzo P, Brini M, Leo S, Fotino C, Pinton P, and Rizzuto R. Mitochondria, calcium and cell death: a deadly triad in neurodegeneration. Biochim Biophys Acta 1787: 335-344, 2009.
36. Chakrabarti S, Munshi S, Banerjee K, Thakurta IG, Sinha M, and Bagh MB. Mitochondrial dysfunction during brain aging: role of oxidative stress and modulation by antioxi-dant supplementation. Aging Dis 2: 242-256, 2011.
37. Chakraborty H, Ray SN, and Chakrabarti S. Lipid peroxidation associated protein damage in rat brain crude syn-aptosomal fraction mediated by iron and ascorbate. Neurochem Int 39: 311-317, 2001.
38. Chan, DC. Mitochondria: dynamic organelles in disease, aging, and development. Cell 125: 1241-1252, 2006.
39. Chen D, Cao G, Hastings T, Feng Y, Pei W, O'Horo C, and Chen J. Age-dependent decline of DNA repair activity for oxidative lesions in rat brain mitochondria. J Neurochem 81: 1273-1284, 2002.
40. Chen H and Chan DC. Physiological functions of mito-chondrial fusion. Ann NY Acad Sci 1201: 21-25, 2010.
41. Cocco T, Sgobbo P, Clemente M, et al. Tissue-specific changes of mitochondrial functions in aged rats: effect of a long-term dietary treatment with N-acetylcysteine. Free Radic Biol Med 38: 796-805, 2005.
42. Cooke MS, Evans MD, Dizdaroglu M, and Lunec J. Oxi-dative DNA damage: mechanisms, mutation, and disease. FASEB J 17: 1195-1214, 2003.
43. Coskun PE, Beal MF, and Wallace DC. Alzheimer' s brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. Proc Natl Acad Sci USA 101: 10726-10731, 2004.
44. Crompton M. The mitochondrial permeability transition pore and its role in cell death. Biochem J 341: 233-249, 1999.
45. Curti D, Rognoni F, Gasparini L, et al. Oxidative metabolism in cultured fibroblasts derived from sporadic Alzheimer's disease (AD) patients. Neurosci Lett 236: 13-16, 1997.
46. de la Monte SM, Luong T, Neely TR, Robinson D, and Wands JR. Mitochondrial DNA damage as a mechanism of cell loss in Alzheimer's disease. Lab Invest 80: 1323-1335, 2000.
47. de Souza-Pinto NC, Eide L, Hogue BA, et al. Repair of 8-oxodeoxyguanosine lesions in mitochondrial DNA depends on the oxoguanine dna glycosylase (OGG1) gene and 8-oxoguanine accumulates in the mitochondrial dna of OGG1-defective mice. Cancer Res 61: 5378-5381, 2001.
48. De Stefani D, Raffaello A, Teardo E, Szabò I, and Rizzuto R. A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476: 336-340, 2011.
49. Demple B and Sung JS. Molecular and biological roles of Ape1 protein in mammalian base excision repair. DNA Repair (Amst) 4: 1442-1449, 2005.
50. Detmer SA and Chan DC. Functions and dysfunctions of mitochondrial dynamics. Nat Rev Mol Cell Biol 8: 870-879, 2007.
51. DiMauro S and Schon EA. Mitochondrial respiratory-chain diseases. N Engl J Med 348: 2656-2668, 2003.
52. Dimroth P, Kaim G, and Matthey U. Crucial role of the membrane potential for ATP synthesis by F(1)F(o) ATP synthases. J Exp Biol 203: 51-59, 2000.
53. Dizdaroglu M, Kirkali G, and Jaruga P. Formami-dopyrimidines in DNA: mechanisms of formation, repair, and biological effects. Free Radic Biol Med 45: 1610-1621, 2008.
54. Dizdaroglu M. Base-excision repair of oxidative DNA damage by DNA glycosylases. Mutat Res 591: 45-59, 2005.
55. Dumont M and Beal MF. Neuroprotective strategies involving ROS in Alzheimer disease. Free Radic Biol Med 51: 1014-1026, 2011.
56. Evans JL, Goldfine ID, Maddux BA, and Grodsky GM. Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. Endocr Rev 23: 599-622, 2002.
57. Fang H, Chen M, Ding Y, et al. Imaging superoxide flash and metabolism-coupled mitochondrial permeability transition in living animals. Cell Res 21: 1295-1304, 2011.
58. Ferrándiz ML, Mart́inez M, Juan ED, D́iez A, Bustos G, and Miquel J. Impairment of mitochondrial oxidative phosphorylation in the brain of aged mice. Brain Res 644: 335-338, 1994.
59. Filosto M, Scarpelli M, Cotelli MS, et al. The role of mitochondria in neurodegenerative diseases. J Neurol 258: 1763-1774, 2011.
60. Finefrock AE, Bush AI, and Doraiswamy PM. Current status of metals as therapeutic targets. J am Geriatr Soc 51: 1143-1148, 2003.
61. Floyd RA and Hensley K. Oxidative stress in brain aging. Implications for therapeutics of neurodegenerative diseases. Neurobiol Aging 23: 795-807, 2002.
62. 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 58: 189-194, 1998.
63. Gabbita SP, Lovell MA, and Markesbery WR. Increased nuclear DNA oxidation in the brain in Alzheimer's disease. J Neurochem 71: 2034-2040, 1998.
64. Gallagher JJ, Finnegan ME, Grehan B, Dobson J, Colling-wood JF, and Lynch MA. Modest amyloid deposition is associated with iron dysregulation, microglial activation, and oxidative stress. J Alzheimers Dis 28: 147-161, 2012.
65. Gao HM, Zhou H, and Hong JS. NADPH oxidases: novel therapeutic targets for neurodegenerative diseases. Trends Pharmacol Sci 33: 295-303, 2012.
66. Gemma C, Mesches MH, Sepesi B, Choo K, Holmes DB, and Bickford PC. Diets enriched in foods with high anti-oxidant activity reverse age-induced decreases in cerebellar b-adrenergic function and increases in proinflammatory cytokines. J Neurosci 22: 6114-6120, 2002.
67. Gilmer LK, Ansari MA, Roberts KN, and Scheff SW. Age-related changes in mitochondrial respiration and oxidative damage in the cerebral cortex of the Fischer 344 rat. Mech Ageing Dev 131: 133-143, 2010.
68. Gredilla R, Garm C, Holm R, Bohr VA, and Stevnsner T. Differential age-related changes in mitochondrial DNA repair activities in mouse brain regions. Neurobiol Aging 31: 993-1002, 2010.
69. Gredilla R, Weissman L, Yang JL, Bohr VA, and Stevnsner T. Mitochondrial base excision repair in mouse synapto-somes during normal aging and in a model of Alzheimer's disease. Neurobiol Aging 33: 694-707, 2012.
70. Gredilla R. DNA damage and base excision repair in mitochondria and their role in aging. J Aging Res 2011: 257093, 2010.
71. Green K, Brand MD, and Murphy MP. Prevention of mi-tochondrial oxidative damage as a therapeutic strategy in diabetes. Diabetes 53 Suppl 1: S110-S118, 2004.
72. Guidi, I, Galimberti D, Lonati S, Novembrino C, et al. Oxidative imbalance in patients with mild cognitive impairment and Alzheimer's disease. Neurobiol Aging 27: 262-269, 2006.
73. Hamanaka RB and Chandel NS. Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes.Trends Biochem Sci 35: 505-513, 2010.
74. Hansen AB, Griner NB, Anderson JP, Kujoth GC, Prolla TA, Loeb LA, and Glick E. Mitochondrial DNA integrity is not dependent on DNA polymerase-beta activity. DNA Repair (Amst) 5: 71-79, 2006.
75. Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol 11: 298-300, 1956.
76. Harman D. The free radical theory of aging. Antioxid Redox Signal 5: 57-56, 2003.
77. Hazra TK, Izumi T, Boldogh I, et al. Identification and characterization of a human DNA glycosylase for repair of modified bases in oxidatively damaged DNA. Proc Natl Acad Sci U S A 99: 3523-3528, 2002.
78. Head E, Liu J, Hagen TM, Muggenburg BA, Milgram NW, Ames BN, and Cotman CW. Oxidative damage increases with age in a canine model of human brain aging. J Neu-rochem 82: 375-381, 2002.
79. Hegde ML, Hegde PM, Holthauzen LM, Hazra TK, Rao KS, and Mitra S. Specific Inhibition of NEIL-initiated repair of oxidized base damage in human genome by copper and iron: potential etiological linkage to neurodegenerative diseases. J Biol Chem 285: 28812-28825, 2010.
80. Hengartner MO. The biochemistry of apoptosis. Nature 407: 770-776, 2000.
81. Hensley K, Hall N, Subramaniam R, et al. Brain regional correspondence between Alzheimer's disease histopathol-ogy and biomarkers of protein oxidation. J Neurochem 65: 2146-2156, 1995.
82. Hoeijmakers, JH. Genome maintenance mechanisms for preventing cancer. Nature 411: 366-374, 2001.
83. Howell N, Elson JL, Chinnery PF, and Turnbull DM. mtDNA mutations and common neurodegenerative disorders. Trends Genet 11: 583-586, 2005.
84. Hu J, de Souza-Pinto NC, Haraguchi K, et al. Repair of formamidopyrimidines in DNA involves different glyco-sylases: role of the OGG1, NTH1, and NEIL1 enzymes. J Biol Chem 280: 40544-40551, 2005.
85. Huang X, Atwood CS, Hartshorn MA, et al. The A beta peptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reduction. Biochem 38: 7609-7616, 1999.
86. Huang X, Moir RD, Tanzi RE, Bush AI, and Rogers JT. Redox-active metals, oxidative stress, and Alzheimer's disease pathology. Ann N Y Acad Sci 1012: 153-163, 2004.
87. Huffman JL, Sundheim O, and Tainer JA. DNA base damage recognition and removal: new twists and grooves. Mutat Res 577: 55-76, 2005.
88. Humpel C and Marksteiner J. Cerebrovascular damage as a cause for Alzheimer's disease. Curr Neurovasc Res 2: 341-347, 2005.
89. Ide H and Kotera M. Human DNA glycosylases involved in the repair of oxidatively damaged DNA. Biol Pharm Bull 27: 480-485, 2004.
90. Imam SZ, Karahalil B, Hogue BA, Souza-Pinto NC, and Bohr VA. Mitochondrial and nuclear DNA-repair capacity of various brain regions in mouse is altered in an age-dependent manner. Neurobiol Aging 27: 1129-1136, 2006.
91. Jeppesen DK, Bohr VA, and Stevnsner T. DNA repair deficiency in neurodegeneration. Prog Neurobiol 94: 166-200, 2011.
92. Jomova K and Valko M. Advances in metal-induced oxi-dative stress and human disease. Toxicol 283: 65-87, 2011.
93. Kaguni LS. DNA polymerase gamma, the mitochondrial replicase. Annu Rev Biochem 73: 293-320, 2004.
94. Karahalil B, de Souza-Pinto NC, Parsons JL, Elder RH, and Bohr VA. Compromised incision of oxidized pyrimidines in liver mitochondria of mice deficient in NTH1 and OGG1 glycosylases. J Biol Chem 278: 33701-33707, 2003.
95. Kasai H and Nishimura S. Hydroxylation of deox-yguanosine at the C-8 position by ascorbic acid and other reducing agents. Nucleic Acids Res 12: 2137-2145, 1984.
96. Kish SJ, Bergeron C, and Rajput, A. Brain cytochrome ox-idase in Alzheimer's disease. J Neurochem 59: 776-779, 1992.
97. Klungland A, Rosewell I, Hollenbach S, Larsen E, Daly G, Epe B, Seeberg E, Lindahl T, and Barnes DE. Accumulation of premutagenic DNA lesions in mice defective in removal of oxidative base damage. Proc Natl Acad Sci U S A 96: 13300-13305, 1999.
98. Kraytsberg Y, Kudryavtseva E, McKee AC, Geula C, Ko-wall NW, and Khrapko K. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat Genet 38: 518-520, 2006.
99. Krokan HE, Nilsen H, Skorpen F, Otterlei M, and Slup-phaug G. Base excision repair of DNA in mammalian cells. FEBS Lett 476: 73-77, 2000.
100. Kruman II, Wersto RP, Cardozo-Pelaez F, Smilenov L, Chan SL, Chrest FJ, Emokpae R Jr, Gorospe M, and Matt-son MP. Cell cycle activation linked to neuronal cell death initiated by DNA damage. Neuron 41: 549-561, 2004.
101. Lauritzen KH, Cheng C, Wiksen H, Bergersen LH, and Klungland A. Mitochondrial DNA toxicity compromises mitochondrial dynamics and induces hippocampal antiox-idant defenses. DNA Repair (Amst) 10: 639-653, 2011.
102. Lauritzen KH, Moldestad O, Eide L, et al. Mitochondrial DNA toxicity in forebrain neurons causes apoptosis, neu-rodegeneration, and impaired behavior. Mol Cell Biol 30: 1357-1367, 2010.
103. Lavados M, Guillon M, Mujica MC, Rojo LE, Fuentes P, and Maccioni RB. Mild cognitive impairment and Alzheimer patients display different levels of redox-active CSF iron. J Alzheimers Dis 13: 225-232, 2008.
104. Linnane AW, Marzuki S, Ozawa T, and Tanaka M. Mi-tochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet 1: 642-645, 1989.
105. Liu P, Qian L, Sung JS, et al. Removal of oxidative DNA damage via FEN1-dependent long-patch base excision repair in human cell mitochondria. Mol Cell Biol 28: 4975-4987, 2008.
106. Lovell MA, Ehmann WD, Butler SM, and Markesbery WR. Elevated thiobarbituric acid-reactive substances and anti-oxidant enzyme activity in the brain in Alzheimer's disease. Neurology 45: 1594-1601, 1995.
107. Lovell MA, Ehmann WD, Mattson MP, and Markesbery WR. Elevated 4-hydroxynonenal in ventricular fluid in Alzheimer's disease. Neurobiol Aging 18: 457-461, 1997.
108. Lovell MA, Gabbita SP, and Markesbery WR. Increased DNA oxidation and decreassed levels of repair products in Alzheimer's disease ventricular CSF. J Neurochem 72: 771-776, 1999.
109. Lu J, Wang K, Rodova M, et al. Polymorphic variation in cytochrome oxidase subunit genes. J Alzheimers Dis 21: 141-154, 2010.
110. Luczaj W and Skrzydlewska E. DNA damage caused by lipid peroxidation products. Cell Mol Biol Lett 8: 391-413, 2003.
111. Lustbader JW, Cirilli M, Lin C, et al. Abeta to mitochondrial toxicity in Alzheimer's disease. Science 304: 448-452, 2004.
112. Lyras L, Cairns NJ, Jenner A, Jenner P, and Halliwell B. An assessment of oxidative damage to proteins, lipids, and DNA in brain from patients with Alzheimer's disease. J Neurochem 68: 2061-2069, 1997.
113. Maki H. Origins of spontaneous mutations: specificity and directionality of base substitution, frameshift, and sequence-substitution mutageneses. Annu Rev Genet 36: 279-303, 2002.
114. Malins DC, Hellstrom KE, Anderson KM, Johnson PM, and Vinson MA. Antioxidant-induced changes in oxidized DNA. Proc Natl Acad Sci U S A 99: 5937-5941, 2002.
115. Mancuso M, Calsolaro V, Orsucci D, Carlesi C, Choub A, Piazza S, and Siciliano G. Mitochondria, cognitive impairment, and Alzheimer's disease. Int J Alzheimers Dis 2009: 951548, 2009.
116. Mannella, CA. Structural diversity of mitochondria: functional implications. Ann N Y Acad Sci 1147: 171-179, 2008.
117. Mao P and Reddy PH. Aging and amyloid beta-induced oxidative DNA damage and mitochondrial dysfunction in Alzheimer's disease: implications for early intervention and therapeutics. Biochim Biophys Acta 1812: 1359-1370, 2011.
118. Marcus DL, Thomas K, Rodriguez C, et al. Increased peroxidation and reduced antioxidant enzyme activity in Alzheimer's disease. Exp Neurol 150: 40-44, 1998.
119. Markesbery WR and Lovell MA. Four-hydroxynonenal, a product of lipid peroxidation, is increased in the brain in Alzheimer's disease. Neurobiol Aging 19: 33-36, 1998.
120. Markesbery WR. Oxidative stress hypothesis in Alzheimer's disease. Free Radic Biol Med 23: 134-147, 1997.
121. Mastrogiacomo F, Bergeron C, and Kish SJ. Brain alpha-ketoglutarate dehydrogenase complex activity in Alzheimer's disease. J Neurochem 61: 2007-2014, 1993.
122. Mattson MP. Metal-catalyzed disruption of membrane protein and lipid signaling in the pathogenesis of neu-rodegenerative disorders. Ann N Y Acad Sci 1012: 37-50, 2004.
123. Mecocci P, Beal MF, Cecchetti R, et al. Mitochondrial membrane fluidity and oxidative damage to mitochondrial DNA in aged and AD human brain. Mol Chem Neuropathol 31: 53-64, 1997.
124. Mecocci P, MacGarvey U, and Beal MF. Oxidative damage to mitochondrial DNA is increased in Alzheimer's disease. Ann Neurol 36: 747-751, 1994.
125. Melov S, Schneider JA, Day BJ, et al. A novel neurological phenotype in mice lacking mitochondrial manganese superoxide dismutase. Nat Genet 18: 159-163, 1998.
126. Milton RH, et al. CLIC1 function is required for beta-amyloid induced generation of reactive oxygen species by microglia. J Neurosci 28: 11488-11499, 2008.
127. Moreira PI, Carvalho C, Zhu X, Smith MA, and Perry G. Mitochondrial dysfunction is a trigger of Alzheimer's disease pathophysiology. Biochim Biophys Acta 1802: 2-10, 2010.
128. Moreira PI, Nunomura A, Nakamura M, et al. Nucleic acid oxidation in Alzheimer disease. Free Radic Biol Med 44: 1493-1505, 2008.
129. Moreira PI, Zhu X, Wang X, et al. Mitochondria: a therapeutic target in neurodegeneration. Biochim Biophys Acta 1802: 212-220, 2010.
130. Moreira PI. Alzheimer's disease and diabetes: an integra-tive view of the role of mitochondria, oxidative stress, and insulin. J Alzheimers Dis 30: 199-215, 2012.
131. Moreira, PI, Duarte AI, Santos MS, Rego AC, and Oliveira CR. An integrative view of the role of oxidative stress, mitochondria and insulin in Alzheimer's disease. J Alzheimers Dis 16: 741-761, 2009.
132. Morland I, Rolseth V, Luna L, Rognes T, Bjoras M, and Seeberg E. Human DNA glycosylases of the bacterial Fpg/MutM superfamily: an alternative pathway for the repair of 8-oxoguanine and other oxidation products in DNA. Nucleic Acids Res 30: 4926-4936, 2002.
133. Murphy MP. How mitochondria produce reactive oxygen species. Biochem J 417: 1-13, 2009.
134. Naga KK, Sullivan PG, and Geddes JW. High cyclophilin D content of synaptic mitochondria results in increased vulnerability to permeability transition. J Neurosci 27: 7469-7475, 2007.
135. Neiman M and Taylor DR. The causes of mutation accumulation in mitochondrial genomes. Proc Biol Sci 276: 1201-1209, 2009.
136. Nilsen H, Otterlei M, Haug T, et al. Nuclear and mito-chondrial uracil-DNA glycosylases are generated by alternative splicing and transcription from different positions in the UNG gene. Nucleic Acids Res 25: 750-755, 1997.
137. Nishioka K, Ohtsubo T, Oda H, Fujiwara T, Kang D, Sugimachi K, and Nakabeppu Y. Expression and differential intracellular localization of two major forms of human 8-oxoguanine DNA glycosylase encoded by alternatively spliced OGG1 mRNAs. Mol Biol Cell 10: 1637-1652, 1999.
138. Nonaka I. Mitochondrial diseases. Curr Opin Neurol Neu-rosurg 5: 622-632, 1992.
139. Nunomura A, Honda K, Takeda A, Hirai K, Zhu X, Smith MA, and Perry G. Oxidative damage to RNA in neurode-generative diseases. J Biomed Biotechnol 2006: 82323, 2006
140. Nunomura A, Moreira PI, Castellani RJ, Lee HG, Zhu X, Smith MA, and Perry G. Oxidative damage to RNA in aging and neurodegenerative disorders. Neurotox Res 22: 231-248, 2012.
141. Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, et al. Oxidative damage is the earliest event in Alzheimer's disease. J Neuropathol Exp Neurol 60: 759-767, 2001.
142. Nunomura A, Perry G, Pappolla MA, Wade R, Hirai K, Chiba S, et al. RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer's disease. J Neurosci 19: 1959-1964, 1999.
143. O'Connor TR, Boiteux S, and Laval J. Ring-opened 7-methylguanine residues in DNA are a block to in vitro DNA synthesis. Nucleic Acids Res 16: 5879-5894, 1988.
144. Ojaimi J, Masters CL, Opeskin K, Mckelvie P, and Byrne E. Mitochondrial respiratory chain activity in the human brain as a function of age. Mech Ageing Dev 111: 39-47, 1999.
145. Park L, Zhou P, Pitstick R, et al. Nox2-derived radicals contribute to neurovascularand behavioral dysfunction in mice overexpressing the amyloid precursor protein. Proc Natl Acad Sci USA 105: 1347-1352, 2008.
146. Parker WD Jr, Filley CM, and Parks JK. Cytochrome oxi-dase deficiency in Alzheimer's disease. Neurol 40: 1302-1303, 1990.
147. Patten DA, Germain M, Kelly MA, and Slack RS. Reactive oxygen species: stuck in the middle of neurodegeneration. J Alzheimer's Dis 20:S357-S367, 2010.
148. Praticò D, Lee VMY, Trojanowski JQ, Rokach J, and Fitzgerald GA. Increased F2-isoprostanes in Alzheimer's disease: evidence for enhanced lipid peroxidation in vivo. FASEB J 12: 1777-1783, 1998.
149. Querfurth HW and LaFerla FM. Alzheimer's disease. N Engl J Med 362: 329-344, 2010.
150. Rasola A and Bernardi P. Mitochondrial permeability transition in Ca(2 + )-dependent apoptosis and necrosis. Cell Calcium 50: 222-233, 2011.
151. Rivkees SA and Kelley MR. Expression of a multifunctional DNA repair enzyme gene, apurinic/apyrimidinic endonu-clease (APE; Ref-1) in the suprachiasmatic, supraoptic and paraventricular nuclei. Brain Res 666: 137-142, 1994.
152. Rizzuto R, Bernardi P, and Pozzan T. Mitochondria as allround players of the calcium game. J Physiol 529: 37-47, 2000.
153. Rizzuto R, Pinton P, Brini M, Chiesa A, Filippin L, and Pozzan T. Mitochondria as biosensors of calcium microdomains. Cell Calcium 26: 193-199, 1999.
154. Sabatini BL, Maravall M, and Svoboda K. Ca(2+) signaling in dendritic spines. Curr Opin Neurobiol 11: 349-356, 2001.
155. Santos RX, Correia SC, Wang X, et al. Alzheimer's disease: diverse aspects of mitochondrial malfunctioning. Int J Clin Exp Pathol 3: 570-581, 2010.
156. Santos RX, Correia SC, Zhu X, et al. Nuclear and mito-chondrial DNA oxidation in Alzheimer's disease. Free Radic Res 6: 565-576, 2012.
157. Sayre LM, Perry G, Harris PL, Liu Y, Schubert KA, and Smith MA. In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer's disease: a central role for bound transition metals. J Neurochem 74: 270-279, 2000.
158. Sayre, LM, Zelasko DA, Harris PL, et al. 4-Hydro-xynonenal-derived advanced lipid peroxidation end products are increased in Alzheimer's disease. J Neurochem 68: 2092-2097, 1997.
159. Scherz-Shouval R and Elazar Z. Regulation of autophagy by ROS: physiology and pathology. Trends Biochem Sci 36: 30-98, 2011.
160. Sen T, Sen N, Jana S, Khan FH, Chatterjee U, and Chak-rabarti S. Depolarization and cardiolipin depletion in aged rat brain mitochondria: relationship with oxidative stress and electron transport chain activity. Neurochem Int 50: 719-722, 2007.
161. Shao C, Xiong S, Li GM, et al. Altered 8-oxoguanine gly-cosylase in mild cognitive impairment and late-stage Alzheimer's disease brain. Free Radic Biol Med 45: 813-819, 2008.
162. Sheu KF, Kim YT, Blass JP, et al. An immunochemical study of the pyruvate dehydrogenase deficit in Alzheimer's disease brain. Ann Neurol 17: 444-449, 1985.
163. Shigenaga MK, Hagen TM, and Ames BN. Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci U S A 91: 10771-10778, 1994.
164. Simon DK, Lin MT, Zheng L, et al. Somatic mitochondrial DNA mutations in cortex and substantia nigra in aging and Parkinson's disease. Neurobiol Aging 25: 71-81, 2004.
165. Sinclair, DA. Toward a unified theory of caloric restriction and longevity regulation. Mech Ageing Dev 126, 987-1002, 2005.
166. Smith CD, Carney JM, Starke-Reed PE, et al. Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. Proc Natl Acad Sci USA 88: 10540-10543, 1991.
167. Smith MA, Richey Harris PL, Sayre LM, Beckman JS, and Perry G. Widespread peroxynitrite-mediated damage in Alzheimer's disease. J Neurosci 17: 2653-2657, 1997.
168. Smith MA, Zhu X, Tabaton M, et al. Increased iron and free radical generation in preclinical Alzheimer disease and mild cognitive impairment. J Alzheimers Dis 19: 363-372, 2010.
169. Soderling TR. CaM-kinases: modulators of synaptic plasticity. Curr Opin Neurobiol 10: 375-380, 2000.
170. Sondheimer N, Glatz CE, Tirone JE, Deardorff MA, Krieger AM, and Hakonarson H. Neutral mitochondrial hetero-plasmy and the influence of aging. Hum Mol Genet 20: 1653-1659, 2011.
171. Starkov AA, Fiskum G, Chinopoulos C et al. Mitochondrial a-ketoglutarate dehydrogenase complex generates reactive oxygen species. J Neurosci 24: 7779-7788, 2004.
172. Steenken S. Purine bases, nucleosides, and nucleotides: aqueous solution redox chemistry and transformation reactions of their radical cations and e-and OH adducts. Chem Rev 89: 503-520, 1989.
173. Stierum RH, Croteau DL, and Bohr VA. Purification and characterization of a mitochondrial thymine glycol endo-nuclease from rat liver. J Biol Chem 274: 7128-7136, 1999.
174. Stierum RH, Dianov GL, and Bohr VA. Single-nucleotide patch base excision repair of uracil in DNA by mitochon-drial protein extracts. Nucleic Acids Res 27: 3712-3719, 1999.
175. Stowe DF and Camara AK. Mitochondrial reactive oxygen species production in excitable cells: modulators of mito-chondrial and cell function. Antioxid Redox Signal 11: 1373-1414, 2009.
176. Straface, E Matarrese P, Gambardella L, et al. Oxidative imbalance and cathepsin D changes as peripheral blood biomarkers of Alzheimer disease: A pilot study. FEBS Lett 579: 2759-2766, 2005.
177. Subba Rao K. Mechanisms of disease: DNA repair defects and neurological disease. Nat Clin Pract Neurol 3: 162-172, 2007.
178. Suzuki YJ, Forman HJ, and Sevanian A. Oxidants as stimulators of signal transduction. Free Radic Biol Med 22: 269-285, 1997.
179. Swerdlow RH and Khan SM. A "mitochondrial cascade hypothesis" for sporadic Alzheimer's disease. Med Hypotheses 63: 8-20, 2004.
180. Swerdlow RH and Khan SM. The Alzheimer's disease mi-tochondrial cascade hypothesis: an update. Exp Neurol 218: 308-315, 2009.
181. Swerdlow RH. Brain aging, Alzheimer's disease, and mitochondria. Biochim Biophys Acta 1812: 1630-1639, 2011.
182. Szabo C. Multiple pathways of peroxynitrite cytotoxicity. Toxicol Lett 140-141: 105-112, 2003.
183. Szczesny B, Bhakat KK, Mitra S, and Boldogh I. Age-dependent modulation of DNA repair enzymes by covalent modification and subcellular distribution. Mech Ageing Dev 125: 755-765, 2004.
184. Szczesny B, Tann AW, Longley MJ, Copeland WC, and Mitra S. Long patch base excision repair in mammalian mitochondrial genomes. J Biol Chem 283: 26349-26356, 2008.
185. Takao M, Aburatani H, Kobayashi K, and Yasui A. Mitochondrial targeting of human DNA glycosylases for repair of oxidative DNA damage. Nucleic Acids Res 26: 2917-2922, 1998.
186. Takuma K, Fang F, Zhang W, et al. RAGE-mediated signaling contributes to intraneuronal transport of amyloid-beta and neuronal dysfunction. Proc Natl Acad Scu USA 106: 20021-20026, 2009.
187. Takuma K, Yao J, Huang J, et al. ABAD enhances Abeta-induced cell stress via mitochondrial dysfunction. FASEB J 19: 597-598, 2005.
188. Tang S and Huang T. Characterization of mitochondrial DNA heteroplasmy using a parallel sequencing system. Biotechniques 48: 287-296, 2010.
189. Taylor RC, Cullen SP, and Martin SJ. Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol 9: 231-241, 2008.
190. Torreilles F, Salman-Tabcheh S, Guerin M, and Torreilles J. Neurodegenerative disorders: the role of peroxynitrite. Brain Res Rev 30: 153-163, 1999.
191. Turrens JF. Mitochondrial formation of reactive oxygen species. J Physiol 552: 335-344, 2003.
192. Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, and Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39: 44-84, 2007.
193. Valla J, Schneider L, Niedzielko T, et al. Impaired platelet mitochondrial activity in Alzheimer's disease and mild cognitive impairment. Mitochondrion 6: 323-330, 2006.
194. Virag L, Szabo E, Gergely P, and Szabo C. Peroxynitrite-induced cytotoxicity: mechanism and opportunities for intervention. Toxicol Lett 140-141: 113-124, 2003.
195. Wallace DC, Stugard C, Murdock D, Schurr T, and Brown MD. Ancient mtDNA sequences in the human nuclear genome: a potential source of errors in identifying pathogenic mutations. Proc Natl Acad Sci USA 94: 14900-14905, 1997.
196. Wallace DC. Animal models for mitochondrial disease. Methods Mol Biol 197: 3-54, 2002.
197. Wang J, Xiong S, Xie C, Markesbery WR, and Lovell MA. Increased oxidative damage in nuclear and mitochondrial DNA in Alzheimer's disease. J Neurochem 93: 953-962, 2005.
198. Wang W, Fang H, Groom L et al. Superoxide Flashes in Single Mitochondria. Cell 134: 279-290, 2008.
199. Weissman L, de Souza-Pinto NC, Stevnsner T, and Bohr VA. DNA repair, mitochondria, and neurodegeneration. Neurosci 145: 1318-1329, 2007.
200. Wilkinson B, et al. Fibrillar beta-amyloid-stimulated intra-cellular signaling cascades require Vav for induction of respiratory burst and phagocytosis in monocytes and mi-croglia. J Biol Chem 281: 20842-20850, 2006.
201. Wilson DM III and Barsky D. The major human abasic endonuclease: formation, consequences and repair of abasic lesions in DNA. Mutat Res 485: 283-307, 2001.
202. Wilson TM, Rivkees SA, Deutsch WA, and Kelley MR. Differential expression of the apurinic/apyrimidinic endo-nuclease (APE/ref-1) multifunctional DNA base excision repair gene during fetal development and in adult rat brain and testis. Mutat Res 362: 237-248, 1996.
203. Wojda U, Salinska E, and Kuznicki J. Calcium ions in neuronal degeneration. IUBMB Life 60: 575-590, 2008.
204. Yakes FM and 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 94: 514-519, 1997.
205. Yang JL, Weissman L, Bohr VA, and Mattson MP. Mi-tochondrial DNA damage and repair in neurodegenerative disorders. DNA Repair (Amst) 7: 1110-1120, 2008.
206. Yao Y, Zhukareva V, Sung S, et al. Enhanced brain levels of 8, 12-iso-iPF2a-VI differentiate AD from frontotemporal dementia. Neurology 61: 475-478, 2003.
207. Zheng L, Zhou M, Guo Z, et al. Human DNA2 is a mito-chondrial nuclease/helicase for efficient processing of DNA replication and repair intermediates. Mol Cell 32: 325-336, 2008.
208. Zimmermann H. Neurotransmitter release. FEBS Lett 268: 394-399, 1990.
209. Zoratti M and Szabo I. The mitochondrial permeability transition. Biochim Biophys Acta 1241: 139-176, 1995.
210. Zucker RS. Calcium-and activity-dependent synaptic plasticity. Curr Opin Neurobiol 9: 305-313, 1999.