Abstract
Development of effective treatments for Alzheimer’s disease is complicated by the poor understanding of its pathophysiology. Recent work suggests mitochondria may play a primary role in neurodegeneration, due to alterations in mitochondria turnover and that the brain is specifically susceptible, due to high energy demand. Mitochondria are the major source of cellular energy through oxidative phosphorylation and regulate intracellular calcium levels and survival pathways. Hypoxia has been implicated in several neurodegenerative diseases including Alzheimer’s disease. During hypoxic events, mitochondrial complex III produces high levels of reactive oxygen species (ROS). These ROS seem to have a primary role in the regulation of the transcription factor hypoxia inducible factor 1α that triggers death effectors. Here we discuss the role of mitochondria in AD putting focus on the activation of hypoxia-mediated mitochondrial pathways, which could eventually lead to cell degeneration and death.
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Acker T, Acker H (2005) J Exp Biol 207:3171
Acker T, Plate KH (2002) J Mol Med 80:562
Adams JA (1975) Br J Anaesth 47:1221
Albrecht S, Bourdeau M, Bennett D, Mufson EJ, Bhattacharjee M, LeBlanc AC (2007) Amer J Pathol 170:1200
Aminova LR, Chavez JC, Lee J, Ryu H, Kung A, LaManna JC, Ratan RR (2005) J Biol Chem 280:3996
Aoyagi A, Saito H, Abe K, Nishiyama N (1998) Brain Res 799:130
Askew EW (2002) Toxicology 180:107
Barhwal K, Singh SB, Hota SK, Jayalakshmi K, Ilavazhagan G (2007) Eur J Pharmacol 570:97
Barhwal K, Hota SK, Prasad D, Singh SB, Ilavazhagan G (2008) Hypoxia-induced Deactivation of NGF-mediated ERK1/2 Signaling in Hippocampal Cells: Neuroprotection by Acetyl-L-Carnitine. J Neurosci Res 86:2705
Beal MF (1996) Curr Opin Neurobiol 6:661
Beal MF (2005) Annu Neurol 58:495
Behl C (2000) J Neural Transm 107:1325
Bell EL, Chandel NS (2007) Essays Biochem 43:17
Bell RD, Zlokovic BV (2009) Acta Neuropathol 118:103
Benzi G, Moretti A (1995) Neurobiol Aging 16:661
Bernaudin M, Marti HH, Roussel S, Divoux D, Nouvelot A, MacKenzie ET, Petit E (1999) J Cereb Blood Flow Metab 19:643
Bharke M, Hale SB (1993) Sports Med 16:97
Bojarski L, Herms J, Kuznicki J (2008) J Neurochem Int 52:621
Bosetti F, Brizzi F, Barogi S, Mancuso M, Siciliano G, Tendi EA, Murri L, Rapoport SI, Solaini G (2002) Neurobiol Aging 23:371
Brines ML, Ghezzi P, Keenan S, Agnello D, de Lanerolle NC, Cerami C, Itri LM, Cerami A (2000) Proc Natl Acad Sci USA 97:10526
Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi MH (2007) Alzheimers Dement 3:186
Brown GC, Borutaite V (2001) IUBMB Life 52:189
Bubber P, Haroutunian V, Fisch G, Blass JP, Gibson GE (2005) Ann Neurol 57:695
Calissano P, Matrone C, Amadoro G (2009) Commun Integrative Biol 2:163
Cay J, Jones DP (1999) J Bioenerg Biomembr 31:327
Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC, Schumacker PT (1998) Proc Natl Acad Sci USA 95:11715
Chandel NS, McClintock DS, Feliciano SE, Wood TM, Melendez JA, Rodriguez AM, Schumacker PT (2000) J Biol Chem 275:25130
Chen M, He H, Zhan S, Krajewski S, Reed JC, Gottlieb RA (2001) J Biol Chem 276:30724
Cribbs DH, Poon WW, Rissman RA, Blurton-Jones M (2004) Amer J Pathol 165:353
de la Torre JC (2004) Lancet Neurol 3:184
Delivoria-Papadopoulos M, Ashraf QM, Mishra OP (2008) Neurosci Lett 438:38
Dröge W (2002) Physiol Rev 82:47
Dykens JA (1997) In Neurodegenerative Diseases: Mitochondria and Free Radicals in Pathogenesis. Beal MF, Bodis-Wollner I, Howell N (Eds) John Wiley & Sons, 29
Erster S, Mihara M, Kim RH, Petrenko O, Moll UM (2004) Mol Cell Biol 24:6728
Farkas E, Luiten PM (2001) Prog Neurobiol 64:575
Fleidervish I, Gebhardt C, Astman N, Gutnick MJ, Heinemann U (2001) J Neurosci 21:4600
Gastard MC, Troncoso JC, Koliatsos VE (2003) Ann Neurol 54:393
Goetz M, Luch A (2008) Cancer Lett 266:73
Görlach A, Berchner-Pfannschmidt U, Wotzlaw C, Cool RH, Fandrey J, Acker H, Jungermann K, Kietzmann T (2003) Thromb Diath Haemorrh 89:926
Green DR, Kroemer G (2004) Science 305:626
Guglielmotto M, Aragno M, Autelli R, Giliberto L, Novo E, Colombatto S, Danni O, Parola M, Smith MA, Perry G, Tamagno E, Tabaton M (2009) J Neurochem 108:1045
Hainsworth R, Drinkhil MJ, Rivera-Chira M (2007) Clin Auton Res 17:13
Harris AL (2002) Nat. Rev. Cancer 2:38
Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, Johnson AB, Kress Y, Vinters HV, Tabaton M, Shimohama S, Cash AD, Siedlak SL, Harris PL, Jones PK, Petersen RB, Perry G, Smith MA (2001) J Neurosci 21:3017
Hirota K, Semenza GL (2001) J Biol Chem 276:21166
Hota SK, Barhwal K, Singh SB, Ilavazhagan G (2007) Neurochem Int 51:384
Hoye A, Davoren J, Wipf P (2008) Acc Chem Res 41:87
Huang HM, Ou HC, Xu H, Chen HL, Fowler C, Gibson GE (2003) J Neurosci Res 74:309
Issam A (1993) In AANS publications committee neurosurgical topics; Awad, M.D., Ed.; American Association of Neurological Surgeons, 327
Jin KL, Mao XO, Greenberg DA (2000) Proc Natl Acad Sci USA 97:10242
Jin K, Zhu Y, Sun Y, Mao XO, Xie L, Greenberg DA (2002) Proc Natl Acad Sci USA 99:11946
Johnson NA, Jahng GH, Weiner MW, Miller BL, Chui HC, Jagust WJ, Gorno-Tempini ML, Schuff N (2005) Radiology 234:851
Kawahara M, Kuroda Y (2000) Brain Res. Bull 53:389
Khurana P, Ashraf QM, Mishra OP, Delivoria-Papadopoulos M (2002) Neurochem Res 27:931
Kish SJ, Bergeron C, Rajput A, Dozic S, Mastrogiacomo F, Chang LJ, Wilson JM, DiStefano LM, Nobrega JN (1992) J Neurochem 59:776
Kitamura Y, Shimohama S, Kamoshima W, Ota T, Matsuoka Y, Nomura Y, Smith MA, Perry G, Whitehouse PJ, Taniguchi T (1996) Brain Res 780:260
Kroemer G, Petit P, Zamzami N, Vayssiere JL, Mignotte B (1995) FASEB J 9:1277
Lange-Asschenfeldt C, Kojda G (2008) Exp Gerontol 43:499
Linnane AW, Marzuki S, Ozawa T, Tanaka M (1989) Lancet 1:642
Louneva N, Cohen JW, Han LY, Talbot K, Wilson RS, Bennett DA, Trojanowski JQ, Arnold SE (2008) Amer J Pathol 173:1488
Maiti P, Singh SB, Sharma AK, Muthuraju S, Banerjee PK, Ilavazhagan G (2006) Neurochem Int 49:709
Maiti P, Singh SB, Muthuraju S, Veleri S, Ilavazhagan G (2007) G Brain Res 1175C:1
Maiti P, Muthuraju S, Ilavazhagan G, Singh SB (2008a) Hypobaric hypoxia induces dendritic plasticity in cortical and hippocampal pyramidal neurons in rat brain. Behav Res 189:233
Maiti P, Singh SB, Mallick BN, Muthuraju S, Ilavazhagan G (2008b) J Chem Neuroanat 36:227
Marchenko ND, Zaika A, Moll UM (2000) J Biol Chem 275:16202
Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P, Moll UM (2003) Molecular Cell 11:577
Miquel J (1991) Arch Gerontol Geriatr 12:99
Mishra OP, Delivoria-Papadopoulos M (2006) Neurosci Lett 401:81
Moreira PI, Cardoso SM, Santos MS, Oliveira CR (2006) J Alzheimer’s Dis 9:101
Moreira PI, Santos MS, Oliveira CR (2007a) Antioxid.Redox Signal 9:1621
Moreira PI, Santos MS, Seiça R, Oliveira CR (2007b) J Neurolog Sci 257:206
Moreira PI, Nunomura A, Nakamura M, Takeda A, Shenk JC, Aliev G, Smith MA, Perry G (2008a) Free Rad Biol Med 44:1493
Moreira PI, Santos MS, Oliveira CR, Shenk JC, Nunomura A, Smith MA, Zhu X, Perry G (2008b) CNS & Neurolog Disord Drug Targets 7:3
Moreira PI, Duarte AI, Santos MS, Rego AC, Oliveira CR (2009) J Alzheimer’s Dis 16:741
Niizuma K, Endo H, Pak H (2009) J Neurochem 109:133
Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA (2001) J Neuropathol Exp Neurol 60:759
Ozawa T (1997) Physiol Rev 77:425
Parker WD Jr, Parks J, Filley CM, Kleinschmidt-DeMasters BK (1994) Neurology 44:1090
Richter C, Kass GE (1991) Chemico-biol Interact 77:1
Ricquier D, Bouillard F (2000) J Physiol 529:3
Rocchi A, Orsucci D, Tognoni G, Ceravolo R, Siciliano G (2009) Curr Alzheimer Res 6:224
Ronnett GV, Ramamurthy S, Kleman AM, Landree LE, Aja S (2009) J Neurochem 109:17
Rombouts SA, Goekoop R, Stam CJ, Barkhof F, Scheltens P (2005) Neuroimage 26:1078
Roy S, Rauk A (2005) Med Hypotheses 65:123
Sarada SK, Himadri P, Ruma D, Sharma SK, Pauline T, Mrinalini (2008) Brain Res 1209:29
Schmidt-Kastner R, Aguirre-Chen C, Kietzmann T, Saul I, Busto R, Ginsberg MD (2004) Brain Res 1001:133
Schmitt CA, Fridman JS, Yang M, Baranov E, Hoffman RM, Lowe SW (2002) Cancer Cell 1:289
Sheu S, Nauduri D, Anders M (2006) Biochim et Biophysica Acta 1762:256
Shibata M, Hattori H, Sasaki T, Gotoh J, Hamada J, Fukuuchi Y (2002) J Cereb Blood Flow Metab 22:810
Shigenaga MK, Hagen TM, Ames BN (1994) Proc Natl Acad Sci USA 91:10771
Simpkins JW, Dykens JA (2007) Brain Res Rev 57:421
Srinivas V, Leshchinsky I, Sang N, King MP, Minchenko A, Caro J (2001) J Biol Chem 276:21995
Stadelmann C, Deckwerth TL, Srinivasan A, Bancher C, Brück W, Jellinger K, Lassmann H (1999) Amer J Pathol 155:1459
Su JH, Kesslak JP, Head E, Cotman CW (2002) Acta Neuropathol 104:1
Sun X, He G, Qing H, Zhou W, Dobie F, Cai F, Staufenbiel M, Huang LE, Song W (2006) Proc Natl Acad Sci USA 103:18727
Suzuki T, Nishiyama K, Yamamoto A, Inazawa J, Iwaki T, Yamada T, Kanazawa I, Sakaki Y (2000) Genomics 63:246
Swerdlow RH, Parks JK, Miller SW, Tuttle JB, Trimmer PA, Sheehan JP, Bennett JP Jr, Davis RE, Parker WD Jr (1996) Ann Neurol 40:663
Swerdlow RH, Parks JK, Cassarino DS, Maguire DJ, Maguire RS, Bennett JP Jr, Davis RE, Parker WD Jr (1997) Neurology 49:918
Swerdlow RH, Parks JK, Cassarino DS, Trimmer PA, Miller SW, Maguire DJ, Sheehan JP, Maguire RS, Pattee G, Juel V, Phillips LH, Tuttle JB, Bennett JP Jr, Davis RE, Parker WD Jr (1998) Exp Neurol 153:135
Taylor CT (2008) Biochem J 409:19
Thannickal VJ, Fanburg BL (2000) Amer J Physiol Lung Cell Mol Physiol 279:L1005
Thomas T, Thomas G, McLendon C, Sutton T, Mullan M (1996) Nature 380:168
Townsend KP, Obregon D, Quadros A, Patel N, Volmar C, Paris D, Mullan M (2002) Ann New York Acad Sci 977:65
Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M (2006) Chemico-biol Interact 160:1
Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J (2007) J. Int J Biochem Cell Biol 39:44
Valla J, Schneider L, Niedzielko T, Coon KD, Caselli R, Sabbagh MN, Ahern GL, Baxter L, Alexander G, Walker DG, Reiman EM (2006) Mitochondrion 6:323
Vaux C, Metzen E, Yeates KM, Ratcliffe PJ (2001) Blood 98:296
Wai MS, Liang Y, Shi C, Cho EY, Kung HF, Yew DT (2009) Biogerontology 10:457
Wallace DC (1992) Science 256:628
Wang R, Zhang YW, Zhang X, Liu R, Zhang X, Hong S, Xia K, Xia J, Zhang Z, Xu H (2006) FASEB J 20:1275
Xiong H, Callaghan D, Jones A, Bai J, Rasquinha I, Smith C, Pei K, Walker D, Lue LF, Stanimirovic D, Zhang W (2009) J Neurosci 29:5463
Yin XM, Luo Y, Cao G, Bai L, Pei W, Kuharsky DK, Chen J (2000) J Biol Chem 277:42074
Zawia NH, Lahiri DK, Cardozo-Pelaez F (2009) Free Radic Biol Med 46:1241
Zhang X, Zhou K, Wang R, Cui J, Lipton SA, Liao FF, Xu H, Zhang YW (2007) J Biol Chem 282:10873
Zhu X, Perry G, Moreira PI, Aliev G, Cash AD, Hirai K, Smith MA (2006) J Alzheimer’s Dis 9:147
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Carvalho, C., Correia, S.C., Santos, R.X. et al. Role of mitochondrial-mediated signaling pathways in Alzheimer disease and hypoxia. J Bioenerg Biomembr 41, 433–440 (2009). https://doi.org/10.1007/s10863-009-9247-1
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DOI: https://doi.org/10.1007/s10863-009-9247-1