Acta Neuropathologica

, Volume 123, Issue 2, pp 173–188 | Cite as

Parkin, PINK1 and mitochondrial integrity: emerging concepts of mitochondrial dysfunction in Parkinson’s disease

  • Anna Pilsl
  • Konstanze F. WinklhoferEmail author


Mitochondria are dynamic organelles which are essential for many cellular processes, such as ATP production by oxidative phosphorylation, lipid metabolism, assembly of iron sulfur clusters, regulation of calcium homeostasis, and cell death pathways. The dynamic changes in mitochondrial morphology, connectivity, and subcellular distribution are critically dependent on a highly regulated fusion and fission machinery. Mitochondrial function, dynamics, and quality control are vital for the maintenance of neuronal integrity. Indeed, there is mounting evidence that mitochondrial dysfunction plays a central role in several neurodegenerative diseases. In particular, the identification of genes linked to rare familial variants of Parkinson’s disease has fueled research on mitochondrial aspects of the disease etiopathogenesis. Studies on the function of parkin and PINK1, which are associated with autosomal recessive parkinsonism, provided compelling evidence that these proteins can functionally interact to maintain mitochondrial integrity and to promote clearance of damaged and dysfunctional mitochondria. In this review we will summarize current knowledge about the impact of parkin and PINK1 on mitochondria.


Mitochondria Mitophagy Neurodegeneration Parkin Parkinson’s disease PINK1 



We thank Daniela Vogt Weisenhorn and Wolfgang Wurst for providing mouse embryonic fibroblasts from PINK1 KO mice. K.F.W. is supported by the Deutsche Forschungsgemeinschaft (SFB 596 “Molecular Mechanisms of Neurodegeneration”), the German Ministry for Education and Research (NGFN plus “Functional Genomics of Parkinson’s Disease”), the Helmholtz Alliance “Mental Health in an Ageing Society”, and the German Center for Neurodegenerative Diseases (DZNE).


  1. 1.
    Abou-Sleiman PM, Muqit MM, Wood NW (2006) Expanding insights of mitochondrial dysfunction in Parkinson’s disease. Nat Rev Neurosci 7:207–219PubMedGoogle Scholar
  2. 2.
    Alexander C, Votruba M, Pesch UE et al (2000) OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet 26:211–215PubMedGoogle Scholar
  3. 3.
    Behrends C, Harper JW (2011) Constructing and decoding unconventional ubiquitin chains. Nat Struct Mol Biol 18:520–528PubMedGoogle Scholar
  4. 4.
    Beilina A, Van Der Brug M, Ahmad R et al (2005) Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability. Proc Natl Acad Sci USA 102:5703–5708PubMedGoogle Scholar
  5. 5.
    Benard G, Karbowski M (2009) Mitochondrial fusion and division: regulation and role in cell viability. Semin Cell Dev Biol 20:365–374PubMedGoogle Scholar
  6. 6.
    Berger AK, Cortese GP, Amodeo KD et al (2009) Parkin selectively alters the intrinsic threshold for mitochondrial cytochrome c release. Hum Mol Genet 18:4317–4328PubMedGoogle Scholar
  7. 7.
    Bogaerts V, Theuns J, van Broeckhoven C (2008) Genetic findings in Parkinson’s disease and translation into treatment: a leading role for mitochondria? Genes Brain Behav 7:129–151PubMedGoogle Scholar
  8. 8.
    Bouman L, Schlierf A, Lutz AK et al (2011) Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress. Cell Death Differ 18:769–782PubMedGoogle Scholar
  9. 9.
    Braak H, Del Tredici K, Rub U et al (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211PubMedGoogle Scholar
  10. 10.
    Bueler H (2010) Mitochondrial dynamics, cell death and the pathogenesis of Parkinson’s disease. Apoptosis 15:1336–1353PubMedGoogle Scholar
  11. 11.
    Burbulla LF, Krebiehl G, Kruger R (2010) Balance is the challenge—the impact of mitochondrial dynamics in Parkinson’s disease. Eur J Clin Invest 40:1048–1060PubMedGoogle Scholar
  12. 12.
    Burke RE, Dauer WT, Vonsattel JP (2008) A critical evaluation of the Braak staging scheme for Parkinson’s disease. Ann Neurol 64:485–491PubMedGoogle Scholar
  13. 13.
    Caughey B, Lansbury PT (2003) Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci 26:267–298PubMedGoogle Scholar
  14. 14.
    Cerveny KL, Jensen RE (2003) The WD-repeats of Net2p interact with Dnm1p and Fis1p to regulate division of mitochondria. Mol Biol Cell 14:4126–4139PubMedGoogle Scholar
  15. 15.
    Cha GH, Kim S, Park J et al (2005) Parkin negatively regulates JNK pathway in the dopaminergic neurons of Drosophila. Proc Natl Acad Sci USA 102:10345–10350PubMedGoogle Scholar
  16. 16.
    Chan NC, Salazar AM, Pham AH et al (2011) Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy. Hum Mol Genet 20:1726–1737PubMedGoogle Scholar
  17. 17.
    Chan P, DeLanney LE, Irwin I, Langston JW, Di Monte D (1991) Rapid ATP loss caused by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine in mouse brain. J Neurochem 57:348–351PubMedGoogle Scholar
  18. 18.
    Chen H, Chan DC (2009) Mitochondrial dynamics—fusion, fission, movement, and mitophagy—in neurodegenerative diseases. Hum Mol Genet 18:R169–R176PubMedGoogle Scholar
  19. 19.
    Chen H, Chomyn A, Chan DC (2005) Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J Biol Chem 280:26185–26192PubMedGoogle Scholar
  20. 20.
    Chen H, McCaffery JM, Chan DC (2007) Mitochondrial fusion protects against neurodegeneration in the cerebellum. Cell 130:548–562PubMedGoogle Scholar
  21. 21.
    Chen H, Vermulst M, Wang YE et al (2010) Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations. Cell 141:280–289PubMedGoogle Scholar
  22. 22.
    Chu CT (2010) A pivotal role for PINK1 and autophagy in mitochondrial quality control: implications for Parkinson disease. Hum Mol Genet 19:R28–R37PubMedGoogle Scholar
  23. 23.
    Chung KK, Thomas B, Li X et al (2004) S-nitrosylation of parkin regulates ubiquitination and compromises parkin’s protective function. Science 304:1328–1331PubMedGoogle Scholar
  24. 24.
    Clark IE, Dodson MW, Jiang C et al (2006) Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441:1162–1166PubMedGoogle Scholar
  25. 25.
    Cui M, Tang X, Christian WV, Yoon Y, Tieu K (2010) Perturbations in mitochondrial dynamics induced by human mutant PINK1 can be rescued by the mitochondrial division inhibitor mdivi-1. J Biol Chem 285:11740–11752PubMedGoogle Scholar
  26. 26.
    Dagda RK, Cherra SJ 3rd, Kulich SM et al (2009) Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J Biol Chem 284:13843–13855PubMedGoogle Scholar
  27. 27.
    Darios F, Corti O, Lucking CB et al (2003) Parkin prevents mitochondrial swelling and cytochrome c release in mitochondria-dependent cell death. Hum Mol Genet 12:517–526PubMedGoogle Scholar
  28. 28.
    Davis GC, Williams AC, Markey SP et al (1979) Chronic Parkinsonism secondary to intravenous injection of meperidine analogues. Psychiatry Res 1:249–254PubMedGoogle Scholar
  29. 29.
    Dawson TM, Dawson VL (2010) The role of parkin in familial and sporadic Parkinson’s disease. Mov Disord 25(Suppl 1):S32–S39PubMedGoogle Scholar
  30. 30.
    Dawson TM, Ko HS, Dawson VL (2010) Genetic animal models of Parkinson’s disease. Neuron 66:646–661PubMedGoogle Scholar
  31. 31.
    Deas E, Plun-Favreau H, Gandhi S et al (2011) PINK1 cleavage at position A103 by the mitochondrial protease PARL. Hum Mol Genet 20:867–879PubMedGoogle Scholar
  32. 32.
    Deas E, Plun-Favreau H, Wood NW (2009) PINK1 function in health and disease. EMBO Mol Med 1:152–165PubMedGoogle Scholar
  33. 33.
    Delettre C, Lenaers G, Griffoin JM et al (2000) Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat Genet 26:207–210PubMedGoogle Scholar
  34. 34.
    Deng H, Dodson MW, Huang H, Guo M (2008) The Parkinson’s disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila. Proc Natl Acad Sci USA 105:14503–14508PubMedGoogle Scholar
  35. 35.
    Detmer SA, Chan DC (2007) Functions and dysfunctions of mitochondrial dynamics. Nat Rev Mol Cell Biol 8:870–879PubMedGoogle Scholar
  36. 36.
    Ding WX, Ni HM, Li M et al (2010) Nix is critical to two distinct phases of mitophagy, reactive oxygen species-mediated autophagy induction and Parkin-ubiquitin-p62-mediated mitochondrial priming. J Biol Chem 285:27879–27890PubMedGoogle Scholar
  37. 37.
    Ekstrand MI, Terzioglu M, Galter D et al (2007) Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proc Natl Acad Sci USA 104:1325–1330PubMedGoogle Scholar
  38. 38.
    Eskelinen EL, Saftig P (2009) Autophagy: a lysosomal degradation pathway with a central role in health and disease. Biochim Biophys Acta 1793:664–673PubMedGoogle Scholar
  39. 39.
    Exner N, Treske B, Paquet D et al (2007) Loss-of-function of human PINK1 results in mitochondrial pathology and can be rescued by parkin. J Neurosci 27:12413–12418PubMedGoogle Scholar
  40. 40.
    Fallon L, Belanger CM, Corera AT et al (2006) A regulated interaction with the UIM protein Eps15 implicates parkin in EGF receptor trafficking and PI(3)K-Akt signalling. Nat Cell Biol 8:834–842PubMedGoogle Scholar
  41. 41.
    Fett ME, Pilsl A, Paquet D et al (2010) Parkin is protective against proteotoxic stress in a transgenic zebrafish model. PLoS One 5:e11783PubMedGoogle Scholar
  42. 42.
    Forno LS (1996) Neuropathology of Parkinson’s disease. J Neuropathol Exp Neurol 55:259–272PubMedGoogle Scholar
  43. 43.
    Gandhi S, Wood-Kaczmar A, Yao Z et al (2009) PINK1-associated Parkinson’s disease is caused by neuronal vulnerability to calcium-induced cell death. Mol Cell 33:627–638PubMedGoogle Scholar
  44. 44.
    Garcia-Arencibia M, Hochfeld WE, Toh PP, Rubinsztein DC (2010) Autophagy, a guardian against neurodegeneration. Semin Cell Dev Biol 21:691–698PubMedGoogle Scholar
  45. 45.
    Gautier CA, Kitada T, Shen J (2008) Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress. Proc Natl Acad Sci USA 105:11364–11369PubMedGoogle Scholar
  46. 46.
    Gegg ME, Cooper JM, Chau KY et al (2010) Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. Hum Mol Genet 19:4861–4870PubMedGoogle Scholar
  47. 47.
    Geisler S, Holmstrom KM, Skujat D et al (2010) PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol 12:119–131PubMedGoogle Scholar
  48. 48.
    Geisler S, Holmstrom KM, Treis A et al (2010) The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations. Autophagy 6:871–878PubMedGoogle Scholar
  49. 49.
    Gispert S, Ricciardi F, Kurz A et al (2009) Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration. PLoS One 4:e5777PubMedGoogle Scholar
  50. 50.
    Glauser L, Sonnay S, Stafa K, Moore DJ (2011) Parkin promotes the ubiquitination and degradation of the mitochondrial fusion factor mitofusin 1. J Neurochem 118:636–645PubMedGoogle Scholar
  51. 51.
    Gomes LC, Di Benedetto G, Scorrano L (2011) During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 13:589–598PubMedGoogle Scholar
  52. 52.
    Greene JC, Whitworth AJ, Kuo I et al (2003) Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc Natl Acad Sci USA 100:4078–4083PubMedGoogle Scholar
  53. 53.
    Grunewald A, Gegg ME, Taanman JW et al (2009) Differential effects of PINK1 nonsense and missense mutations on mitochondrial function and morphology. Exp Neurol 219:266–273PubMedGoogle Scholar
  54. 54.
    Grunewald A, Voges L, Rakovic A et al (2010) Mutant Parkin impairs mitochondrial function and morphology in human fibroblasts. PLoS One 5:e12962PubMedGoogle Scholar
  55. 55.
    Haque ME, Thomas KJ, D’Souza C et al (2008) Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP. Proc Natl Acad Sci USA 105:1716–1721PubMedGoogle Scholar
  56. 56.
    Hardy J (2010) Genetic analysis of pathways to Parkinson disease. Neuron 68:201–206PubMedGoogle Scholar
  57. 57.
    Hardy J, Lewis P, Revesz T, Lees A, Paisan-Ruiz C (2009) The genetics of Parkinson’s syndromes: a critical review. Curr Opin Genet Dev 19:254–265PubMedGoogle Scholar
  58. 58.
    Hasegawa T, Treis A, Patenge N et al (2008) Parkin protects against tyrosinase-mediated dopamine neurotoxicity by suppressing stress-activated protein kinase pathways. J Neurochem 105:1700–1715PubMedGoogle Scholar
  59. 59.
    Henchcliffe C, Beal MF (2008) Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis. Nat Clin Pract Neurol 4:600–609PubMedGoogle Scholar
  60. 60.
    Henn IH, Bouman L, Schlehe JS et al (2007) Parkin mediates neuroprotection through activation of IkappaB kinase/nuclear factor-kappaB signaling. J Neurosci 27:1868–1878PubMedGoogle Scholar
  61. 61.
    Higashi Y, Asanuma M, Miyazaki I et al (2004) Parkin attenuates manganese-induced dopaminergic cell death. J Neurochem 89:1490–1497PubMedGoogle Scholar
  62. 62.
    Hoepken HH, Gispert S, Morales B et al (2007) Mitochondrial dysfunction, peroxidation damage and changes in glutathione metabolism in PARK6. Neurobiol Dis 25:401–411PubMedGoogle Scholar
  63. 63.
    Hoppins S, Nunnari J (2009) The molecular mechanism of mitochondrial fusion. Biochim Biophys Acta 1793:20–26PubMedGoogle Scholar
  64. 64.
    Hristova VA, Beasley SA, Rylett RJ, Shaw GS (2009) Identification of a novel Zn2+ -binding domain in the autosomal recessive juvenile Parkinson-related E3 ligase parkin. J Biol Chem 284:14978–14986PubMedGoogle Scholar
  65. 65.
    Ikeda F, Dikic I (2008) Atypical ubiquitin chains: new molecular signals ‘Protein Modifications: Beyond the Usual Suspects’ review series. EMBO Rep 9:536–542PubMedGoogle Scholar
  66. 66.
    Imai Y, Soda M, Takahashi R (2000) Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity. J Biol Chem 275:35661–35664PubMedGoogle Scholar
  67. 67.
    Ishihara N, Nomura M, Jofuku A et al (2009) Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice. Nat Cell Biol 11:958–966PubMedGoogle Scholar
  68. 68.
    Javitch JA, D’Amato RJ, Strittmatter SM, Snyder SH (1985) Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-1, 2, 3, 6 -tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity. Proc Natl Acad Sci USA 82:2173–2177PubMedGoogle Scholar
  69. 69.
    Jiang H, Ren Y, Zhao J, Feng J (2004) Parkin protects human dopaminergic neuroblastoma cells against dopamine-induced apoptosis. Hum Mol Genet 13:1745–1754PubMedGoogle Scholar
  70. 70.
    Jin SM, Lazarou M, Wang C et al (2010) Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J Cell Biol 191:933–942PubMedGoogle Scholar
  71. 71.
    Karbowski M, Youle RJ (2011) Regulating mitochondrial outer membrane proteins by ubiquitination and proteasomal degradation. Curr Opin Cell Biol 23:476–482PubMedGoogle Scholar
  72. 72.
    Kawaguchi Y, Kovacs JJ, McLaurin A et al (2003) The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 115:727–738PubMedGoogle Scholar
  73. 73.
    Kawajiri S, Saiki S, Sato S, Hattori N (2011) Genetic mutations and functions of PINK1. Trends Pharmacol Sci 32:573–580PubMedGoogle Scholar
  74. 74.
    Kawajiri S, Saiki S, Sato S et al (2010) PINK1 is recruited to mitochondria with parkin and associates with LC3 in mitophagy. FEBS Lett 584:1073–1079PubMedGoogle Scholar
  75. 75.
    Kim Y, Park J, Kim S et al (2008) PINK1 controls mitochondrial localization of Parkin through direct phosphorylation. Biochem Biophys Res Commun 377:975–980PubMedGoogle Scholar
  76. 76.
    Kirkin V, McEwan DG, Novak I, Dikic I (2009) A role for ubiquitin in selective autophagy. Mol Cell 34:259–269PubMedGoogle Scholar
  77. 77.
    Kitada T, Asakawa S, Hattori N et al (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605–608PubMedGoogle Scholar
  78. 78.
    Kitada T, Pisani A, Porter DR et al (2007) Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proc Natl Acad Sci USA 104:11441–11446PubMedGoogle Scholar
  79. 79.
    Kitada T, Tong Y, Gautier CA, Shen J (2009) Absence of nigral degeneration in aged parkin/DJ-1/PINK1 triple knockout mice. J Neurochem 111:696–702PubMedGoogle Scholar
  80. 80.
    Knott AB, Bossy-Wetzel E (2008) Impairing the mitochondrial fission and fusion balance: a new mechanism of neurodegeneration. Ann N Y Acad Sci 1147:283–292PubMedGoogle Scholar
  81. 81.
    Knott AB, Perkins G, Schwarzenbacher R, Bossy-Wetzel E (2008) Mitochondrial fragmentation in neurodegeneration. Nat Rev Neurosci 9:505–518PubMedGoogle Scholar
  82. 82.
    Komander D (2009) The emerging complexity of protein ubiquitination. Biochem Soc Trans 37:937–953PubMedGoogle Scholar
  83. 83.
    Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW (2008) Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat Med 14:504–506PubMedGoogle Scholar
  84. 84.
    Kraft C, Peter M, Hofmann K (2010) Selective autophagy: ubiquitin-mediated recognition and beyond. Nat Cell Biol 12:836–841PubMedGoogle Scholar
  85. 85.
    Lamark T, Kirkin V, Dikic I, Johansen T (2009) NBR1 and p62 as cargo receptors for selective autophagy of ubiquitinated targets. Cell Cycle 8:1986–1990PubMedGoogle Scholar
  86. 86.
    Landes T, Leroy I, Bertholet A et al (2010) OPA1 (dys)functions. Semin Cell Dev Biol 21:593–598PubMedGoogle Scholar
  87. 87.
    Lang AE, Obeso JA (2004) Challenges in Parkinson’s disease: restoration of the nigrostriatal dopamine system is not enough. Lancet Neurol 3:309–316PubMedGoogle Scholar
  88. 88.
    Langston JW, Ballard PA Jr (1983) Parkinson’s disease in a chemist working with 1-methyl-4-phenyl-1, 2, 5, 6-tetrahydropyridine. N Engl J Med 309:310PubMedGoogle Scholar
  89. 89.
    Langston JW, Forno LS, Tetrud J et al (1999) Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine exposure. Ann Neurol 46:598–605PubMedGoogle Scholar
  90. 90.
    LaVoie MJ, Cortese GP, Ostaszewski BL, Schlossmacher MG (2007) The effects of oxidative stress on parkin and other E3 ligases. J Neurochem 103:2354–2368PubMedGoogle Scholar
  91. 91.
    LaVoie MJ, Ostaszewski BL, Weihofen A, Schlossmacher MG, Selkoe DJ (2005) Dopamine covalently modifies and functionally inactivates parkin. Nat Med 11:1214–1221PubMedGoogle Scholar
  92. 92.
    Lee JY, Koga H, Kawaguchi Y et al (2010) HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy. EMBO J 29:969–980PubMedGoogle Scholar
  93. 93.
    Lee JY, Nagano Y, Taylor JP, Lim KL, Yao TP (2010) Disease-causing mutations in parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy. J Cell Biol 189:671–679PubMedGoogle Scholar
  94. 94.
    Lee YJ, Jeong SY, Karbowski M, Smith CL, Youle RJ (2004) Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol Biol Cell 15:5001–5011PubMedGoogle Scholar
  95. 95.
    Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132:27–42PubMedGoogle Scholar
  96. 96.
    Li JY, Englund E, Holton JL et al (2008) Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat Med 14:501–503PubMedGoogle Scholar
  97. 97.
    Lin W, Kang UJ (2008) Characterization of PINK1 processing, stability, and subcellular localization. J Neurochem 106:464–474PubMedGoogle Scholar
  98. 98.
    Lin W, Kang UJ (2010) Structural determinants of PINK1 topology and dual subcellular distribution. BMC Cell Biol 11:90PubMedGoogle Scholar
  99. 99.
    Livnat-Levanon N, Glickman MH (2011) Ubiquitin-proteasome system and mitochondria—reciprocity. Biochim Biophys Acta 1809:80–87PubMedGoogle Scholar
  100. 100.
    Lo Bianco C, Schneider BL, Bauer M et al (2004) Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an alpha-synuclein rat model of Parkinson’s disease. Proc Natl Acad Sci USA 101:17510–17515PubMedGoogle Scholar
  101. 101.
    Lutz AK, Exner N, Fett ME et al (2009) Loss of parkin or PINK1 function increases Drp1-dependent mitochondrial fragmentation. J Biol Chem 284:22938–22951PubMedGoogle Scholar
  102. 102.
    Magen I, Chesselet MF (2010) Genetic mouse models of Parkinson’s disease The state of the art. Prog Brain Res 184:53–87PubMedGoogle Scholar
  103. 103.
    Mandemakers W, Morais VA, De Strooper B (2007) A cell biological perspective on mitochondrial dysfunction in Parkinson disease and other neurodegenerative diseases. J Cell Sci 120:1707–1716PubMedGoogle Scholar
  104. 104.
    Markey SP, Johannessen JN, Chiueh CC, Burns RS, Herkenham MA (1984) Intraneuronal generation of a pyridinium metabolite may cause drug-induced parkinsonism. Nature 311:464–467PubMedGoogle Scholar
  105. 105.
    Martin I, Dawson VL, Dawson TM (2011) Recent Advances in the Genetics of Parkinson’s Disease. Annual Review of Genomics and Human Genetics 12: nullGoogle Scholar
  106. 106.
    Martinelli P, Rugarli EI (2010) Emerging roles of mitochondrial proteases in neurodegeneration. Biochim Biophys Acta 1797:1–10PubMedGoogle Scholar
  107. 107.
    Matsuda N, Sato S, Shiba K et al (2010) PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol 189:211–221PubMedGoogle Scholar
  108. 108.
    Mattson MP, Gleichmann M, Cheng A (2008) Mitochondria in neuroplasticity and neurological disorders. Neuron 60:748–766PubMedGoogle Scholar
  109. 109.
    Meissner C, Lorenz H, Weihofen A, Selkoe DJ, Lemberg MK (2011) The mitochondrial intramembrane protease PARL cleaves human Pink1 to regulate Pink1 trafficking. J Neurochem 117:856–867PubMedGoogle Scholar
  110. 110.
    Mendez I, Vinuela A, Astradsson A et al (2008) Dopamine neurons implanted into people with Parkinson’s disease survive without pathology for 14 years. Nat Med 14:507–509PubMedGoogle Scholar
  111. 111.
    Miller KE, Sheetz MP (2004) Axonal mitochondrial transport and potential are correlated. J Cell Sci 117:2791–2804PubMedGoogle Scholar
  112. 112.
    Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451:1069–1075PubMedGoogle Scholar
  113. 113.
    Moore DJ (2006) Parkin: a multifaceted ubiquitin ligase. Biochem Soc Trans 34:749–753PubMedGoogle Scholar
  114. 114.
    Morais VA, Verstreken P, Roethig A et al (2009) Parkinson’s disease mutations in PINK1 result in decreased Complex I activity and deficient synaptic function. EMBO Mol Med 1:99–111PubMedGoogle Scholar
  115. 115.
    Mortiboys H, Thomas KJ, Koopman WJ et al (2008) Mitochondrial function and morphology are impaired in parkin-mutant fibroblasts. Ann Neurol 64:555–565PubMedGoogle Scholar
  116. 116.
    Muqit MM, Davidson SM, Payne Smith MD et al (2004) Parkin is recruited into aggresomes in a stress-specific manner: over-expression of parkin reduces aggresome formation but can be dissociated from parkin’s effect on neuronal survival. Hum Mol Genet 13:117–135PubMedGoogle Scholar
  117. 117.
    Nakada K, Inoue K, Ono T et al (2001) Inter-mitochondrial complementation: mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA. Nat Med 7:934–940PubMedGoogle Scholar
  118. 118.
    Narendra D, Kane LA, Hauser DN, Fearnley IM, Youle RJ (2010) p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both. Autophagy 6:1090–1106PubMedGoogle Scholar
  119. 119.
    Narendra D, Tanaka A, Suen DF, Youle RJ (2008) Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 183:795–803PubMedGoogle Scholar
  120. 120.
    Narendra DP, Jin SM, Tanaka A et al (2010) PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol 8:e1000298PubMedGoogle Scholar
  121. 121.
    Nicklas WJ, Vyas I, Heikkila RE (1985) Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1, 2, 5, 6-tetrahydropyridine. Life Sci 36:2503–2508PubMedGoogle Scholar
  122. 122.
    Nuytemans K, Theuns J, Cruts M, Van Broeckhoven C (2010) Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update. Hum Mutat 31:763–780PubMedGoogle Scholar
  123. 123.
    Obeso JA, Rodriguez-Oroz MC, Goetz CG et al (2010) Missing pieces in the Parkinson’s disease puzzle. Nat Med 16:653–661PubMedGoogle Scholar
  124. 124.
    Okatsu K, Saisho K, Shimanuki M et al (2010) p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria. Genes Cells 15:887–900PubMedGoogle Scholar
  125. 125.
    Palacino JJ, Sagi D, Goldberg MS et al (2004) Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem 279:18614–18622PubMedGoogle Scholar
  126. 126.
    Park J, Lee G, Chung J (2009) The PINK1-Parkin pathway is involved in the regulation of mitochondrial remodeling process. Biochem Biophys Res Commun 378:518–523PubMedGoogle Scholar
  127. 127.
    Park J, Lee SB, Lee S et al (2006) Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441:1157–1161PubMedGoogle Scholar
  128. 128.
    Petrucelli L, O’Farrell C, Lockhart PJ et al (2002) Parkin protects against the toxicity associated with mutant alpha-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons. Neuron 36:1007–1019PubMedGoogle Scholar
  129. 129.
    Plun-Favreau H, Klupsch K, Moisoi N et al (2007) The mitochondrial protease HtrA2 is regulated by Parkinson’s disease-associated kinase PINK1. Nat Cell Biol 9:1243–1252PubMedGoogle Scholar
  130. 130.
    Poole AC, Thomas RE, Andrews LA et al (2008) The PINK1/Parkin pathway regulates mitochondrial morphology. Proc Natl Acad Sci USA 105:1638–1643PubMedGoogle Scholar
  131. 131.
    Poole AC, Thomas RE, Yu S, Vincow ES, Pallanck L (2010) The mitochondrial fusion-promoting factor mitofusin is a substrate of the PINK1/parkin pathway. PLoS One 5:e10054PubMedGoogle Scholar
  132. 132.
    Pridgeon JW, Olzmann JA, Chin LS, Li L (2007) PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1. PLoS Biol 5:e172PubMedGoogle Scholar
  133. 133.
    Przedborski S, Jackson-Lewis V, Yokoyama R et al (1996) Role of neuronal nitric oxide in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity. Proc Natl Acad Sci USA 93:4565–4571PubMedGoogle Scholar
  134. 134.
    Rambold AS, Kostelecky B, Elia N, Lippincott-Schwartz J (2011) Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation. Proc Natl Acad Sci USA 108:10190–10195PubMedGoogle Scholar
  135. 135.
    Rodgers JT, Lerin C, Gerhart-Hines Z, Puigserver P (2008) Metabolic adaptations through the PGC-1 alpha and SIRT1 pathways. FEBS Lett 582:46–53PubMedGoogle Scholar
  136. 136.
    Rosen KM, Veereshwarayya V, Moussa CE et al (2006) Parkin protects against mitochondrial toxins and beta-amyloid accumulation in skeletal muscle cells. J Biol Chem 281:12809–12816PubMedGoogle Scholar
  137. 137.
    Sandebring A, Thomas KJ, Beilina A et al (2009) Mitochondrial alterations in PINK1 deficient cells are influenced by calcineurin-dependent dephosphorylation of dynamin-related protein 1. PLoS One 4:e5701PubMedGoogle Scholar
  138. 138.
    Satake W, Nakabayashi Y, Mizuta I et al (2009) Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson’s disease. Nat Genet 41:1303–1307PubMedGoogle Scholar
  139. 139.
    Scarpulla RC (2011) Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta 1813:1269–1278PubMedGoogle Scholar
  140. 140.
    Schapira AH (2008) Mitochondria in the aetiology and pathogenesis of Parkinson’s disease. Lancet Neurol 7:97–109PubMedGoogle Scholar
  141. 141.
    Schapira AH, Cooper JM, Dexter D et al (1989) Mitochondrial complex I deficiency in Parkinson’s disease. Lancet 1:1269PubMedGoogle Scholar
  142. 142.
    Schlehe JS, Lutz AK, Pilsl A et al (2008) Aberrant folding of pathogenic Parkin mutants: aggregation versus degradation. J Biol Chem 283:13771–13779PubMedGoogle Scholar
  143. 143.
    Schon EA, Przedborski S (2011) Mitochondria: the next (neurode)generation. Neuron 70:1033–1053PubMedGoogle Scholar
  144. 144.
    Seibler P, Graziotto J, Jeong H et al (2011) Mitochondrial Parkin recruitment is impaired in neurons derived from mutant PINK1 induced pluripotent stem cells. J Neurosci 31:5970–5976PubMedGoogle Scholar
  145. 145.
    Sha D, Chin LS, Li L (2010) Phosphorylation of parkin by Parkinson disease-linked kinase PINK1 activates parkin E3 ligase function and NF-kappaB signaling. Hum Mol Genet 19:352–363PubMedGoogle Scholar
  146. 146.
    Shi G, Lee JR, Grimes DA et al (2011) Functional alteration of PARL contributes to mitochondrial dysregulation in Parkinson’s disease. Hum Mol Genet 20:1966–1974PubMedGoogle Scholar
  147. 147.
    Shiba K, Arai T, Sato S et al (2009) Parkin stabilizes PINK1 through direct interaction. Biochem Biophys Res Commun 383:331–335PubMedGoogle Scholar
  148. 148.
    Shin JH, Ko HS, Kang H et al (2011) PARIS (ZNF746) repression of PGC-1alpha contributes to neurodegeneration in Parkinson’s disease. Cell 144:689–702PubMedGoogle Scholar
  149. 149.
    Shulman JM, De Jager PL, Feany MB (2011) Parkinson’s disease: genetics and pathogenesis. Annu Rev Pathol 6:193–222PubMedGoogle Scholar
  150. 150.
    Silvestri L, Caputo V, Bellacchio E et al (2005) Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism. Hum Mol Genet 14:3477–3492PubMedGoogle Scholar
  151. 151.
    Simon-Sanchez J, Schulte C, Bras JM et al (2009) Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet 41:1308–1312PubMedGoogle Scholar
  152. 152.
    Soubannier V, McBride HM (2009) Positioning mitochondrial plasticity within cellular signaling cascades. Biochim Biophys Acta 1793:154–170PubMedGoogle Scholar
  153. 153.
    Spillantini MG, Schmidt ML, Lee VM et al (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840PubMedGoogle Scholar
  154. 154.
    Staropoli JF, McDermott C, Martinat C et al (2003) Parkin is a component of an SCF-like ubiquitin ligase complex and protects postmitotic neurons from kainate excitotoxicity. Neuron 37:735–749PubMedGoogle Scholar
  155. 155.
    Sterky FH, Lee S, Wibom R, Olson L, Larsson NG (2011) Impaired mitochondrial transport and Parkin-independent degeneration of respiratory chain-deficient dopamine neurons in vivo. Proc Natl Acad Sci USA 108:12937–12942PubMedGoogle Scholar
  156. 156.
    Tain LS, Chowdhury RB, Tao RN et al (2009) Drosophila HtrA2 is dispensable for apoptosis but acts downstream of PINK1 independently from Parkin. Cell Death Differ 16:1118–1125PubMedGoogle Scholar
  157. 157.
    Takatori S, Ito G, Iwatsubo T (2008) Cytoplasmic localization and proteasomal degradation of N-terminally cleaved form of PINK1. Neurosci Lett 430:13–17PubMedGoogle Scholar
  158. 158.
    Tan EK, Puong KY, Chan DK et al (2005) Impaired transcriptional upregulation of Parkin promoter variant under oxidative stress and proteasomal inhibition: clinical association. Hum Genet 118:484–488PubMedGoogle Scholar
  159. 159.
    Tanaka A, Cleland MM, Xu S et al (2010) Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J Cell Biol 191:1367–1380PubMedGoogle Scholar
  160. 160.
    Tatsuta T, Langer T (2008) Quality control of mitochondria: protection against neurodegeneration and ageing. EMBO J 27:306–314PubMedGoogle Scholar
  161. 161.
    Terzioglu M, Galter D (2008) Parkinson’s disease: genetic versus toxin-induced rodent models. Febs J 275:1384–1391PubMedGoogle Scholar
  162. 162.
    Thomas KJ, Cookson MR (2009) The role of PTEN-induced kinase 1 in mitochondrial dysfunction and dynamics. Int J Biochem Cell Biol 41:2025–2035PubMedGoogle Scholar
  163. 163.
    Tondera D, Grandemange S, Jourdain A et al (2009) SLP-2 is required for stress-induced mitochondrial hyperfusion. EMBO J 28:1589–1600PubMedGoogle Scholar
  164. 164.
    Twig G, Elorza A, Molina AJ et al (2008) Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 27:433–446PubMedGoogle Scholar
  165. 165.
    Ulusoy A, Kirik D (2008) Can overexpression of parkin provide a novel strategy for neuroprotection in Parkinson’s disease? Exp Neurol 212:258–260PubMedGoogle Scholar
  166. 166.
    Um JW, Stichel-Gunkel C, Lubbert H, Lee G, Chung KC (2009) Molecular interaction between parkin and PINK1 in mammalian neuronal cells. Mol Cell Neurosci 40:421–432PubMedGoogle Scholar
  167. 167.
    Valente EM, Abou-Sleiman PM, Caputo V et al (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304:1158–1160PubMedGoogle Scholar
  168. 168.
    Van Humbeeck C, Cornelissen T, Hofkens H et al (2011) Parkin interacts with ambra1 to induce mitophagy. J Neurosci 31:10249–10261PubMedGoogle Scholar
  169. 169.
    Van Laar VS, Arnold B, Cassady SJ et al (2011) Bioenergetics of neurons inhibit the translocation response of Parkin following rapid mitochondrial depolarization. Hum Mol Genet 20:927–940PubMedGoogle Scholar
  170. 170.
    Van Laar VS, Berman SB (2009) Mitochondrial dynamics in Parkinson’s disease. Exp Neurol 218:247–256PubMedGoogle Scholar
  171. 171.
    Vila M, Ramonet D, Perier C (2008) Mitochondrial alterations in Parkinson’s disease: new clues. J Neurochem 107:317–328PubMedGoogle Scholar
  172. 172.
    Vives-Bauza C, Zhou C, Huang Y et al (2010) PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc Natl Acad Sci USA 107:378–383PubMedGoogle Scholar
  173. 173.
    Volpicelli-Daley LA, Luk KC, Patel TP et al (2011) Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72:57–71PubMedGoogle Scholar
  174. 174.
    Wang C, Ko HS, Thomas B et al (2005) Stress-induced alterations in parkin solubility promote parkin aggregation and compromise parkin’s protective function. Hum Mol Genet 14:3885–3897PubMedGoogle Scholar
  175. 175.
    Wang H, Song P, Du L et al (2011) Parkin ubiquitinates Drp1 for proteasome-dependent degradation: implication of dysregulated mitochondrial dynamics in Parkinson disease. J Biol Chem 286:11649–11658PubMedGoogle Scholar
  176. 176.
    Weihofen A, Ostaszewski B, Minami Y, Selkoe DJ (2008) Pink1 Parkinson mutations, the Cdc37/Hsp90 chaperones and Parkin all influence the maturation or subcellular distribution of Pink1. Hum Mol Genet 17:602–616PubMedGoogle Scholar
  177. 177.
    Weihofen A, Thomas KJ, Ostaszewski BL, Cookson MR, Selkoe DJ (2009) Pink1 forms a multiprotein complex with Miro and Milton, linking Pink1 function to mitochondrial trafficking. Biochemistry 48:2045–2052PubMedGoogle Scholar
  178. 178.
    Wenz T (2009) PGC-1alpha activation as a therapeutic approach in mitochondrial disease. IUBMB Life 61:1051–1062PubMedGoogle Scholar
  179. 179.
    Whitworth AJ, Lee JR, Ho VM et al (2008) Rhomboid-7 and HtrA2/Omi act in a common pathway with the Parkinson’s disease factors Pink1 and Parkin. Dis Model Mech 1:168–174 discussion 173PubMedGoogle Scholar
  180. 180.
    Winklhofer KF (2007) The parkin protein as a therapeutic target in Parkinson’s disease. Expert Opin Ther Targets 11:1543–1552PubMedGoogle Scholar
  181. 181.
    Winklhofer KF, Haass C (2010) Mitochondrial dysfunction in Parkinson’s disease. Biochim Biophys Acta 1802:29–44PubMedGoogle Scholar
  182. 182.
    Winklhofer KF, Henn IH, Kay-Jackson PC, Heller U, Tatzelt J (2003) Inactivation of parkin by oxidative stress and C-terminal truncations: a protective role of molecular chaperones. J Biol Chem 278:47199–47208PubMedGoogle Scholar
  183. 183.
    Winklhofer KF, Tatzelt J, Haass C (2008) The two faces of protein misfolding: gain- and loss-of-function in neurodegenerative diseases. EMBO J 27:336–349PubMedGoogle Scholar
  184. 184.
    Wong ES, Tan JM, Wang C et al (2007) Relative sensitivity of parkin and other cysteine-containing enzymes to stress-induced solubility alterations. J Biol Chem 282:12310–12318PubMedGoogle Scholar
  185. 185.
    Wood-Kaczmar A, Gandhi S, Yao Z et al (2008) PINK1 is necessary for long term survival and mitochondrial function in human dopaminergic neurons. PLoS One 3:e2455PubMedGoogle Scholar
  186. 186.
    Yamaguchi R, Perkins G (2009) Dynamics of mitochondrial structure during apoptosis and the enigma of Opa1. Biochim Biophys Acta 1787:963–972PubMedGoogle Scholar
  187. 187.
    Yang Y, Gehrke S, Imai Y et al (2006) Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin. Proc Natl Acad Sci USA 103:10793–10798PubMedGoogle Scholar
  188. 188.
    Yang Y, Ouyang Y, Yang L et al (2008) Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery. Proc Natl Acad Sci USA 105:7070–7075PubMedGoogle Scholar
  189. 189.
    Yang Z, Klionsky DJ (2010) Eaten alive: a history of macroautophagy. Nat Cell Biol 12:814–822PubMedGoogle Scholar
  190. 190.
    Yao D, Gu Z, Nakamura T et al (2004) Nitrosative stress linked to sporadic Parkinson’s disease: S-nitrosylation of parkin regulates its E3 ubiquitin ligase activity. Proc Natl Acad Sci USA 101:10810–10814PubMedGoogle Scholar
  191. 191.
    Yoshii SR, Kishi C, Ishihara N, Mizushima N (2011) Parkin mediates proteasome-dependent protein degradation and rupture of the outer mitochondrial membrane. J Biol Chem 286:19630–19640PubMedGoogle Scholar
  192. 192.
    Yun J, Cao JH, Dodson MW et al (2008) Loss-of-function analysis suggests that Omi/HtrA2 is not an essential component of the PINK1/PARKIN pathway in vivo. J Neurosci 28:14500–14510PubMedGoogle Scholar
  193. 193.
    Zhou C, Huang Y, Shao Y et al (2008) The kinase domain of mitochondrial PINK1 faces the cytoplasm. Proc Natl Acad Sci USA 105:12022–12027PubMedGoogle Scholar
  194. 194.
    Zhou H, Falkenburger BH, Schulz JB et al (2007) Silencing of the Pink1 gene expression by conditional RNAi does not induce dopaminergic neuron death in mice. Int J Biol Sci 3:242–250PubMedGoogle Scholar
  195. 195.
    Ziviani E, Tao RN, Whitworth AJ (2010) Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin. Proc Natl Acad Sci USA 107:5018–5023PubMedGoogle Scholar
  196. 196.
    Zuchner S, Mersiyanova IV, Muglia M et al (2004) Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet 36:449–451PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Neurobiochemistry, Adolf Butenandt InstituteLudwig Maximilians UniversityMunichGermany
  2. 2.German Center for Neurodegenerative Diseases (DZNE)MunichGermany

Personalised recommendations