Mitochondria as a therapeutic target for aging and neurodegenerative diseases

Current Alzheimer Research

Volumn 8, Issue 4, 2011, Pages 393-409

  Reddy, P H ^a,b   Reddy, T P ^a  

^a OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

^b OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

Author keywords

Abnormal mitochondrial dynamics; Aging; Alzheimer's disease; Huntington's disease; Mitochondria; Mitochondria targeted antioxidants; Neurodegenerative disease; Parkinson's disease

Indexed keywords

1,2,3,6 TETRAHYDRO 1 METHYL 4 PHENYLPYRIDINE; ADENOSINE TRIPHOSPHATE; AMYLOID BETA PROTEIN; AMYLOID PRECURSOR PROTEIN; APOLIPOPROTEIN E4; BETA SECRETASE; CALCIUM; CLUSTERIN; COMPLEMENT RECEPTOR; DIMEBON; HTT PROTEIN; INSULIN; MAMMALIAN TARGET OF RAPAMYCIN; MITOCHONDRIAL DNA; MITOQ; NOOTROPIC AGENT; OLESOXIME; PROTEIN; REACTIVE OXYGEN METABOLITE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE DEHYDROGENASE (UBIQUINONE); RESVERATROL; SIRTUIN; SOMATOMEDIN C; SORTILIN; SS 31; TELOMERASE; UNCLASSIFIED DRUG;

AGING; ALZHEIMER DISEASE; AMINO TERMINAL SEQUENCE; AMYOTROPHIC LATERAL SCLEROSIS; ARTICLE; BLOOD BRAIN BARRIER; CALCIUM HOMEOSTASIS; CALCIUM TRANSPORT; CELL DEATH; DISORDERS OF MITOCHONDRIAL FUNCTIONS; DNA DAMAGE; DNA METHYLATION; DOWN SYNDROME; DRUG TARGETING; ENZYME ACTIVITY; EPIGENETICS; GENE DELETION; GENE DOSAGE; GENE MUTATION; HUMAN; HUNTINGTON CHOREA; LEBER HEREDITARY OPTIC NEUROPATHY; LIFESPAN; MITOCHONDRIAL MEMBRANE POTENTIAL; MITOCHONDRIAL RESPIRATION; MITOCHONDRION; OXIDATIVE PHOSPHORYLATION; OXIDATIVE STRESS; PARKINSON DISEASE; PATHOGENESIS; PHENOTYPE; PRIORITY JOURNAL; RESPIRATORY CHAIN; SIGNAL TRANSDUCTION;

AGING; ANIMALS; BRAIN; DNA, MITOCHONDRIAL; HUMANS; MITOCHONDRIA; MITOCHONDRIAL DISEASES; MODELS, BIOLOGICAL; NEURODEGENERATIVE DISEASES;

EID: 79959344446     PISSN: 15672050     EISSN: 18755828     Source Type: Journal    
DOI: 10.2174/156720511795745401     Document Type: Article

References (174)

1. Reddy PH. Mitochondrial medicine for aging and neurodegenerative diseases. Neuromolecular Med. 10, 291-315 (2008).
2. Beal MF. Mitochondria take center stage in aging and neurodegeneration. Ann Neurol. 58: 495-505 (2005).
3. Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature. 443: 787-795 (2006).
4. Reddy PH. Amyloid beta, mitochondrial structural and functional dynamics in Alzheimer's disease. Exp Neurol. 218: 286-292 (2009).
5. Swerdlow RH. Mitochondrial Medicine and the Neurodegenerative Mitochondriopathies. Pharmaceuticals 2: 150-167 (2009).
6. Beers M, Jones TV. Merck Manual of Health and Aging. Merck (2004).
7. Fontana L, Partridge L, Longo VD. Extending healthy life span from yeast to humans. Science. Apr 16;328(5976):321-326 (2010).
8. Austad SN. Why We Age: What Science Is Discovering about the Body's Journey through Life. JohnWiley & Sons, New York (1997).
9. Strehler BL. Time, Cells, and Aging. Demetriades Brothers, Larnaca (1999).
10. Beckman KB, Ames BN. The free radical theory of aging matures. Physiol Rev. 78: 547-581. (1998)
11. de Carvalho CV, Payao SL, Smith MA. DNA methylation, ageing and ribosomal genes activity. Biogerontology 1: 357-361 (2000).
12. Mattson MP. Emerging neuroprotective strategies for Alzheimer's disease: dietary restriction, telomerase activation, and stem cell therapy. Exp Gerontol. 35: 489-502 (2000).
13. Vijg J. Somatic mutations and aging: a re-evaluation. Mutat. Res. 447: 117-135 (2000).
14. Perry G, Nunomura A, Hirai K, et al. Is oxidative damage the fundamental pathogenic mechanism of Alzheimer's and other neu-rodegenerative diseases? Free Radic. Biol. Med. 1: 1475-1479 (2002).
15. Harman D. Aging: minimizing free radical damage. J. Anti-Aging Med. 2: 15-36 (1999).
16. Cadenas E, Davies KJ. Mitochondrial free radical generation, oxi-dative stress, and aging. Free Radic Biol Med. 29: 222-230 (2000).
17. Biersalski HK. Free radical theory of aging. Curr Opin Clin. Nutr Metab. Care 5: 5-10 (2002).
18. Bishop NA, Lu T, Yankner BA. Neural mechanisms of ageing and cognitive decline. Nature. 464: 529-535 (2010).
19. Sahin E, Depinho RA. Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature. Mar 25;464(7288):520-528 (2010).
20. Swerdlow RH, Khan SM. A mitochondrial cascade hypothesis for sporadic Alzheimer's disease. Med Hypotheses. 63: 8-20 (2004).
21. Reddy PH. Amyloid precursor protein-mediated free radicals and oxidative damage: implications for the development and progression of Alzheimer's disease. J Neurochem. 96: 1-13 (2006).
22. Reddy PH. Mitochondrial dysfunction in aging and Alzheimer's disease: strategies to protect neurons. Antioxidants & Redox Signaling. 9: 1647-1658 (2007).
23. DiMauro S, Schon EA. Mitochondrial disorders in the nervous system. Annu Rev Neurosci. 31: 91-123 (2008).
24. Reddy PH, Beal MF. Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease. Trends Mol Med.14: 45-53 (2008).
25. Swerdlow RH, Khan SM. The Alzheimer's disease mitochondrial cascade hypothesis: an update. Exp Neurol. 218: 308-315 (2009).
26. Swerdlow RH, Burns JM, Khan SM. The Alzheimer's disease mitochondrial cascade hypothesis. J Alzheimers Dis. 20 Suppl 2:S265-S279 (2010).
27. Reddy PH, Beal MF. Are mitochondria critical in the pathogenesis of Alzheimer's disease? Brain Res Brain Res Rev. 49: 618-632 (2005).
28. Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, Schreier PH, Smith AJ, Staden R, Young IG. Sequence and organization of the human mitochondrial genome. Nature 290: 457-465 (1981).
29. Cooper JM, Mann VM, Schapira AH. Analyses of mitochondrial respiratory chain function and mitochondrial DNA deletion in human skeletal muscle: effect of ageing. J Neurol Sci. 113: 91-98 (1992).
30. Mao P, Gallagher P, Nedungadi S, Manczak M, Kohama S, Ferguson B, Park BS, Reddy PH. Mitochondrial DNA deletions in Rhesus monkeys: Implications to aging. Submitted to Journal of Alzheimer's Disease (2009).
31. Trifunovic A, Wredenberg A, Falkenberg M, et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature. 429: 417-423 (2004).
32. Kujoth GC, Hiona A, Pugh TD et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science. 309: 481-448 (2005).
33. Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, Yankner BA. Gene regulation and DNA damage in the ageing human brain. Nature. 429:883-891 (2004).
34. Wang AL, Lukas TJ, Yuan M, Neufeld AH. Age-related increase in mitochondrial DNA damage and loss of DNA repair capacity in the neural retina. Neurobiol Aging. Dec 10 (2008).
35. Hoeijmakers JH. DNA damage, aging, and cancer. N Engl J Med. 361: 1475-1485 (2009).
36. Schriner SE, Linford NJ, Martin GM, et al. Extension of murine lifespan by overexpression of catalase targeted to mitochondria. Science. 308: 1909-1911 (2005).
37. Swerdlow RH, Parks JK, Miller SW, Tuttle JB, Trimmer PA, Sheehan JP, Bennett JP, Davis RE, Parker WD. Origin and functional consequences of the complex I defect in Parkinson's disease. Ann Neurol 40: 663-670 (1996).
38. Swerdlow RH, Parks JK, Cassarino DS, Maguire DJ, Maguire RS, Bennett JP, Parker WD. Cybrids in Alzheimer's disease: A cellular model of the disease? Neurology 49: 918-925 (1997).
39. Swerdlow RH, Miller SW, Parks JK, Sheehan JP, Cassarino DS, Maguire DJ, Maguire RS, Bennett JP, Juel VC, Phillips LH, Trimmer PA, Pattee G, Tuttle JB, Davis RE, Parker WD. Mitochondria in sporadic amyotrophic lateral sclerosis. Experimental Neurology 153:135-142 (1998).
40. Reddy PH, McWeeney S. Mapping cellular transcriptosomes in autopsied Alzheimer's disease subjects and relevant animal models. Neurobiol Aging. 27: 1060-1077 (2006).
41. Alzheimer Association Report: 2010 Alzheimer Disease Facts and Figures.
42. Reddy PH, Mani G, Park BS, Jacques J, Murdoch G, Whetsell W Jr, Kaye J, Manczak M. Differential loss of synaptic proteins in Alzheimer's disease: implications for synaptic dysfunction. J Alz-heimers Dis. 7: 103-117; discussion 173-180 (2005).
43. Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Law-lor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schürmann B, van den Bussche H, Heuser I, Korn-huber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Hüll M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Mühleisen TW, Nöthen MM, Moebus S, Jöckel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pank-ratz VS, Younkin SG, Holmans PA, O'Donovan M, Owen MJ, Williams J. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet. 41: 1088-1093. (2009).
44. Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, Combarros O, Zelenika D, Bullido MJ, Tavernier B, Letenneur L, Bettens K, Berr C, Pasquier F, Fiévet N, Barberger-Gateau P, Engelborghs S, De Deyn P, Mateo I, Franck A, Helisalmi S, Por-cellini E, Hanon O; de Pancorbo MM, Lendon C, Dufouil C, Jaillard C, Lev-eillard T, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossù P, Piccardi P, Annoni G, Seripa D, Galimberti D, Hannequin D, Licastro F, Soininen H, Ritchie K, Blanché H, Dartigues JF, Tzourio C, Gut I, Van Broeckhoven C, Alpérovitch A, Lathrop M, Amouyel P. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet. 41(10):1094-1099 (2009).
45. Reddy PH, Manczak M, Mao P, Calkins MJ, Reddy AP, Shirendeb U. Amyloid-beta and mitochondria in aging and Alzheimer's disease: implications for synaptic damage and cognitive decline. J Alzheimers Dis. 20 Suppl 2:S499-S512 (2010).
46. Du H, Guo L, Yan S, Sosunov AA, McKhann GM, Yan SS. Early deficits in synaptic mitochondria in an Alzheimer's disease mouse model. Proc Natl Acad Sci U S A. 107(43):18670-18675 (2010).
47. 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. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol. 60: 759-767 (2001).
48. Lin MT, Simon DK, Ahn CH, Kim LM, Beal MF. High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer's disease brain. Hum Mol Genet. 11: 133-145 (2002).
49. Coskun PE, Beal MF, Wallace DC. Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochon-drial transcription and replication. Proc Natl Acad Sci U S A. 101: 10726-10731 (2004).
50. Coskun PE, Wyrembak J, Derbereva O, Melkonian G, Doran E, Lott IT, Head E, Cotman CW, Wallace DC. Systemic mitochon-drial dysfunction and the etiology of Alzheimer's disease and down syndrome dementia. J Alzheimers Dis. 20 Suppl 2:S293-S310 (2010).
51. Lakatos A, Derbeneva O, Younes D, Keator D, Bakken T, Lvova M, Brandon M, Guffanti G, Reglodi D, Saykin A, Weiner M, Mac-ciardi F, Schork N, Wallace DC, Potkin SG; Alzheimer's Disease Neuroimaging Initiative. Association between mitochondrial DNA variations and Alzheimer's disease in the ADNI cohort. Neurobiol Aging. Jun 8. [Epub ahead of print] (2010).
52. Manczak M, Anekonda TS, Henson E, Park BS, Quinn J, Reddy PH. Mitochondria are a direct site of A beta accumulation in Alzheimer's disease neurons:implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet. 15: 1437-1449 (2006).
53. Yao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT, Brinton RD. Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 106: 14670-14675 (2009).
54. Caspersen C, Wang N, Yao J, Sosunov A, Chen X, Lustbader JW, Xu HW, Stern D, McKhann G, Yan SD. Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease. FASEB J.19: 2040-2041 (2005).
55. Reddy PH, McWeeney S, Park BS, Manczak M, Gutala RV, Par-tovi D, Jung Y, Yau V, Searles R, Mori M, Quinn J. Gene expression profiles of transcripts in amyloid precursor protein transgenic mice: up regulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimer's disease. Hum Mol Genet. 13: 1225-1240 (2004).
56. Manczak M, Park BS, Jung Y, Reddy PH. Differential expression of oxidative phosphorylation genes in patients with Alzheimer's disease: implications for early mitochondrial dysfunction and oxidative damage. Neuromolecular Med. 5: 147-162 (2004).
57. Manczak M, Mao P, Calkins MJ, Cornea A, Reddy AP, Murphy MP, Szeto HH, Park B, Reddy PH. Mitochondria-targeted antioxi-dants protect against amyloid-beta toxicity in Alzheimer's disease neurons. J Alzheimers Dis. Suppl 2:S609-S631 (2010).
58. Lustbader JW, Cirilli M, Lin C, et al. ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease. Science. 304: 448-452 (2004).
59. Crouch PJ, Blake R, Duce JA, Ciccotosto GD, Li QX, Barnham KJ, Curtain CC, Cherny RA, Cappai R, Dyrks T, Masters CL, Trounce IA. Copper-dependent inhibition of human cytochrome c oxidase by a dimeric conformer of amyloid-beta1-42. J Neurosci. 25: 672-679 (2005).
60. Devi L, Prabhu BM, Galati DF, Avadhani NG, Anandatheertha-varada HK. Accumulation of amyloid precursor protein in the mi-tochondrial import channels of human Alzheimer's disease brain is associated with mitochondrial dysfunction. J Neurosci. 26: 9057-9068 (2006).
61. Du H, Guo L, Fang F, Chen D, Sosunov AA, McKhann GM, Yan Y, Wang C, Zhang H, Molkentin JD, Gunn-Moore FJ, Vonsattel JP, Arancio O, Chen JX, Yan SD. Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease. Nat Med. 14: 1097-1105 (2008).
62. Wang X, Su B, Siedlak SL, Moreira PI, Fujioka H, Wang Y, Casadesus G, Zhu X. Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mito-chondrial fission/fusion proteins. Proc Natl Acad Sci U S A. 105: 19318-19323 (2008).
63. Zhao XL, Wang WA, Tan JX, Huang JK, Zhang X, Zhang BZ, Wang YH, YangCheng HY, Zhu HL, Sun XJ, Huang FD. Expression of beta-amyloid Induced age-dependent presynaptic and axonal changes in Drosophila. J Neurosci. 30: 1512-1522 (2010).
64. Chan DC. Mitochondrial fusion and fission in mammals. Annu Rev Cell Dev Biol. 22: 79-99 (2006).
65. Gibson GE, Sheu KF, Blass JP. Abnormalities of mitochondrial enzymes in Alzheimer disease. J NeuralTransm. 105: 855-870 (1998).
66. Parker WD Jr, Filley CM, Parks JK. Cytochrome oxidase deficiency in Alzheimer's disease. Neurology. 40: 1302-303 (1990).
67. Maurer I, Zierz S, Möller HJ. A selective defect of cytochrome c oxidase is present in brain of Alzheimer disease patients. Neurobiol Aging. 21: 455-462 (2000).
68. Smith MA, Perry G, Richey PL, Sayre LM, Anderson VE, Beal MF, Kowall N. Oxidative damage in Alzheimer's. Nature. 382: 120-121 (1996).
69. Dragicevic N, Mamcarz M, Zhu Y, Buzzeo R, Tan J, Arendash GW, Bradshaw PC. Mitochondrial amyloid-beta levels are associated with the extent of mitochondrial dysfunction in different brain regionsand the degree of cognitive impairment in Alzheimer's transgenic mice. J Alzheimers Dis. 20 Suppl 2: S535-S550 (2010).
70. Vonsattel, J.P., Myers, R.H., Stevens, T.J, Ferrante, R.J., Bird, E.D., Richardson, E.P.Jr. Neuropathological classification of Huntington's disease. J Neuropathol Exp Neurol. 44: 559-577 (1985).
71. Folstein SE. Huntington's Disease. Johns Hopkins University Press (1990).
72. Montoya A, Price BH, Menear M, Lepage M. Brain imaging and cognitive dysfunctions in Huntington's disease. J Psychiatry Neuro-sci. 31: 21-29 (2006).
73. Byers RK, Gilles FH, Fung C. Huntington's disease in children. Neuropathologic study of four cases. Neurology. 23: 561-569 (1973).
74. Spargo E, Everall IP, Lantos PL. Neuronal loss in the hippocampus in Huntington's disease: a comparison with HIV infection. J Neurol Neurosurg Psychiatry. 56: 487-491 (1993).
75. Reddy PH, Charles V, Williams M, Miller G, Whetsell WO Jr, Tagle DA. Transgenic mice expressing mutated full-length HD cDNA: a paradigm for locomotor changes and selective neuronal loss in Huntington's disease. Philos Trans R Soc Lond B Biol Sci. 354: 1035-1045 (1999).
76. Reddy PH, Williams M, Tagle DA. Recent advances in understanding the pathogenesis of Huntington's disease. Trends Neurosci. 22: 248-255 (1999).
77. Reddy PH, Tagle DA. Biology of trinucleotide repeat disorders. In Genetic Aberrancies and Neurodegenerative Disorders Edited by Mark P. Mattson Vol 3 Advances in cell aging and gerontology. Jai press Inc. Stanford and Connecticut (1999).
78. Reddy PH, Williams M, Charles V, Garrett L, Pike-Buchanan L, Whetsell WO Jr, Miller G, Tagle DA. Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD cDNA. Nat Genet. 20: 198-202 (1998).
79. Reddy PH, Mao P, Manczak M. Mitochondrial structural and functional dynamics in Huntington's disease. Brain Res Rev. 61: 33-48 (2009).
80. Li S, Li XJ. Multiple pathways contribute to the pathogenesis of Huntington disease. Mol Neurodegener. 1: 19 (2006).
81. Bates GP. History of genetic disease: the molecular genetics of Huntington disease - a history. Nat Rev Genet. 6: 766-773 (2005).
82. Orr HT, Zoghbi HY. Trinucleotide repeat disorders. Ann Rev Neu-rosci 30: 575-621 (2007).
83. Borrell-Pagès M, Zala D, Humbert S, Saudou F. Huntington's disease: from huntingtin function and dysfunction to therapeutic strategies. Cell Mol Life Sci. 63: 2642-2660 (2006).
84. Sayer JA, Manczak M, Akileswaran L, Reddy PH, Coghlan VM. Interaction of the nuclear matrix protein NAKAP with HypA and huntingtin: implications for nuclear toxicity in Huntington's disease pathogenesis. Neuromolecular Med. 7: 297-310 (2005).
85. Rigamonti D, Bauer JH, De-Fraja C, Conti L, Sipione S, Sciorati C, Clementi E, Hackam A, Hayden MR, Li Y, Cooper JK, Ross CA, Govoni S, Vincenz C, Cattaneo E. Wild-type huntingtin protects from apoptosis upstream of caspase-3. J Neurosci. 20: 3705-3713 (2000).
86. Jana NR, Zemskov EA, Wang GH, Nukina N. Altered proteasomal function due to the expression of polyglutamine-expanded truncated N-terminal huntingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release. Hum Mol Genet. 10: 1049-1059 (2001).
87. Hermel E, Gafni J, Propp SS, Leavitt BR, Wellington CL, Young JE, Hackam AS, Logvinova AV, Peel AL, Chen SF, Hook V, Sin-garaja R, Krajewski S, Goldsmith PC, Ellerby HM, Hayden MR, Bredesen DE, Ellerby LM. Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease. Cell Death Differ. 11: 424-438 (2004).
88. Zhang Y, Leavitt BR, van Raamsdonk JM, Dragatsis I, Goldowitz D, MacDonald ME, Hayden MR, Friedlander RM. Huntingtin inhibits caspase-3 activation. EMBO J. 25: 5896-5906 (2006).
89. Lee WT, Chang C. Magnetic resonance imaging and spectroscopy in assessing 3-nitropropionic acidinduced brain lesions: an animal model of Huntington's disease. Prog Neurobiol. 72: 87-110 (2004)
90. Fernandes HB, Baimbridge KG, Church J, Hayden MR, Ray-mondLA. Mitochondrial sensitivity and altered calcium handling underlie enhanced NMDA induced apoptosis in YAC128 model of Huntington's disease. J Neurosci. 27: 13614-13623 (2007).
91. Panov AV, Gutekunst CA, Leavitt BR, Hayden MR, Burke JR, Strittmatter WJ, Greenamyre JT. Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines. Nat Neurosci. 5: 731-736 (2002).
92. Panov AV, Lund S, Greenamyre JT. Ca2+-induced permeability transition in humanlymphoblastoid cell mitochondria from normal and Huntington's disease individuals. Mol Cell Biochem. 269: 143-152 (2005).
93. Oliveira JM, Chen S, Almeida S, Riley R, Gonçalves J, Oliveira CR, Hayden MR, Nicholls DG, Ellerby LM, Rego AC. Mitochon-drial-dependent Ca2+ handling in Huntington's disease striatal cells: effect of histone deacetylase inhibitors. J Neurosci. 26: 11174-11186 (2006).
94. Milakovic T, Quintanilla RA, Johnson GV. Mutant huntingtin expression induces mitochondrial calcium handling defects in clonal striatal cells: functional consequences. J Biol Chem. 281: 34785-34795 (2006).
95. Oliveira JM, Jekabsons MB, Chen S, Lin A, Rego AC, Gonçalves J, Ellerby LM, Nicholls DG. Mitochondrial dysfunction in Huntington's disease: the bioenergetics of isolated and in situ mitochondria from transgenic mice. J Neurochem. 101: 241-249 (2007).
96. Gellerich FN, Gizatullina Z, Nguyen HP, Trumbeckaite S, Viel-haber S, Seppet E, Zierz S, Landwehrmeyer B, Riess O, von Hör-sten S, Striggow F. Impaired regulation of brain mitochondriaby extramitochondrial Ca2+ in transgenic Huntington disease rats. J Biol Chem. 283: 30715-30724 (2008).
97. Lim D, Fedrizzi L, Tartari M, Zuccato C, Cattaneo E, Brini M, Carafoli E. Calcium homeostasisand mitochondrial dysfunction in striatal neurons of Huntington disease. J Biol Chem. 283: 5780-5789 (2008).
98. Oliveira JM, Gonçalves J. In situ mitochondrial Ca2+ buffering differences of intact neurons and astrocytes from cortex and stria-tum. J Biol Chem. 284: 5010-5020 (2009).
99. Browne SE, Beal MF. The energetics of Huntington's disease. Neurochem Res. 29: 531-546 (2004).
100. Browne SE, Beal MF. Oxidative damage in Huntington's disease pathogenesis. Antioxid Redox Signal. 8: 2061-2073 (2006).
101. Trushina E, Dyer RB, Badger JD 2nd, Ure D, Eide L, Tran DD, Vrieze BT, Legendre-Guillemin V, McPherson PS, Mandavilli BS, Van Houten B, Zeitlin S, McNiven M, Aebersold R, Hayden M, Pa-risi JE, Seeberg E, Dragatsis I, Doyle K, Bender A, Chacko C, McMurray CT. Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro. Mol Cell Biol. 24: 8195-8209 (2004).
102. Chang DT, Rintoul GL, Pandipati S, Reynolds IJ. Mutant hunting-tin aggregates impair mitochondrial movement and trafficking in cortical neurons. Neurobiol Dis. 22: 388-400 (2006).
103. Orr AL, Li S, Wang CE, Li H, Wang J, Rong J, Xu X, Mastrober-ardino PG, Greenamyre JT, Li XJ. N-terminal mutant huntingtin associates with mitochondria and impairs mitochondrial trafficking. J Neurosci. 28: 2783-2792 (2008).
104. Browne SE, Bowling AC, MacGarvey U, Baik MJ, Berger SC, Muqit MM, Bird ED, Beal MF. Oxidative damage and metabolic dysfunction in Huntington's disease: selective vulnerability of the basal ganglia. Ann Neurol. 41: 646-653 (1997).
105. Tabrizin SJ, Cleeter MW, Xuereb J, Taanman JW, Cooper JM, Schapira AH. Biochemical abnormalities and excitotoxicity in Huntington's disease brain. Ann Neurol. 45: 25-32 (1999).
106. Senatorov VV, Charles V, Reddy PH, Tagle DA, Chuang DM. Overexpression and nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase in a transgenic mouse model of Huntington's disease. Mol Cell Neurosci. 22:285-297 (2003).
107. Fukui H, Moraes CT. Extended polyglutamine repeats trigger a feedback loop involving the mitochondrial complex III, the protea-some and huntingtin aggregates. Hum Mol Genet. 16:783-797 (2007).
108. Pandey M, Varghese M, Sindhu KM, Sreetama S, Navneet AK, Mohanakumar KP, Usha R. Mitochondrial NAD+-linked State 3 respiration and complex-I activity are compromised in the cerebral cortex of 3-nitropropionic acid-induced rat model of Huntington's disease. J Neurochem. 104: 420-434 (2008).
109. Seong IS, Ivanova E, Lee JM, et al. HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism. Hum Mol Genet. 14, 2871-2880 (2005).
110. Acevedo-Torres K, Berríos L, Rosario N, Dufault V, Skatchkov S, Eaton MJ, Torres-Ramos CA, Ayala-Torres S. Mitochondrial DNA damage is a hallmark ofchemically induced and the R6/2 transgenic model of Huntington's disease. DNA Repair (Amst) 8: 126-136 (2009).
111. Chen CM, Wu YR, Cheng ML, Liu JL, Lee YM, Lee PW, Soong BW, Chiu DT. Increased oxidative damage and mitochondrial abnormalities in the peripheral blood of Huntington's disease patients. Biochem Biophys Res Commun. 359: 335-340 (2007).
112. Banoei MM, Houshmand M, Panahi MS, Shariati P, Rostami M, Manshadi MD, Majidizadeh T. Huntington's disease and mitochon-drial DNA deletions: event or regular mechanism for mutant hunt-ingtin protein and CAG repeats expansion?! Cell Mol Neurobiol. 27: 867-875 (2007).
113. Ono T, Isobe K, Nakada K, Hayashi JI. Human cells are protected from mitochondrial dysfunction by complementation of DNA products in fused mitochondria. Nat Genet. 28: 272-275 (2001).
114. Solans A, Zambrano A, Rodríguez M, Barrientos A. Cytotoxicity of a mutant huntingtin fragment in yeastinvolves early alterations in mitochondrial OXPHOS complexes II and III. Hum Mol Genet. 15: 3063-3081 (2006).
115. Gandhi S, Wood NW. Molecular pathogenesis of Parkinson's disease. Hum Mol Genet. 14 Spec No. 2: 2749-2755 (2005).
116. Abeliovich A, Beal MF. Parkinsonism genes: culprits and clues. J Neurochem 99: 1062-1072 (2006).
117. Martin LJ. Mitochondriopathy in Parkinson disease and amyotro-phic lateral sclerosis. J Neuropathol Exp Neurol. 65: 1103-1110 (2006).
118. Thomas B, Beal MF. Parkinson's disease. Hum Mol Genet. 16 Spec No. 2:R183-R194 (2007).
119. Langston JW, Ballard P, Tetrud JW, Irwin, I. Chronic Parkin-sonism in humans due to a product of meperidine-analog synthesis. Science. 219: 979-980 (1983).
120. Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science. 276: 2045-2047 (1997).
121. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 392: 605-608 (1998).
122. Bonifati V, Rizzu P, van Baren MJ, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset Parkin-sonism. Science 299: 256-259 (2003).
123. Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Al-banese A, Nussbaum R, González-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science. 304: 1158-1160 (2004).
124. Strauss KM, Martins LM, Plun-Favreau H, et al. Loss of function mutations in the gene encodingOmi/HtrA2 in Parkinson's disease. Hum Mol Genet. 14: 2099-2111 (2005).
125. Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron. 44: 601-607 (2004).
126. Leroy E, Boyer R, Auburger G, et al. The ubiquitin pathway in Parkinson's disease. Nature. 395: 451-452 (1998).
127. Schapira AH, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD. Mitochondrialcomplex I deficiency in Parkinson's disease. J Neurochem. 54: 823-827 (1990).
128. Parker WD Jr, Boyson SJ, Parks JK. Abnormalities of the electron transport chain in idiopathic Parkinson's disease. Ann Neurol. 719-723 (1989).
129. Dagda RK, Zhu J, Chu CT. Mitochondrial kinases in Parkinson's disease: converging insights from neurotoxin and genetic models. Mitochondrion. 9: 289-98 (2009).
130. Andersen JK. Iron dysregulation and Parkinson's disease. J Alz-heimers Dis. 6: S47-S52 (2006).
131. Sian J, Dexter DT, Lees AJ, Daniel S, Agid Y, Javoy-Agid F, Jen-ner P, Marsden, CD. Alterations in glutathione levels in Parkinson's disease and other neurodegenerative disorders affecting basalgan-glia. Ann Neurol. 36: 348-355 (1994).
132. Simon DK, Pulst SM, Sutton JP, Browne SE, Beal MF, Johns DR. Familial multisystem degeneration with parkinsonism associated with the 11778 mitochondrial DNA mutation. Neurology. 53: 1787-1793 (1999).
133. Zhu J, Chu CT. Mitochondrial dysfunction in Parkinson's disease. J Alzheimers Dis.2010;20 Suppl 2:S325-S334 (2010).
134. Dagda RK, Cherra SJ 3rd, Kulich SM, Tandon A, Park D, Chu CT. Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J Biol Chem. 284: 13843-13855 (2009).
135. Poole AC, Thomas RE, Andrews LA, McBride HM, Whitworth AJ, Pallanck LJ. The PINK1/Parkin pathway regulates mitochon-drial morphology. Proc Natl Acad Sci U S A. 105: 1638-1643 (2008).
136. Deng H, Dodson MW, Huang H, Guo M. The Parkinson's disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila. Proc Natl Acad Sci U S A. 105: 14503-14508 (2008).
137. Devi L, Raghavendran V, Prabhu BM, Avadhani NG, Anan-datheerthavarada HK. Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. J Biol Chem. 283: 9089-9100 (2008).
138. Parihar MS, Parihar A, Fujita M, Hashimoto M, Ghafourifar P. Mitochondrial association of alpha-synuclein causes oxidative stress. Cell Mol Life Sci. 65: 1272-1284 (2008).
139. Shavali S, Brown-Borg HM, Ebadi M, Porter J. Mitochondrial localization of alpha-synuclein protein in alpha-synuclein overex-pressing cells. Neurosci Lett. 439:125-128 (2008).
140. West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, Ross CA, Dawson VL, Dawson TM. Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci U S A. 102: 16842-16847 (2005).
141. Zhang L, Shimoji M, Thomas B, Moore DJ, Yu SW, Marupudi NI, Torp R, Torgner IA, Ottersen OP, Dawson TM, Dawson VL. Mito-chondrial localization of the Parkinson's disease related protein DJ-1: implications for pathogenesis. Hum Mol Genet. 14: 2063-2073 (2005).
142. Hervias I, Beal MF, Manfredi G. Mitochondrial dysfunction and amyotrophic lateral sclerosis. Muscle Nerve. 33:598-608 (2006).
143. Wong M, Martin LJ. Skeletal muscle-restricted expression of human SOD1 causes motor neuron degeneration in transgenic mice. Hum Mol Genet. 19: 2284-2302 (2010).
144. Hirano A, Donnenfeld H, Sasaki S, Nakano I. Fine structural observations of neurofilamentous changes in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol. 43: 461-470 (1984).
145. Dupuis L. Oxidative stress sensitivity in ALS muscle cells. Exp Neurol. 220(2): 219-223 (2009).
146. Kawamata H, Manfredi G. Mitochondrial dysfunction and intracel-lular calcium dysregulation in ALS. Mech Ageing Dev. May 18. [Epub ahead of print] PubMed (2010).
147. Martin LJ. Mitochondrial pathobiology in Parkinson's disease and amyotrophic lateral sclerosis. J Alzheimers Dis. 20 Suppl 2: 335-356 (2010).
148. Shi P, Wei Y, Zhang J, Gal J, Zhu H. Mitochondrial dysfunction is a converging point of multiple pathological pathways in amyotro-phic lateral sclerosis. J Alzheimers Dis. 20 Suppl 2:S311-S324 (2010).
149. Pedrini S, Sau D, Guareschi S, Bogush M, Brown RH Jr, Naniche N, et al. ALS-linked mutant SOD1 damages mitochondria by promoting conformational changes in Bcl-2. Hum Mol Genet 19: 2974-2986 (2010).
150. Keeney PM, Bennett JP Jr. ALS spinal neurons show varied and reduced mtDNA gene copy numbers and increased mtDNA gene deletions. Mol Neurodegener. 5: 21 (2010).
151. Chung MJ, Suh YL. Ultrastructural changes of mitochondria in the skeletal muscle of patients with amyotrophic lateral sclerosis. Ul-trastruct Pathol. 26: 3-7 (2002).
152. Dupuis L, di Scala F, Rene F, de Tapia M, Oudart H, Pradat PF, Meininger V, Loeffler JP. Up-regulation of mitochondrial uncoupling protein 3 reveals an early muscular metabolic defect in amyotrophic lateral sclerosis. FASEB J. 17:2091-2093 (2003).
153. Bergemalm D, Jonsson PA, Graffmo KS, Andersen PM, Brann-strom T, Rehnmark A, Marklund SL. Overloading of stable and exclusion of unstable human superoxide dismutase-1 variants in mitochondria of murine amyotrophic lateral sclerosis models. J Neu-rosci. 26: 4147-4154 (2006).
154. Deng HX, Shi Y, Furukawa Y, Zhai H. et al. Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermo-lecular linked insoluble aggregates of SOD1 in mitochondria. Proc Natl Acad Sci U S A. 103: 7142-7147 (2006).
155. Liu J, Lillo C, Jonsson PA, et al. Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria. Neuron. 43: 5-17 (2004).
156. Vijayvergiya C, Beal MF, Buck J, Manfredi G. Mutant superoxide dismutase 1 forms aggregates in the brain mitochondrial matrix of amyotrophic lateral sclerosis mice. J Neurosci. 25: 2463-2470 (2005).
157. Higgins CM, Jung C, Ding H, Xu Z. Mutant Cu, Zn superoxide dismutase that causes motoneuron degeneration is present in mitochondria in the CNS. J Neurosci. 22: RC215 (2002).
158. Magrané J, Hervias I, Henning MS, Damiano M, Kawamata H, Manfredi G. Mutant SOD1 in neuronal mitochondria causes toxicity and mitochondrial dynamics abnormalities. Hum Mol Genet. 18: 4552-4564. (2009).
159. Martin LJ. The mitochondrial permeability transition pore: a molecular target for amyotrophic lateral sclerosis therapy. Biochim Biophys Acta. 180: 186-197 (2010).
160. Beal MF. Mitochondrial dysfunction and oxidative damage in Alzheimer's and Parkinson's diseases and coenzyme Q10 as a potential treatment. J Bioenerg Biomembr. 36: 381-386 (2004).
161. Thomas B, Beal MF. Mitochondrial therapies for Parkinson's disease. Mov Disord. 2010;25 Suppl 1:S155-S160 (2010).
162. Cleren C, Yang L, Lorenzo B, Calingasan NY, Schomer A, Sireci A, Wille EJ, Beal MF. Therapeutic effects of coenzyme Q10 (CoQ10) and reduced CoQ10 in the MPTP model of Parkinsonism. J Neurochem. 104: 1613-1621 (2008).
163. Henchcliffe C, Beal MF. Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis. Nat Clin Pract Neurol. 4: 600-609 (2008).
164. Yang L, Calingasan NY, Wille EJ, Cormier K, Smith K, Ferrante RJ, Beal MF. Combination therapy with coenzyme Q10 and creatine produces additive neuroprotective effects in models of Parkinson's and Huntington's diseases. J Neurochem. 109: 1427-1439 (2009).
165. Anekonda TS, Reddy PH. Can Plants Provide a New Generation of Drugs for Treating Alzheimer's Disease? 50: 361-376 (2005).
166. Anekonda TS, Reddy PH. Neuronal protection by sirtuins in Alzheimer's disease. J Neurochem. 96: 305-313 (2006).
167. Anekonda TS. Resveratrol--a boon for treating Alzheimer's disease? Brain Res Rev. 52:316-26 (2006).
168. Du H, Yan SS. Unlocking the Door to Neuronal Woes in Alzheimer's Disease: Aβ and Mitochondrial Permeability Transition Pore. Pharmaceuticals 3: 1936-1948 (2010).
169. Cardoso S, Santos R, Correia S, Carvalho C, Zhu X, Lee H-G, Casadesus G, Smith MA, Perry G, Moreira PI. Insulin and Insulin-Sensitizing Drugs in Neurodegeneration: Mitochondria as Therapeutic Targets. Pharmaceuticals 2009, 2: 250-286 (2009).
170. Praticò D. Oxidative stress hypothesis in Alzheimer's disease: a reappraisal. Trends Pharmacol Sci. 29: 609-615 (2008).
171. Bordet T, Berna P, Abitbol JL, Pruss RM. Olesoxime (TRO19622): A Novel Mitochondrial-Targeted Neuroprotective Compound. Pharmaceuticals 3: 345-368 (2010).
172. Szeto HH. Development of mitochondria-targeted aromatic-cationic peptides for neurodegenerativediseases. Ann N Y Acad Sci. 1147: 112-121 (2008).
173. Murphy MP, Smith RA. Targeting antioxidants to mitochondria by conjugation to lipophilic cations. Annu Rev Pharmacol Toxicol. 47: 629-656 (2007).
174. Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, Seely L, Hung D, dimebon investigators. Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study. Lancet. 372: 207-215 (2008).