Mitochondrial Importance in Alzheimer’s, Huntington’s and Parkinson’s Diseases

  • Sónia C. Correia
  • Renato X. Santos
  • George Perry
  • Xiongwei ZhuEmail author
  • Paula I. Moreira
  • Mark A. Smith
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 724)


Mitochondria have been long known as “gatekeepers of life and death”. Indeed, these dynamic organelles are the master coordinators of energy metabolism, being responsible for the generation of the majority of cellular ATP. Notably, mitochondria are also one of the primary producers of intracellular reactive oxygen species which are the main inducer of oxidative damage. Neurons, as metabolically active cells with high energy demands, are predominantly dependent on mitochondrial function, as reflected by the observation that mitochondrial defects are key features of chronic neurodegenerative diseases. Indeed, morphologic, biochemical and molecular genetic studies posit that mitochondria constitute a convergence point for neurodegeneration. Moreover, recent findings convey that neurons are particularly reliant on the dynamic properties of mitochondria, further emphasizing the critical role of mitochondria in neuronal functions. This chapter highlights how mitochondrial pathobiology might contribute to neurodegeneration in Alzheimer's, Parkinson's and Huntington's diseases.


Neurodegenerative Disease Lipoic Acid Mutant Huntingtin Mitochondrial Alteration Mitochondrial Movement 
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.


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  1. 1.
    Correia SC, Moreira PI. Hypoxia-inducible factor 1: a new hope to counteract neurodegeneration? J Neurochem 2010; 112:1–12.PubMedCrossRefGoogle Scholar
  2. 2.
    Przedborski S, Vila M, Jackson-Lewis V. Neurodegeneration: what is it and where are we? J Clin Invest 2003; 111:3–10.PubMedGoogle Scholar
  3. 3.
    Migliore L, Coppede F. Environmental-induced oxidative stress in neurodegenerative disorders and aging. Mutat Res 2009; 674:73–84.PubMedGoogle Scholar
  4. 4.
    Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006; 443:787–795.PubMedCrossRefGoogle Scholar
  5. 5.
    Moreira PI, Zhu X, Wang X et al. Mitochondria: a therapeutic target in neurodegeneration. Biochim Biophys Acta 2010; 1802:212–220.PubMedGoogle Scholar
  6. 6.
    Green DR, Kroemer G. The pathophysiology of mitochondrial cell death. Science 2004; 305:626–629.PubMedCrossRefGoogle Scholar
  7. 7.
    Beal MF. Mitochondria take center stage in aging and neurodegeneration. Ann Neurol 2005; 58:495–505.PubMedCrossRefGoogle Scholar
  8. 8.
    Mattson MP, Gleichmann M, Cheng A. Mitochondria in neuroplasticity and neurological disorders. Neuron 2008; 60:748–766.PubMedCrossRefGoogle Scholar
  9. 9.
    Moreira PI, Duarte AI, Santos MS et al. An integrative view of the role of oxidative stress, mitochondria and insulin in Alzheimer’s disease. J Alzheimers Dis 2009; 16:741–761.PubMedGoogle Scholar
  10. 10.
    Murphy AN, Fiskum G, Beal MF. Mitochondria in neurodegeneration: bioenergetic function in cell life and death. J Cereb Blood Flow Metab 1999; 19:231–245.PubMedCrossRefGoogle Scholar
  11. 11.
    Petrozzi L, Ricci G, Giglioli NJ et al. Mitochondria and neurodegeneration. Biosci Rep 2007; 27:87–104.PubMedCrossRefGoogle Scholar
  12. 12.
    Nunomura A, Honda K, Takeda A et al. Oxidative damage to RNA in neurodegenerative diseases. J Biomed Biotechnol 2006:82323.Google Scholar
  13. 13.
    Chen H, Chan DC. Mitochondrial dynamics—fusion, fission, movement and mitophagy—in neurodegenerative diseases. Hum Mol Genet 2009; 18:R169–176.PubMedCrossRefGoogle Scholar
  14. 14.
    Parone PA, Da Cruz S, Tondera D et al. Preventing mitochondrial fission impairs mitochondrial function and leads to loss of mitochondrial DNA. PLoS One 2008; 3:e3257.CrossRefGoogle Scholar
  15. 15.
    Westermann B. Merging mitochondria matters: cellular role and molecular machinery of mitochondrial fusion. EMBO Rep 2002; 3:527–531.PubMedCrossRefGoogle Scholar
  16. 16.
    Suen DF, Norris KL, Youle RJ. Mitochondrial dynamics and apoptosis. Genes Dev 2008; 22:1577–1590.PubMedCrossRefGoogle Scholar
  17. 17.
    Li Z, Okamoto K, Hayashi Y et al. The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 2004; 119:873–887.PubMedCrossRefGoogle Scholar
  18. 18.
    Chen H, McCaffery JM, Chan DC. Mitochondrial fusion protects against neurodegeneration in the cerebellum. Cell 2007; 130:548–562.PubMedCrossRefGoogle Scholar
  19. 19.
    Liu QA, Shio H. Mitochondrial morphogenesis, dendrite development and synapse formation in cerebellum require both Bcl-w and the glutamate receptor delta2. PLoS Genet 2008; 4:e1000097.CrossRefGoogle Scholar
  20. 20.
    Stowers RS, Megeath LJ, Gorska-Andrzejak J et al. Axonal transport of mitochondria to synapses depends on milton, a novel Drosophila protein. Neuron 2002; 36:1063–1077.PubMedCrossRefGoogle Scholar
  21. 21.
    Verstreken P, Ly CV, Venken KJ et al. Synaptic mitochondria are critical for mobilization of reserve pool vesicles at Drosophila neuromuscular junctions. Neuron 2005; 47:365–378.PubMedCrossRefGoogle Scholar
  22. 22.
    Querfurth HW, LaFerla FM. Alzheimer’s disease. N Engl J Med 2010; 362:329–344.PubMedCrossRefGoogle Scholar
  23. 23.
    Selkoe DJ. Alzheimer’s disease results from the cerebral accumulation and cytotoxicity of amyloid beta-protein. J Alzheimers Dis 2001; 3:75–80.PubMedGoogle Scholar
  24. 24.
    Moreira PI, Honda K, Zhu X et al. Brain and brawn: parallels in oxidative strength. Neurology 2006; 66:S97–101.CrossRefGoogle Scholar
  25. 25.
    Moreira PI, Santos MS, Oliveira CR. Alzheimer’s disease: a lesson from mitochondrial dysfunction. Antioxid Redox Signal 2007; 9:1621–1630.PubMedCrossRefGoogle Scholar
  26. 26.
    Swerdlow RH, Khan SM. A “mitochondrial cascade hypothesis” for sporadic Alzheimer’s disease. Med Hypotheses 2004; 63:8–20.PubMedCrossRefGoogle Scholar
  27. 27.
    Swerdlow RH, Khan SM. The Alzheimer’s disease mitochondrial cascade hypothesis: an update. Exp Neurol 2009; 218:308–315.PubMedCrossRefGoogle Scholar
  28. 28.
    Aksenov MY, Tucker HM, Nair P et al. The expression of key oxidative stress-handling genes in different brain regions in Alzheimer’s disease. J Mol Neurosci 1998; 11:151–164.PubMedCrossRefGoogle Scholar
  29. 29.
    Aliev G, Smith MA, Obrenovich ME et al. Role of vascular hypoperfusion-induced oxidative stress and mitochondria failure in the pathogenesis of Azheimer disease. Neurotox Res 2003; 5:491–504.PubMedCrossRefGoogle Scholar
  30. 30.
    Hirai K, Aliev G, Nunomura A et al. Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci 2001; 21:3017–3023.PubMedGoogle Scholar
  31. 31.
    Anderson GL, Limacher M, Assaf AR et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004; 291:1701–1712.PubMedCrossRefGoogle Scholar
  32. 32.
    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 1993; 13:438–447.PubMedCrossRefGoogle Scholar
  33. 33.
    Small GW, Komo S, La Rue A et al. Early detection of Alzheimer’s disease by combining apolipoprotein E and neuroimaging. Ann N Y Acad Sci 1996; 802:70–78.PubMedCrossRefGoogle Scholar
  34. 34.
    Silverman DH, Small GW, Chang CY et al. Positron emission tomography in evaluation of dementia: Regional brain metabolism and long-term outcome. JAMA 2001; 286:2120–2127.PubMedCrossRefGoogle Scholar
  35. 35.
    Hoyer S, Nitsch R. Cerebral excess release of neurotransmitter amino acids subsequent to reduced cerebral glucose metabolism in early-onset dementia of Alzheimer type. J Neural Transm 1989; 75:227–232.PubMedCrossRefGoogle Scholar
  36. 36.
    Huang HM, Ou HC, Xu H et al. Inhibition of alpha-ketoglutarate dehydrogenase complex promotes cytochrome c release from mitochondria, caspase-3 activation and necrotic cell death. J Neurosci Res 2003; 74:309–317.PubMedCrossRefGoogle Scholar
  37. 37.
    Bubber P, Haroutunian V, Fisch G et al. Mitochondrial abnormalities in Alzheimer brain: mechanistic implications. Ann Neurol 2005; 57:695–703.PubMedCrossRefGoogle Scholar
  38. 38.
    Tretter L, Adam-Vizi V. Inhibition of Krebs cycle enzymes by hydrogen peroxide: A key role of [alpha]-ketoglutarate dehydrogenase in limiting NADH production under oxidative stress. J Neurosci 2000; 20:8972–8979.PubMedGoogle Scholar
  39. 39.
    Kish SJ, Bergeron C, Rajput A et al. Brain cytochrome oxidase in Alzheimer’s disease. J Neurochem 1992; 59:776–779.PubMedCrossRefGoogle Scholar
  40. 40.
    Parker WD, Jr., Mahr NJ, Filley CM et al. Reduced platelet cytochrome c oxidase activity in Alzheimer’s disease. Neurology 1994; 44:1086–1090.PubMedGoogle Scholar
  41. 41.
    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 2002; 23:371–376.PubMedCrossRefGoogle Scholar
  42. 42.
    Valla J, Schneider L, Niedzielko T et al. Impaired platelet mitochondrial activity in Alzheimer’s disease and mild cognitive impairment. Mitochondrion 2006; 6:323–330.PubMedCrossRefGoogle Scholar
  43. 43.
    Pereira C, Santos MS, Oliveira C. Mitochondrial function impairment induced by amyloid beta-peptide on PC12 cells. Neuroreport 1998; 9:1749–1755.PubMedCrossRefGoogle Scholar
  44. 44.
    Fattoretti P, Balietti M, Casoli T et al. Decreased numeric density of succinic dehydrogenase-positive mitochondria in CA1 pyramidal neurons of 3xTg-AD mice. Rejuvenation Res 2010; 13:144–147.PubMedCrossRefGoogle Scholar
  45. 45.
    Moreira PI, Harris PL, Zhu X et al. Lipoic acid and N-acetyl cysteine decrease mitochondrial-related oxidative stress in Alzheimer disease patient fibroblasts. J Alzheimers Dis 2007; 12:195–206.PubMedGoogle Scholar
  46. 46.
    de la Monte SM, Wands JR. Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer’s disease. J Alzheimers Dis 2006; 9:167–181.PubMedGoogle Scholar
  47. 47.
    Castellani RJ, Harris PL, Sayre LM et al. Active glycation in neurofibrillary pathology of Alzheimer disease: N(epsilon)-(carboxymethyl) lysine and hexitol-lysine. Free Radic Biol Med 2001; 31:175–180.PubMedCrossRefGoogle Scholar
  48. 48.
    Nunomura A, Perry G, Pappolla MA et al. RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer’s disease. J Neurosci 1999; 19:1959–1964.PubMedGoogle Scholar
  49. 49.
    Nunomura A, Perry G, Aliev G et al. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 2001; 60:759–767.PubMedGoogle Scholar
  50. 50.
    Smith MA, Richey Harris PL, Sayre LM et al. Widespread peroxynitrite-mediated damage in Alzheimer’s disease. J Neurosci 1997; 17:2653–2657.PubMedGoogle Scholar
  51. 51.
    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 2005; 579:2759–2766.PubMedCrossRefGoogle Scholar
  52. 52.
    Hamblet NS, Ragland B, Ali M et al. Mutations in mitochondrial-encoded cytochrome c oxidase subunits I, II and III genes detected in Alzheimer’s disease using single-strand conformation polymorphism. Electrophoresis 2006; 27:398–408.PubMedCrossRefGoogle Scholar
  53. 53.
    Qiu X, Chen Y, Zhou M. Two point mutations in mitochondrial DNA of cytochrome c oxidase coexist with normal mtDNA in a patient with Alzheimer’s disease. Brain Res 2001; 893:261–263.PubMedCrossRefGoogle Scholar
  54. 54.
    Lin MT, Simon DK, Ahn CH et al. High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer’s disease brain. Hum Mol Genet 2002; 11:133–145.PubMedCrossRefGoogle Scholar
  55. 55.
    Coskun PE, Beal MF, Wallace DC. Alzheimer’s brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. Proc Natl Acad Sci USA 2004; 101:10726–10731.PubMedCrossRefGoogle Scholar
  56. 56.
    Rhein V, Baysang G, Rao S et al. Amyloid-beta leads to impaired cellular respiration, energy production and mitochondrial electron chain complex activities in human neuroblastoma cells. Cell Mol Neurobiol 2009; 29:1063–1071.PubMedCrossRefGoogle Scholar
  57. 57.
    Takuma K, Yao J, Huang J et al. ABAD enhances Abeta-induced cell stress via mitochondrial dysfunction. FASEB J 2005; 19:597–598.PubMedGoogle Scholar
  58. 58.
    Massaad CA, Washington TM, Pautler RG et al. Overexpression of SOD-2 reduces hippocampal superoxide and prevents memory deficits in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 2009; 106:13576–13581.PubMedCrossRefGoogle Scholar
  59. 59.
    Anantharaman M, Tangpong J, Keller JN et al. Beta-amyloid mediated nitration of manganese superoxide dismutase: implication for oxidative stress in a APPNLH/NLH X PS-1P264L/P264L double knock-in mouse model of Alzheimer’s disease. Am J Pathol 2006; 168:1608–1618.PubMedCrossRefGoogle Scholar
  60. 60.
    Melov S, Adlard PA, Morten K et al. Mitochondrial oxidative stress causes hyperphosphorylation of tau. PLoS ONE 2007; 2:e536.CrossRefGoogle Scholar
  61. 61.
    Esposito L, Raber J, Kekonius L et al. Reduction in mitochondrial superoxide dismutase modulates Alzheimer’s disease-like pathology and accelerates the onset of behavioral changes in human amyloid precursor protein transgenic mice. J Neurosci 2006; 26:5167–5179.PubMedCrossRefGoogle Scholar
  62. 62.
    Li F, Calingasan NY, Yu F et al. Increased plaque burden in brains of APP mutant MnSOD heterozygous knockout mice. J Neurochem 2004; 89:1308–1312.PubMedCrossRefGoogle Scholar
  63. 63.
    Massaad CA, Amin SK, Hu L et al. Mitochondrial superoxide contributes to blood flow and axonal transport deficits in the Tg2576 mouse model of Alzheimer’s disease. PLoS One 2010; 5:e10561.CrossRefGoogle Scholar
  64. 64.
    Crouch PJ, Blake R, Duce JA et al. Copper-dependent inhibition of human cytochrome c oxidase by a dimeric conformer of amyloid-beta1-42. J Neurosci 2005; 25:672–679.PubMedCrossRefGoogle Scholar
  65. 65.
    Marques CA, Keil U, Bonert A et al. Neurotoxic mechanisms caused by the Alzheimer’s disease-linked Swedish amyloid precursor protein mutation: oxidative stress, caspases and the JNK pathway. J Biol Chem 2003; 278:28294–28302.PubMedCrossRefGoogle Scholar
  66. 66.
    Devi L, Prabhu BM, Galati DF et al. Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer’s disease brain is associated with mitochondrial dysfunction. J Neurosci 2006; 26:9057–9068.PubMedCrossRefGoogle Scholar
  67. 67.
    Anandatheerthavarada HK, Biswas G, Robin MA et al. Mitochondrial targeting and a novel transmembrane arrest of Alzheimer’s amyloid precursor protein impairs mitochondrial function in neuronal cells. J Cell Biol 2003; 161:41–54.PubMedCrossRefGoogle Scholar
  68. 68.
    Caspersen C, Wang N, Yao J et al. Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer’s disease. FASEB J 2005; 19:2040–2041.PubMedGoogle Scholar
  69. 69.
    Manczak M, Anekonda TS, Henson E et al. 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 2006; 15:1437–1449.PubMedCrossRefGoogle Scholar
  70. 70.
    Pavlov PF, Wiehager B, Sakai J et al. Mitochondrial gamma-secretase participates in the metabolism of mitochondria-associated amyloid precursor protein. FASEB J 2010Google Scholar
  71. 71.
    Iijima-Ando K, Hearn SA, Shenton C et al. Mitochondrial mislocalization underlies Abeta42-induced neuronal dysfunction in a Drosophila model of Alzheimer’s disease. PLoS One 2009; 4:e8310.CrossRefGoogle Scholar
  72. 72.
    Yan SD, Stern DM. Mitochondrial dysfunction and Alzheimer’s disease: role of amyloid-beta peptide alcohol dehydrogenase (ABAD). Int J Exp Pathol 2005; 86:161–171.PubMedCrossRefGoogle Scholar
  73. 73.
    Lustbader JW, Cirilli M, Lin C et al. ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease. Science 2004; 304:448–452.PubMedCrossRefGoogle Scholar
  74. 74.
    Hansson Petersen CA, Alikhani N, Behbahani H et al. The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae. Proc Natl Acad Sci USA 2008; 105:13145–13150.PubMedCrossRefGoogle Scholar
  75. 75.
    Moreira PI, Santos MS, Moreno A et al. Amyloid beta-peptide promotes permeability transition pore in brain mitochondria. Biosci Rep 2001; 21:789–800.PubMedCrossRefGoogle Scholar
  76. 76.
    Moreira PI, Santos MS, Moreno A et al. Effect of amyloid beta-peptide on permeability transition pore: a comparative study. J Neurosci Res 2002; 69:257–267.PubMedCrossRefGoogle Scholar
  77. 77.
    Du H, Guo L, Fang F et al. Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nat Med 2008; 14:1097–1105.PubMedCrossRefGoogle Scholar
  78. 78.
    Falkevall A, Alikhani N, Bhushan S et al. Degradation of the amyloid beta-protein by the novel mitochondrial peptidasome, PreP. J Biol Chem 2006; 281:29096–29104.PubMedCrossRefGoogle Scholar
  79. 79.
    Rhein V, Song X, Wiesner A et al. Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer’s disease mice. Proc Natl Acad Sci USA 2009; 106:20057–20062.PubMedGoogle Scholar
  80. 80.
    David DC, Hauptmann S, Scherping I et al. Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice. J Biol Chem 2005; 280:23802–23814.PubMedCrossRefGoogle Scholar
  81. 81.
    Gray CW, Ward RV, Karran E et al. Characterization of human HtrA2, a novel serine protease involved in the mammalian cellular stress response. Eur J Biochem 2000; 267:5699–5710.PubMedCrossRefGoogle Scholar
  82. 82.
    Gupta S, Singh R, Datta P et al. The C-terminal tail of presenilin regulates Omi/HtrA2 protease activity. J Biol Chem 2004; 279:45844–45854.PubMedCrossRefGoogle Scholar
  83. 83.
    Park HJ, Seong YM, Choi JY et al. Alzheimer’s disease-associated amyloid beta interacts with the human serine protease HtrA2/Omi. Neurosci Lett 2004; 357:63–67.PubMedCrossRefGoogle Scholar
  84. 84.
    Kooistra J, Milojevic J, Melacini G et al. A new function of human HtrA2 as an amyloid-beta oligomerization inhibitor. J Alzheimers Dis 2009; 17:281–294.PubMedGoogle Scholar
  85. 85.
    Park HJ, Kim SS, Seong YM et al. Beta-amyloid precursor protein is a direct cleavage target of HtrA2 serine protease. Implications for the physiological function of HtrA2 in the mitochondria. J Biol Chem 2006; 281:34277–34287.PubMedCrossRefGoogle Scholar
  86. 86.
    Behbahani H, Pavlov PF, Wiehager B et al. Association of Omi/HtrA2 with gamma-secretase in mitochondria. Neurochem Int 2010; 57:668–675.PubMedCrossRefGoogle Scholar
  87. 87.
    Baloyannis SJ. Mitochondrial alterations in Alzheimer’s disease. J Alzheimers Dis 2006; 9:119–126.PubMedGoogle Scholar
  88. 88.
    Moreira PI, Siedlak SL, Wang X et al. Increased autophagic degradation of mitochondria in Alzheimer disease. Autophagy 2007; 3:614–615.PubMedGoogle Scholar
  89. 89.
    Moreira PI, Siedlak SL, Wang X et al. Autophagocytosis of mitochondria is prominent in Alzheimer disease. J Neuropathol Exp Neurol 2007; 66:525–532.PubMedCrossRefGoogle Scholar
  90. 90.
    Wang X, Su B, Fujioka H et al. Dynamin-like protein 1 reduction underlies mitochondrial morphology and distribution abnormalities in fibroblasts from sporadic Alzheimer’s disease patients. Am J Pathol 2008; 173:470–482.PubMedCrossRefGoogle Scholar
  91. 91.
    Wang X, Su B, Zheng L et al. The role of abnormal mitochondrial dynamics in the pathogenesis of Alzheimer’s disease. J Neurochem 2009; 109 Suppl 1:153–159.PubMedCrossRefGoogle Scholar
  92. 92.
    Wang X, Su B, Siedlak SL et al. Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci USA 2008; 105:19318–19323.PubMedCrossRefGoogle Scholar
  93. 93.
    Wang X, Su B, Lee HG et al. Impaired balance of mitochondrial fission and fusion in Alzheimer’s disease. J Neurosci 2009; 29:9090–9103.PubMedCrossRefGoogle Scholar
  94. 94.
    Lassmann H, Fischer P, Jellinger K. Synaptic pathology of Alzheimer’s disease. Ann N Y Acad Sci 1993; 695:59–64.PubMedCrossRefGoogle Scholar
  95. 95.
    Blennow K, Bogdanovic N, Alafuzoff I et al. Synaptic pathology in Alzheimer’s disease: relation to severity of dementia, but not to senile plaques, neurofibrillary tangles, or the ApoE4 allele. J Neural Transm 1996; 103:603–618.PubMedCrossRefGoogle Scholar
  96. 96.
    Stokin GB, Lillo C, Falzone TL et al. Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science 2005; 307:1282–1288.PubMedCrossRefGoogle Scholar
  97. 97.
    Shankar GM, Li S, Mehta TH et al. Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 2008; 14:837–842.PubMedCrossRefGoogle Scholar
  98. 98.
    Rui Y, Tiwari P, Xie Z et al. Acute impairment of mitochondrial trafficking by beta-amyloid peptides in hippocampal neurons. J Neurosci 2006; 26:10480–10487.PubMedCrossRefGoogle Scholar
  99. 99.
    Wang X, Perry G, Smith MA et al. Amyloid-beta-derived diffusible ligands cause impaired axonal transport of mitochondria in neurons. Neurodegener Dis 2010; 7:56–59.PubMedCrossRefGoogle Scholar
  100. 100.
    Rui Y, Gu J, Yu K et al. Inhibition of AMPA receptor trafficking at hippocampal synapses by beta-amyloid oligomers: the mitochondrial contribution. Mol Brain 2010; 3:10.PubMedGoogle Scholar
  101. 101.
    de Rijk MC, Rocca WA, Anderson DW et al. A population perspective on diagnostic criteria for Parkinson’s disease. Neurology 1997; 48:1277–1281.PubMedGoogle Scholar
  102. 102.
    de Lau LM, Giesbergen PC, de Rijk MC et al. Incidence of parkinsonism and Parkinson disease in a general population: the Rotterdam Study. Neurology 2004; 63:1240–1244.PubMedGoogle Scholar
  103. 103.
    Cardoso SM, Moreira PI, Agostinho P et al. Neurodegenerative pathways in Parkinson’s disease: therapeutic strategies. Curr Drug Targets CNS Neurol Disord 2005; 4:405–419.PubMedCrossRefGoogle Scholar
  104. 104.
    Bueler H. Impaired mitochondrial dynamics and function in the pathogenesis of Parkinson’s disease. Exp Neurol 2009; 218:235–246.PubMedCrossRefGoogle Scholar
  105. 105.
    Hardy J, Cai H, Cookson MR et al. Genetics of Parkinson’s disease and parkinsonism. Ann Neurol 2006; 60:389–398.PubMedCrossRefGoogle Scholar
  106. 106.
    Banerjee R, Starkov AA, Beal MF et al. Mitochondrial dysfunction in the limelight of Parkinson’s disease pathogenesis. Biochim Biophys Acta 2009; 1792:651–663.PubMedGoogle Scholar
  107. 107.
    Schapira AH. Mitochondria in the aetiology and pathogenesis of Parkinson’s disease. Lancet Neurol 2008; 7:97–109.PubMedCrossRefGoogle Scholar
  108. 108.
    Schapira AH, Cooper JM, Dexter D et al. Mitochondrial complex I deficiency in Parkinson’s disease. J Neurochem 1990; 54:823–827.PubMedCrossRefGoogle Scholar
  109. 109.
    Mann VM, Cooper JM, Daniel SE et al. Complex I, iron and ferritin in Parkinson’s disease substantia nigra. Ann Neurol 1994; 36:876–881.PubMedCrossRefGoogle Scholar
  110. 110.
    Parker WD, Jr., Boyson SJ, Parks JK. Abnormalities of the electron transport chain in idiopathic Parkinson’s disease. Ann Neurol 1989; 26:719–723.PubMedCrossRefGoogle Scholar
  111. 111.
    Krige D, Carroll MT, Cooper JM et al. Platelet mitochondrial function in Parkinson’s disease. The Royal Kings and Queens Parkinson Disease Research Group. Ann Neurol 1992; 32:782–788.PubMedCrossRefGoogle Scholar
  112. 112.
    Haas RH, Nasirian F, Nakano K et al. Low platelet mitochondrial complex I and complex II/III activity in early untreated Parkinson’s disease. Ann Neurol 1995; 37:714–722.PubMedCrossRefGoogle Scholar
  113. 113.
    Blandini F, Nappi G, Greenamyre JT. Quantitative study of mitochondrial complex I in platelets of parkinsonian patients. Mov Disord 1998; 13:11–15.PubMedCrossRefGoogle Scholar
  114. 114.
    Barroso N, Campos Y, Huertas R et al. Respiratory chain enzyme activities in lymphocytes from untreated patients with Parkinson disease. Clin Chem 1993; 39:667–669.PubMedGoogle Scholar
  115. 115.
    Yoshino H, Nakagawa-Hattori Y, Kondo T et al. Mitochondrial complex I and II activities of lymphocytes and platelets in Parkinson’s disease. J Neural Transm Park Dis Dement Sect 1992; 4:27–34.PubMedCrossRefGoogle Scholar
  116. 116.
    Taylor DJ, Krige D, Barnes PR et al. A 31P magnetic resonance spectroscopy study of mitochondrial function in skeletal muscle of patients with Parkinson’s disease. J Neurol Sci 1994; 125:77–81.PubMedCrossRefGoogle Scholar
  117. 117.
    Penn AM, Roberts T, Hodder J et al. Generalized mitochondrial dysfunction in Parkinson’s disease detected by magnetic resonance spectroscopy of muscle. Neurology 1995; 45:2097–2099.PubMedGoogle Scholar
  118. 118.
    Parker WD, Jr., Parks JK, Swerdlow RH. Complex I deficiency in Parkinson’s disease frontal cortex. Brain Res 2008; 1189:215–218.PubMedCrossRefGoogle Scholar
  119. 119.
    Chinta SJ, Andersen JK. Redox imbalance in Parkinson’s disease. Biochim Biophys Acta 2008; 1780:1362–1367.PubMedCrossRefGoogle Scholar
  120. 120.
    Veech GA, Dennis J, Keeney PM et al. Disrupted mitochondrial electron transport function increases expression of anti-apoptotic bcl-2 and bcl-X(L) proteins in SH-SY5Y neuroblastoma and in Parkinson disease cybrid cells through oxidative stress. J Neurosci Res 2000; 61:693–700.PubMedCrossRefGoogle Scholar
  121. 121.
    Trimmer PA, Borland MK, Keeney PM et al. Parkinson’s disease transgenic mitochondrial cybrids generate Lewy inclusion bodies. J Neurochem 2004; 88:800–812.PubMedCrossRefGoogle Scholar
  122. 122.
    Betarbet R, Sherer TB, MacKenzie G et al. Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 2000; 3:1301–1306.PubMedCrossRefGoogle Scholar
  123. 123.
    Gash DM, Rutland K, Hudson NL et al. Trichloroethylene: Parkinsonism and complex 1 mitochondrial neurotoxicity. Ann Neurol 2008; 63:184–192.PubMedCrossRefGoogle Scholar
  124. 124.
    Sherer TB, Richardson JR, Testa CM et al. Mechanism of toxicity of pesticides acting at complex I: relevance to environmental etiologies of Parkinson’s disease. J Neurochem 2007; 100:1469–1479.PubMedGoogle Scholar
  125. 125.
    Jin J, Hulette C, Wang Y et al. Proteomic identification of a stress protein, mortalin/mthsp70/GRP75: relevance to Parkinson disease. Mol Cell Proteomics 2006; 5:1193–1204.PubMedCrossRefGoogle Scholar
  126. 126.
    Banerjee K, Sinha M, Pham Cle L et al. Alpha-synuclein induced membrane depolarization and loss of phosphorylation capacity of isolated rat brain mitochondria: implications in Parkinson’s disease. FEBS Lett 2010; 584:1571–1576.PubMedCrossRefGoogle Scholar
  127. 127.
    Thomas B, Beal MF. Parkinson’s disease. Hum Mol Genet 2007; 16 Spec No. 2:R183–194.PubMedCrossRefGoogle Scholar
  128. 128.
    Pyle A, Foltynie T, Tiangyou W et al. Mitochondrial DNA haplogroup cluster UKJT reduces the risk of PD. Ann Neurol 2005; 57:564–567.PubMedCrossRefGoogle Scholar
  129. 129.
    Swerdlow RH, Parks JK, Davis JN, 2nd et al. Matrilineal inheritance of complex I dysfunction in a multigenerational Parkinson’s disease family. Ann Neurol 1998; 44:873–881.PubMedCrossRefGoogle Scholar
  130. 130.
    Kraytsberg Y, Kudryavtseva E, McKee AC et al. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat Genet 2006; 38:518–520.PubMedCrossRefGoogle Scholar
  131. 131.
    Ekstrand MI, Terzioglu M, Galter D et al. Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proc Natl Acad Sci USA 2007; 104:1325–1330.PubMedCrossRefGoogle Scholar
  132. 132.
    Knott AB, Perkins G, Schwarzenbacher R et al. Mitochondrial fragmentation in neurodegeneration. Nat Rev Neurosci 2008; 9:505–518.PubMedCrossRefGoogle Scholar
  133. 133.
    Liu W, Vives-Bauza C, Acin-Perez R et al. PINK1 defect causes mitochondrial dysfunction, proteasomal deficit and alpha-synuclein aggregation in cell culture models of Parkinson’s disease. PLoS ONE 2009; 4:e4597.CrossRefGoogle Scholar
  134. 134.
    Moisoi N, Klupsch K, Fedele V et al. Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response. Cell Death Differ 2009; 16:449–464.PubMedCrossRefGoogle Scholar
  135. 135.
    Song DD, Shults CW, Sisk A et al. Enhanced substantia nigra mitochondrial pathology in human alpha-synuclein transgenic mice after treatment with MPTP. Exp Neurol 2004; 186:158–172.PubMedCrossRefGoogle Scholar
  136. 136.
    Hsu LJ, Sagara Y, Arroyo A et al alpha-synuclein promotes mitochondrial deficit and oxidative stress. Am J Pathol 2000; 157:401–410.PubMedCrossRefGoogle Scholar
  137. 137.
    Klivenyi P, Siwek D, Gardian G et al. Mice lacking alpha-synuclein are resistant to mitochondrial toxins. Neurobiol Dis 2006; 21:541–548.PubMedCrossRefGoogle Scholar
  138. 138.
    Dauer W, Kholodilov N, Vila M et al. Resistance of alpha-synuclein null mice to the parkinsonian neurotoxin MPTP. Proc Natl Acad Sci USA 2002; 99:14524–14529.PubMedCrossRefGoogle Scholar
  139. 139.
    Vives-Bauza C, Zhou C, Huang Y et al. PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc Natl Acad Sci USA 2010; 107:378–383.PubMedCrossRefGoogle Scholar
  140. 140.
    Kawajiri S, Saiki S, Sato S et al. PINK1 is recruited to mitochondria with parkin and associates with LC3 in mitophagy. FEBS Lett 2010; 584:1073–1079.PubMedCrossRefGoogle Scholar
  141. 141.
    Matsuda N, Sato S, Shiba K et al. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol 2010; 189:211–221.PubMedCrossRefGoogle Scholar
  142. 142.
    Narendra DP, Jin SM, Tanaka A et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol 2010; 8:e1000298.CrossRefGoogle Scholar
  143. 143.
    Geisler S, Holmstrom KM, Skujat D et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol 2010; 12:119–131.PubMedCrossRefGoogle Scholar
  144. 144.
    Geisler S, Holmstrom KM, Treis A et al. The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations. Autophagy 2010; 6:871–878.PubMedCrossRefGoogle Scholar
  145. 145.
    Poole AC, Thomas RE, Andrews LA et al. The PINK1/Parkin pathway regulates mitochondrial morphology. Proc Natl Acad Sci USA 2008; 105:1638–1643.PubMedCrossRefGoogle Scholar
  146. 146.
    Deng H, Dodson MW, Huang H et al. The Parkinson’s disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila. Proc Natl Acad Sci USA 2008; 105:14503–14508.PubMedCrossRefGoogle Scholar
  147. 147.
    Lutz AK, Exner N, Fett ME et al. Loss of parkin or PINK1 function increases Drp1-dependent mitochondrial fragmentation. J Biol Chem 2009; 284:22938–22951.PubMedCrossRefGoogle Scholar
  148. 148.
    Cui M, Tang X, Christian WV et al. Perturbations in mitochondrial dynamics induced by human mutant PINK1 can be rescued by the mitochondrial division inhibitor mdivi-1. J Biol Chem 2010; 285:11740–11752.PubMedCrossRefGoogle Scholar
  149. 149.
    Bates GP. History of genetic disease: the molecular genetics of Huntington disease—a history. Nat Rev Genet 2005; 6:766–773.PubMedCrossRefGoogle Scholar
  150. 150.
    Bossy-Wetzel E, Petrilli A, Knott AB. Mutant huntingtin and mitochondrial dysfunction. Trends Neurosci 2008; 31:609–616.PubMedCrossRefGoogle Scholar
  151. 151.
    Jenkins BG, Andreassen OA, Dedeoglu A et al. Effects of CAG repeat length, HTT protein length and protein context on cerebral metabolism measured using magnetic resonance spectroscopy in transgenic mouse models of Huntington’s disease. J Neurochem 2005; 95:553–562.PubMedCrossRefGoogle Scholar
  152. 152.
    Gu M, Gash MT, Mann VM et al. Mitochondrial defect in Huntington’s disease caudate nucleus. Ann Neurol 1996; 39:385–389.PubMedCrossRefGoogle Scholar
  153. 153.
    Milakovic T, Johnson GV. Mitochondrial respiration and ATP production are significantly impaired in striatal cells expressing mutant huntingtin. J Biol Chem 2005; 280:30773–30782.PubMedCrossRefGoogle Scholar
  154. 154.
    Panov AV, Gutekunst CA, Leavitt BR et al. Early mitochondrial calcium defects in Huntington’s disease are a direct effect of polyglutamines. Nat Neurosci 2002; 5:731–736.PubMedGoogle Scholar
  155. 155.
    Brouillet E, Hantraye P. Effects of chronic MPTP and 3-nitropropionic acid in nonhuman primates. Curr Opin Neurol 1995; 8:469–473.PubMedCrossRefGoogle Scholar
  156. 156.
    Rubinsztein DC. Lessons from animal models of Huntington’s disease. Trends Genet 2002; 18:202–209.PubMedCrossRefGoogle Scholar
  157. 157.
    Cattaneo E, Rigamonti D, Goffredo D et al. Loss of normal huntingtin function: new developments in Huntington’s disease research. Trends Neurosci 2001; 24:182–188.PubMedCrossRefGoogle Scholar
  158. 158.
    Sipione S, Cattaneo E. Modeling Huntington’s disease in cells, flies and mice. Mol Neurobiol 2001; 23:21–51.PubMedCrossRefGoogle Scholar
  159. 159.
    Banoei MM, Houshmand M, Panahi MS et al. Huntington’s disease and mitochondrial DNA deletions: event or regular mechanism for mutant huntingtin protein and CAG repeats expansion?! Cell Mol Neurobiol 2007; 27:867–875.PubMedCrossRefGoogle Scholar
  160. 160.
    Acevedo-Torres K, Berrios L, Rosario N et al. Mitochondrial DNA damage is a hallmark of chemically induced and the R6/2 transgenic model of Huntington’s disease. DNA Repair (Amst) 2009; 8:126–136.CrossRefGoogle Scholar
  161. 161.
    Squitieri F, Cannella M, Sgarbi G et al. Severe ultrastructural mitochondrial changes in lymphoblasts homozygous for Huntington disease mutation. Mech Ageing Dev 2006; 127:217–220.PubMedCrossRefGoogle Scholar
  162. 162.
    Liot G, Bossy B, Lubitz S et al. Complex II inhibition by 3-NP causes mitochondrial fragmentation and neuronal cell death via an NMDA-and ROS-dependent pathway. Cell Death Differ 2009; 16:899–909.PubMedCrossRefGoogle Scholar
  163. 163.
    Wang H, Lim PJ, Karbowski M et al. Effects of overexpression of huntingtin proteins on mitochondrial integrity. Hum Mol Genet 2009; 18:737–752.PubMedCrossRefGoogle Scholar
  164. 164.
    Chang DT, Rintoul GL, Pandipati S et al. Mutant huntingtin aggregates impair mitochondrial movement and trafficking in cortical neurons. Neurobiol Dis 2006; 22:388–400.PubMedCrossRefGoogle Scholar
  165. 165.
    Trushina E, Dyer RB, Badger JD, 2nd et al. Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro. Mol Cell Biol 2004; 24:8195–8209.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2012

Authors and Affiliations

  • Sónia C. Correia
    • 1
    • 2
  • Renato X. Santos
    • 1
    • 2
  • George Perry
    • 3
    • 4
  • Xiongwei Zhu
    • 3
    Email author
  • Paula I. Moreira
    • 1
    • 5
  • Mark A. Smith
    • 3
  1. 1.Center for Neuroscience and Cell Biology of CoimbraUniversity of CoimbraCoimbraPortugal
  2. 2.Faculty of Sciences and Technology, Department of Life SciencesUniversity of CoimbraCoimbraPortugal
  3. 3.Department of PathologyCase Western Reserve UniversityClevelandUSA
  4. 4.UTSA Neurosciences Institute and Department of BiologyUniversity of Texas at San AntonioSan AntonioUSA
  5. 5.Faculty of Medicine, Institute of PhysiologyUniversity of CoimbraCoimbraPortugal

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