, Volume 15, Issue 11, pp 1336–1353 | Cite as

Mitochondrial dynamics, cell death and the pathogenesis of Parkinson’s disease

  • Hansruedi BüelerEmail author
Apoptosis in the aging brain


The structure and function of the mitochondrial network is regulated by mitochondrial biogenesis, fission, fusion, transport and degradation. A well-maintained balance of these processes (mitochondrial dynamics) is essential for neuronal signaling, plasticity and transmitter release. Core proteins of the mitochondrial dynamics machinery play important roles in the regulation of apoptosis, and mutations or abnormal expression of these factors are associated with inherited and age-dependent neurodegenerative disorders. In Parkinson’s disease (PD), oxidative stress and mitochondrial dysfunction underlie the development of neuropathology. The recessive Parkinsonism-linked genes PTEN-induced kinase 1 (PINK1) and Parkin maintain mitochondrial integrity by regulating diverse aspects of mitochondrial function, including membrane potential, calcium homeostasis, cristae structure, respiratory activity, and mtDNA integrity. In addition, Parkin is crucial for autophagy-dependent clearance of dysfunctional mitochondria. In the absence of PINK1 or Parkin, cells often develop fragmented mitochondria. Whereas excessive fission may cause apoptosis, coordinated induction of fission and autophagy is believed to facilitate the removal of damaged mitochondria through mitophagy, and has been observed in some types of cells. Compensatory mechanisms may also occur in mice lacking PINK1 that, in contrast to cells and Drosophila, have only mild mitochondrial dysfunction and lack dopaminergic neuron loss. A better understanding of the relationship between the specific changes in mitochondrial dynamics/turnover and cell death will be instrumental to identify potentially neuroprotective pathways steering PINK1-deficient cells towards survival. Such pathways may be manipulated in the future by specific drugs to treat PD and perhaps other neurodegenerative disorders characterized by abnormal mitochondrial function and dynamics.


PINK1 Parkin Mitophagy Calcium Cristae Mitochondria 



I thank Dr. Ravi Akundi of the Department of Anatomy and Neurobiology, University of Kentucky for valuable comments on the manuscript.


  1. 1.
    Mattson MP, Gleichmann M, Cheng A (2008) Mitochondria in neuroplasticity and neurological disorders. Neuron 60:748–766PubMedCrossRefGoogle Scholar
  2. 2.
    Elstner M, Andreoli C, Klopstock T, Meitinger T, Prokisch H (2009) The mitochondrial proteome database: MitoP2. Methods Enzymol 457:3–20PubMedCrossRefGoogle Scholar
  3. 3.
    Bolender N, Sickmann A, Wagner R, Meisinger C, Pfanner N (2008) Multiple pathways for sorting mitochondrial precursor proteins. EMBO Rep 9:42–49PubMedCrossRefGoogle Scholar
  4. 4.
    Westermann B (2008) Molecular machinery of mitochondrial fusion and fission. J Biol Chem 283:13501–13505PubMedCrossRefGoogle Scholar
  5. 5.
    Hoppins S, Lackner L, Nunnari J (2007) The machines that divide and fuse mitochondria. Annu Rev Biochem 76:751–780PubMedCrossRefGoogle Scholar
  6. 6.
    McBride HM, Neuspiel M, Wasiak S (2006) Mitochondria: more than just a powerhouse. Curr Biol 16:R551–R560PubMedCrossRefGoogle Scholar
  7. 7.
    Cerveny KL, Tamura Y, Zhang Z, Jensen RE, Sesaki H (2007) Regulation of mitochondrial fusion and division. Trends Cell Biol 17:563–569PubMedCrossRefGoogle Scholar
  8. 8.
    Chan DC (2006) Mitochondria: dynamic organelles in disease, aging, and development. Cell 125:1241–1252PubMedCrossRefGoogle Scholar
  9. 9.
    Chan DC (2006) Mitochondrial fusion and fission in mammals. Annu Rev Cell Dev Biol 22:79–99PubMedCrossRefGoogle Scholar
  10. 10.
    Soubannier V, McBride HM (2009) Positioning mitochondrial plasticity within cellular signaling cascades. Biochim Biophys Acta 1793:154–170PubMedCrossRefGoogle Scholar
  11. 11.
    Suen DF, Norris KL, Youle RJ (2008) Mitochondrial dynamics and apoptosis. Genes Dev 22:1577–1590PubMedCrossRefGoogle Scholar
  12. 12.
    Pitts KR, Yoon Y, Krueger EW, McNiven MA (1999) The dynamin-like protein DLP1 is essential for normal distribution and morphology of the endoplasmic reticulum and mitochondria in mammalian cells. Mol Biol Cell 10:4403–4417PubMedGoogle Scholar
  13. 13.
    Yoon Y, Pitts KR, McNiven MA (2001) Mammalian dynamin-like protein DLP1 tubulates membranes. Mol Biol Cell 12:2894–2905PubMedGoogle Scholar
  14. 14.
    Smirnova E, Griparic L, Shurland DL, van der Bliek AM (2001) Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol Biol Cell 12:2245–2256PubMedGoogle Scholar
  15. 15.
    Serasinghe MN, Yoon Y (2008) The mitochondrial outer membrane protein hFis1 regulates mitochondrial morphology and fission through self-interaction. Exp Cell Res 314:3494–3507PubMedCrossRefGoogle Scholar
  16. 16.
    James DI, Parone PA, Mattenberger Y, Martinou JC (2003) hFis1, a novel component of the mammalian mitochondrial fission machinery. J Biol Chem 278:36373–36379PubMedCrossRefGoogle Scholar
  17. 17.
    Koch A, Yoon Y, Bonekamp NA, McNiven MA, Schrader M (2005) A role for Fis1 in both mitochondrial and peroxisomal fission in mammalian cells. Mol Biol Cell 16:5077–5086PubMedCrossRefGoogle Scholar
  18. 18.
    Lee S, Jeong SY, Lim WC et al (2007) Mitochondrial fission and fusion mediators, hFis1 and OPA1, modulate cellular senescence. J Biol Chem 282:22977–22983PubMedCrossRefGoogle Scholar
  19. 19.
    Yoon Y, Krueger EW, Oswald BJ, McNiven MA (2003) The mitochondrial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1. Mol Cell Biol 23:5409–5420PubMedCrossRefGoogle Scholar
  20. 20.
    Yu T, Fox RJ, Burwell LS, Yoon Y (2005) Regulation of mitochondrial fission and apoptosis by the mitochondrial outer membrane protein hFis1. J Cell Sci 118:4141–4151PubMedCrossRefGoogle Scholar
  21. 21.
    Karbowski M, Jeong SY, Youle RJ (2004) Endophilin B1 is required for the maintenance of mitochondrial morphology. J Cell Biol 166:1027–1039PubMedCrossRefGoogle Scholar
  22. 22.
    Santel A, Frank S (2008) Shaping mitochondria: the complex posttranslational regulation of the mitochondrial fission protein DRP1. IUBMB Life 60:448–455PubMedCrossRefGoogle Scholar
  23. 23.
    Taguchi N, Ishihara N, Jofuku A, Oka T, Mihara K (2007) Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission. J Biol Chem 282:11521–11529PubMedCrossRefGoogle Scholar
  24. 24.
    Cribbs JT, Strack S (2007) Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death. EMBO Rep 8:939–944PubMedCrossRefGoogle Scholar
  25. 25.
    Chang CR, Blackstone C (2007) Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology. J Biol Chem 282:21583–21587PubMedCrossRefGoogle Scholar
  26. 26.
    Cereghetti GM, Stangherlin A, Martins de Brito O et al (2008) Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria. Proc Natl Acad Sci USA 105:15803–15808PubMedCrossRefGoogle Scholar
  27. 27.
    Chang CR, Blackstone C (2007) Drp1 phosphorylation and mitochondrial regulation. EMBO Rep 8:1088–1089PubMedCrossRefGoogle Scholar
  28. 28.
    Cribbs JT, Strack S (2009) Functional characterization of phosphorylation sites in dynamin-related protein 1. Methods Enzymol 457:231–253PubMedCrossRefGoogle Scholar
  29. 29.
    Harder Z, Zunino R, McBride H (2004) Sumo1 conjugates mitochondrial substrates and participates in mitochondrial fission. Curr Biol 14:340–345PubMedGoogle Scholar
  30. 30.
    Zunino R, Braschi E, Xu L, McBride HM (2009) Translocation of SenP5 from the nucleoli to the mitochondria modulates DRP1-dependent fission during mitosis. J Biol Chem 284:17783–17795PubMedCrossRefGoogle Scholar
  31. 31.
    Zunino R, Schauss A, Rippstein P, Andrade-Navarro M, McBride HM (2007) The SUMO protease SENP5 is required to maintain mitochondrial morphology and function. J Cell Sci 120:1178–1188PubMedCrossRefGoogle Scholar
  32. 32.
    Braschi E, Zunino R, McBride HM (2009) MAPL is a new mitochondrial SUMO E3 ligase that regulates mitochondrial fission. EMBO Rep 10:748–754PubMedCrossRefGoogle Scholar
  33. 33.
    Neutzner A, Benard G, Youle RJ, Karbowski M (2008) Role of the ubiquitin conjugation system in the maintenance of mitochondrial homeostasis. Ann N Y Acad Sci 1147:242–253PubMedCrossRefGoogle Scholar
  34. 34.
    Neuspiel M, Schauss AC, Braschi E et al (2008) Cargo-selected transport from the mitochondria to peroxisomes is mediated by vesicular carriers. Curr Biol 18:102–108PubMedCrossRefGoogle Scholar
  35. 35.
    Yonashiro R, Ishido S, Kyo S et al (2006) A novel mitochondrial ubiquitin ligase plays a critical role in mitochondrial dynamics. EMBO J 25:3618–3626PubMedCrossRefGoogle Scholar
  36. 36.
    Karbowski M, Neutzner A, Youle RJ (2007) The mitochondrial E3 ubiquitin ligase MARCH5 is required for Drp1 dependent mitochondrial division. J Cell Biol 178:71–84PubMedCrossRefGoogle Scholar
  37. 37.
    Nakamura N, Kimura Y, Tokuda M, Honda S, Hirose S (2006) MARCH-V is a novel mitofusin 2- and Drp1-binding protein able to change mitochondrial morphology. EMBO Rep 7:1019–1022PubMedCrossRefGoogle Scholar
  38. 38.
    Chen H, Detmer SA, Ewald AJ, Griffin EE, Fraser SE, Chan DC (2003) Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol 160:189–200PubMedCrossRefGoogle Scholar
  39. 39.
    Koshiba T, Detmer SA, Kaiser JT, Chen H, McCaffery JM, Chan DC (2004) Structural basis of mitochondrial tethering by mitofusin complexes. Science 305:858–862PubMedCrossRefGoogle Scholar
  40. 40.
    Chen H, Chomyn A, Chan DC (2005) Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J Biol Chem 280:26185–26192PubMedCrossRefGoogle Scholar
  41. 41.
    Meeusen S, DeVay R, Block J et al (2006) Mitochondrial inner-membrane fusion and crista maintenance requires the dynamin-related GTPase Mgm1. Cell 127:383–395PubMedCrossRefGoogle Scholar
  42. 42.
    Cipolat S, Martins de Brito O, Dal Zilio B, Scorrano L (2004) OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci USA 101:15927–15932PubMedCrossRefGoogle Scholar
  43. 43.
    Griparic L, van der Wel NN, Orozco IJ, Peters PJ, van der Bliek AM (2004) Loss of the intermembrane space protein Mgm1/OPA1 induces swelling and localized constrictions along the lengths of mitochondria. J Biol Chem 279:18792–18798PubMedCrossRefGoogle Scholar
  44. 44.
    Misaka T, Murate M, Fujimoto K, Kubo Y (2006) The dynamin-related mouse mitochondrial GTPase OPA1 alters the structure of the mitochondrial inner membrane when exogenously introduced into COS-7 cells. Neurosci Res 55:123–133PubMedCrossRefGoogle Scholar
  45. 45.
    Sesaki H, Dunn CD, Iijima M et al (2006) Ups1p, a conserved intermembrane space protein, regulates mitochondrial shape and alternative topogenesis of Mgm1p. J Cell Biol 173:651–658PubMedCrossRefGoogle Scholar
  46. 46.
    Fox EJ, Stubbs SA, Kyaw Tun J, Leek JP, Markham AF, Wright SC (2004) PRELI (protein of relevant evolutionary and lymphoid interest) is located within an evolutionarily conserved gene cluster on chromosome 5q34–q35 and encodes a novel mitochondrial protein. Biochem J 378:817–825PubMedCrossRefGoogle Scholar
  47. 47.
    Chen H, Chan DC (2006) Critical dependence of neurons on mitochondrial dynamics. Curr Opin Cell Biol 18:453–459PubMedCrossRefGoogle Scholar
  48. 48.
    Keating DJ (2008) Mitochondrial dysfunction, oxidative stress, regulation of exocytosis and their relevance to neurodegenerative diseases. J Neurochem 104:298–305PubMedGoogle Scholar
  49. 49.
    Chang DT, Reynolds IJ (2006) Mitochondrial trafficking and morphology in healthy and injured neurons. Prog Neurobiol 80:241–268PubMedCrossRefGoogle Scholar
  50. 50.
    Kang JS, Tian JH, Pan PY et al (2008) Docking of axonal mitochondria by syntaphilin controls their mobility and affects short-term facilitation. Cell 132:137–148PubMedCrossRefGoogle Scholar
  51. 51.
    Morris RL, Hollenbeck PJ (1993) The regulation of bidirectional mitochondrial transport is coordinated with axonal outgrowth. J Cell Sci 104:917–927PubMedGoogle Scholar
  52. 52.
    David G, Barrett EF (2003) Mitochondrial Ca2+ uptake prevents desynchronization of quantal release and minimizes depletion during repetitive stimulation of mouse motor nerve terminals. J Physiol 548:425–438PubMedCrossRefGoogle Scholar
  53. 53.
    Guo X, Macleod GT, Wellington A et al (2005) The GTPase dMiro is required for axonal transport of mitochondria to Drosophila synapses. Neuron 47:379–393PubMedCrossRefGoogle Scholar
  54. 54.
    Verstreken P, Ly CV, Venken KJ, Koh TW, Zhou Y, Bellen HJ (2005) Synaptic mitochondria are critical for mobilization of reserve pool vesicles at Drosophila neuromuscular junctions. Neuron 47:365–378PubMedCrossRefGoogle Scholar
  55. 55.
    Hollenbeck PJ (2005) Mitochondria and neurotransmission: evacuating the synapse. Neuron 47:331–333PubMedCrossRefGoogle Scholar
  56. 56.
    Garcia-Chacon LE, Nguyen KT, David G, Barrett EF (2006) Extrusion of Ca2+ from mouse motor terminal mitochondria via a Na+–Ca2+ exchanger increases post-tetanic evoked release. J Physiol 574:663–675PubMedCrossRefGoogle Scholar
  57. 57.
    Kann O, Kovacs R (2007) Mitochondria and neuronal activity. Am J Physiol Cell Physiol 292:C641–C657PubMedCrossRefGoogle Scholar
  58. 58.
    Stowers RS, Megeath LJ, Gorska-Andrzejak J, Meinertzhagen IA, Schwarz TL (2002) Axonal transport of mitochondria to synapses depends on milton, a novel Drosophila protein. Neuron 36:1063–1077PubMedCrossRefGoogle Scholar
  59. 59.
    Tong JJ (2007) Mitochondrial delivery is essential for synaptic potentiation. Biol Bull 212:169–175PubMedCrossRefGoogle Scholar
  60. 60.
    Hirokawa N, Takemura R (2005) Molecular motors and mechanisms of directional transport in neurons. Nat Rev Neurosci 6:201–214PubMedCrossRefGoogle Scholar
  61. 61.
    Glater EE, Megeath LJ, Stowers RS, Schwarz TL (2006) Axonal transport of mitochondria requires milton to recruit kinesin heavy chain and is light chain independent. J Cell Biol 173:545–557PubMedCrossRefGoogle Scholar
  62. 62.
    MacAskill AF, Brickley K, Stephenson FA, Kittler JT (2009) GTPase dependent recruitment of Grif-1 by Miro1 regulates mitochondrial trafficking in hippocampal neurons. Mol Cell Neurosci 40:301–312PubMedCrossRefGoogle Scholar
  63. 63.
    Reis K, Fransson A, Aspenstrom P (2009) The Miro GTPases: at the heart of the mitochondrial transport machinery. FEBS Lett 583:1391–1398PubMedCrossRefGoogle Scholar
  64. 64.
    Macaskill AF, Rinholm JE, Twelvetrees AE et al (2009) Miro1 is a calcium sensor for glutamate receptor-dependent localization of mitochondria at synapses. Neuron 61:541–555PubMedCrossRefGoogle Scholar
  65. 65.
    Saotome M, Safiulina D, Szabadkai G et al (2008) Bidirectional Ca2+-dependent control of mitochondrial dynamics by the Miro GTPase. Proc Natl Acad Sci USA 105:20728–20733PubMedCrossRefGoogle Scholar
  66. 66.
    Liu X, Hajnoczky G (2009) Ca(2+)-dependent regulation of mitochondrial dynamics by the Miro-Milton complex. Int J Biochem Cell Biol 41:1972–1976PubMedCrossRefGoogle Scholar
  67. 67.
    Jeyaraju DV, Cisbani G, Pellegrini L (2008) Calcium regulation of mitochondria motility and morphology. Biochim Biophys Acta 1787:1363–1373PubMedGoogle Scholar
  68. 68.
    Cai Q, Pan PY, Sheng ZH (2007) Syntabulin-kinesin-1 family member 5B-mediated axonal transport contributes to activity-dependent presynaptic assembly. J Neurosci 27:7284–7296PubMedCrossRefGoogle Scholar
  69. 69.
    Cai Q, Gerwin C, Sheng ZH (2005) Syntabulin-mediated anterograde transport of mitochondria along neuronal processes. J Cell Biol 170:959–969PubMedCrossRefGoogle Scholar
  70. 70.
    Li W, Bengtson MH, Ulbrich A et al (2008) Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle’s dynamics and signaling. PLoS One 3:e1487PubMedCrossRefGoogle Scholar
  71. 71.
    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 15:5001–5011PubMedCrossRefGoogle Scholar
  72. 72.
    Neuspiel M, Zunino R, Gangaraju S, Rippstein P, McBride H (2005) Activated mitofusin 2 signals mitochondrial fusion, interferes with Bax activation, and reduces susceptibility to radical induced depolarization. J Biol Chem 280:25060–25070PubMedCrossRefGoogle Scholar
  73. 73.
    Parone PA, James DI, Da Cruz S et al (2006) Inhibiting the mitochondrial fission machinery does not prevent Bax/Bak-dependent apoptosis. Mol Cell Biol 26:7397–7408PubMedCrossRefGoogle Scholar
  74. 74.
    Parone PA, Martinou JC (2006) Mitochondrial fission and apoptosis: an ongoing trial. Biochim Biophys Acta 1763:522–530PubMedCrossRefGoogle Scholar
  75. 75.
    Cassidy-Stone A, Chipuk JE, Ingerman E et al (2008) Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell 14:193–204PubMedCrossRefGoogle Scholar
  76. 76.
    Tanaka A, Youle RJ (2008) A chemical inhibitor of DRP1 uncouples mitochondrial fission and apoptosis. Mol Cell 29:409–410PubMedCrossRefGoogle Scholar
  77. 77.
    Sheridan C, Delivani P, Cullen SP, Martin SJ (2008) Bax- or Bak-induced mitochondrial fission can be uncoupled from cytochrome C release. Mol Cell 31:570–585PubMedCrossRefGoogle Scholar
  78. 78.
    James DI, Martinou JC (2008) Mitochondrial dynamics and apoptosis: a painful separation. Dev Cell 15:341–343PubMedCrossRefGoogle Scholar
  79. 79.
    Karbowski M, Lee YJ, Gaume B et al (2002) Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis. J Cell Biol 159:931–938PubMedCrossRefGoogle Scholar
  80. 80.
    Wasiak S, Zunino R, McBride HM (2007) Bax/Bak promote sumoylation of DRP1 and its stable association with mitochondria during apoptotic cell death. J Cell Biol 177:439–450PubMedCrossRefGoogle Scholar
  81. 81.
    Olichon A, Baricault L, Gas N et al (2003) Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem 278:7743–7746PubMedCrossRefGoogle Scholar
  82. 82.
    Sugioka R, Shimizu S, Tsujimoto Y (2004) Fzo1, a protein involved in mitochondrial fusion, inhibits apoptosis. J Biol Chem 279:52726–52734PubMedCrossRefGoogle Scholar
  83. 83.
    Scorrano L, Ashiya M, Buttle K et al (2002) A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Dev Cell 2:55–67PubMedCrossRefGoogle Scholar
  84. 84.
    Arnoult D, Grodet A, Lee YJ, Estaquier J, Blackstone C (2005) Release of OPA1 during apoptosis participates in the rapid and complete release of cytochrome c and subsequent mitochondrial fragmentation. J Biol Chem 280:35742–35750PubMedCrossRefGoogle Scholar
  85. 85.
    Frezza C, Cipolat S, Martins de Brito O et al (2006) OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell 126:177–189PubMedCrossRefGoogle Scholar
  86. 86.
    Yamaguchi R, Lartigue L, Perkins G et al (2008) Opa1-mediated cristae opening is Bax/Bak and BH3 dependent, required for apoptosis, and independent of Bak oligomerization. Mol Cell 31:557–569PubMedCrossRefGoogle Scholar
  87. 87.
    Germain M, Mathai JP, McBride HM, Shore GC (2005) Endoplasmic reticulum BIK initiates DRP1-regulated remodelling of mitochondrial cristae during apoptosis. EMBO J 24:1546–1556PubMedCrossRefGoogle Scholar
  88. 88.
    Zhang D, Lu C, Whiteman M, Chance B, Armstrong JS (2008) The mitochondrial permeability transition regulates cytochrome c release for apoptosis during endoplasmic reticulum stress by remodeling the cristae junction. J Biol Chem 283:3476–3486PubMedCrossRefGoogle Scholar
  89. 89.
    Delettre C, Griffoin JM, Kaplan J et al (2001) Mutation spectrum and splicing variants in the OPA1 gene. Hum Genet 109:584–591PubMedCrossRefGoogle Scholar
  90. 90.
    Guillery O, Malka F, Landes T et al (2008) Metalloprotease-mediated OPA1 processing is modulated by the mitochondrial membrane potential. Biol Cell 100:315–325PubMedCrossRefGoogle Scholar
  91. 91.
    Olichon A, Elachouri G, Baricault L, Delettre C, Belenguer P, Lenaers G (2007) OPA1 alternate splicing uncouples an evolutionary conserved function in mitochondrial fusion from a vertebrate restricted function in apoptosis. Cell Death Differ 14:682–692PubMedCrossRefGoogle Scholar
  92. 92.
    Cipolat S, Rudka T, Hartmann D et al (2006) Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling. Cell 126:163–175PubMedCrossRefGoogle Scholar
  93. 93.
    Pellegrini L, Scorrano L (2007) A cut short to death: Parl and Opa1 in the regulation of mitochondrial morphology and apoptosis. Cell Death Differ 14:1275–1284PubMedCrossRefGoogle Scholar
  94. 94.
    Merkwirth C, Dargazanli S, Tatsuta T et al (2008) Prohibitins control cell proliferation and apoptosis by regulating OPA1-dependent cristae morphogenesis in mitochondria. Genes Dev 22:476–488PubMedCrossRefGoogle Scholar
  95. 95.
    Merkwirth C, Langer T (2009) Prohibitin function within mitochondria: essential roles for cell proliferation and cristae morphogenesis. Biochim Biophys Acta 1793:27–32PubMedCrossRefGoogle Scholar
  96. 96.
    Duvezin-Caubet S, Jagasia R, Wagener J et al (2006) Proteolytic processing of OPA1 links mitochondrial dysfunction to alterations in mitochondrial morphology. J Biol Chem 281:37972–37979PubMedCrossRefGoogle Scholar
  97. 97.
    Ishihara N, Jofuku A, Eura Y, Mihara K (2003) Regulation of mitochondrial morphology by membrane potential, and DRP1-dependent division and FZO1-dependent fusion reaction in mammalian cells. Biochem Biophys Res Commun 301:891–898PubMedCrossRefGoogle Scholar
  98. 98.
    Griparic L, Kanazawa T, van der Bliek AM (2007) Regulation of the mitochondrial dynamin-like protein Opa1 by proteolytic cleavage. J Cell Biol 178:757–764PubMedCrossRefGoogle Scholar
  99. 99.
    Perkins G, Bossy-Wetzel E, Ellisman MH (2009) New insights into mitochondrial structure during cell death. Exp Neurol 218:183–192PubMedCrossRefGoogle Scholar
  100. 100.
    Henchcliffe C, Beal MF (2008) Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis. Nat Clin Pract Neurol 4:600–609PubMedCrossRefGoogle Scholar
  101. 101.
    Bueler H (2009) Impaired mitochondrial dynamics and function in the pathogenesis of Parkinson’s disease. Exp Neurol 218:235–246PubMedCrossRefGoogle Scholar
  102. 102.
    Van Laar VS, Berman SB (2009) Mitochondrial dynamics in Parkinson’s disease. Exp Neurol 218:247–256PubMedCrossRefGoogle Scholar
  103. 103.
    Kitada T, Asakawa S, Hattori N et al (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605–608PubMedCrossRefGoogle Scholar
  104. 104.
    Abbas N, Lucking CB, Ricard S et al (1999) A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. French Parkinson’s disease genetics study group and the European consortium on genetic susceptibility in Parkinson’s disease. Hum Mol Genet 8:567–574PubMedCrossRefGoogle Scholar
  105. 105.
    Shimura H, Hattori N, Kubo S et al (2000) Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 25:302–305PubMedCrossRefGoogle Scholar
  106. 106.
    Zhang Y, Gao J, Chung KK, Huang H, Dawson VL, Dawson TM (2000) Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proc Natl Acad Sci USA 97:13354–13359PubMedCrossRefGoogle Scholar
  107. 107.
    Imai Y, Soda M, Inoue H, Hattori N, Mizuno Y, Takahashi R (2001) An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 105:891–902PubMedCrossRefGoogle Scholar
  108. 108.
    Corti O, Hampe C, Koutnikova H et al (2003) The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate: linking protein biosynthesis and neurodegeneration. Hum Mol Genet 12:1427–1437PubMedCrossRefGoogle Scholar
  109. 109.
    Murakami T, Shoji M, Imai Y et al (2004) Pael-R is accumulated in lewy bodies of Parkinson’s disease. Ann Neurol 55:439–442PubMedCrossRefGoogle Scholar
  110. 110.
    Periquet M, Corti O, Jacquier S, Brice A (2005) Proteomic analysis of parkin knockout mice: alterations in energy metabolism, protein handling and synaptic function. J Neurochem 95:1259–1276PubMedCrossRefGoogle Scholar
  111. 111.
    Fukae J, Sato S, Shiba K et al (2009) Programmed cell death-2 isoform1 is ubiquitinated by parkin and increased in the substantia nigra of patients with autosomal recessive Parkinson’s disease. FEBS Lett 583:521–525PubMedCrossRefGoogle Scholar
  112. 112.
    Greene JC, Whitworth AJ, Kuo I, Andrews LA, Feany MB, Pallanck LJ (2003) Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc Natl Acad Sci USA 100:4078–4083PubMedCrossRefGoogle Scholar
  113. 113.
    Pesah Y, Pham T, Burgess H et al (2004) Drosophila parkin mutants have decreased mass and cell size and increased sensitivity to oxygen radical stress. Development 131:2183–2194PubMedCrossRefGoogle Scholar
  114. 114.
    Greene JC, Whitworth AJ, Andrews LA, Parker TJ, Pallanck LJ (2005) Genetic and genomic studies of Drosophila parkin mutants implicate oxidative stress and innate immune responses in pathogenesis. Hum Mol Genet 14:799–811PubMedCrossRefGoogle Scholar
  115. 115.
    Palacino JJ, Sagi D, Goldberg MS et al (2004) Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem 279:18614–18622PubMedCrossRefGoogle Scholar
  116. 116.
    Goldberg MS, Fleming SM, Palacino JJ et al (2003) Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J Biol Chem 278:43628–43635PubMedCrossRefGoogle Scholar
  117. 117.
    Itier JM, Ibanez P, Mena MA et al (2003) Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse. Hum Mol Genet 12:2277–2291PubMedCrossRefGoogle Scholar
  118. 118.
    Flinn L, Mortiboys H, Volkmann K, Koster RW, Ingham PW, Bandmann O (2009) Complex I deficiency and dopaminergic neuronal cell loss in parkin-deficient zebrafish (Danio rerio). Brain 132:1613–1623PubMedCrossRefGoogle Scholar
  119. 119.
    Mortiboys H, Thomas KJ, Koopman WJ et al (2008) Mitochondrial function and morphology are impaired in parkin-mutant fibroblasts. Ann Neurol 64:555–565PubMedCrossRefGoogle Scholar
  120. 120.
    Kuroda Y, Mitsui T, Kunishige M et al (2006) Parkin enhances mitochondrial biogenesis in proliferating cells. Hum Mol Genet 15:883–895PubMedCrossRefGoogle Scholar
  121. 121.
    Wang C, Lu R, Ouyang X et al (2007) Drosophila overexpressing parkin R275 W mutant exhibits dopaminergic neuron degeneration and mitochondrial abnormalities. J Neurosci 27:8563–8570PubMedCrossRefGoogle Scholar
  122. 122.
    Sang TK, Chang HY, Lawless GM et al (2007) A Drosophila model of mutant human parkin-induced toxicity demonstrates selective loss of dopaminergic neurons and dependence on cellular dopamine. J Neurosci 27:981–992PubMedCrossRefGoogle Scholar
  123. 123.
    Lu XH, Fleming SM, Meurers B et al (2009) Bacterial artificial chromosome transgenic mice expressing a truncated mutant parkin exhibit age-dependent hypokinetic motor deficits, dopaminergic neuron degeneration, and accumulation of proteinase K-resistant alpha-synuclein. J Neurosci 29:1962–1976PubMedCrossRefGoogle Scholar
  124. 124.
    Kao SY (2009) Regulation of DNA repair by parkin. Biochem Biophys Res Commun 382:321–325PubMedCrossRefGoogle Scholar
  125. 125.
    Rothfuss O, Fischer H, Hasegawa T et al (2009) Parkin protects mitochondrial genome integrity and supports mitochondrial DNA repair. Hum Mol Genet 18:3832–3850PubMedCrossRefGoogle Scholar
  126. 126.
    Valente EM, Abou-Sleiman PM, Caputo V et al (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304:1158–1160PubMedCrossRefGoogle Scholar
  127. 127.
    Hatano Y, Li Y, Sato K et al (2004) Novel PINK1 mutations in early-onset parkinsonism. Ann Neurol 56:424–427PubMedCrossRefGoogle Scholar
  128. 128.
    Bonifati V, Rohe CF, Breedveld GJ et al (2005) Early-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes. Neurology 65:87–95PubMedCrossRefGoogle Scholar
  129. 129.
    Hedrich K, Hagenah J, Djarmati A et al (2006) Clinical spectrum of homozygous and heterozygous PINK1 mutations in a large German family with Parkinson disease: role of a single hit? Arch Neurol 63:833–838PubMedCrossRefGoogle Scholar
  130. 130.
    Prestel J, Gempel K, Hauser TK et al (2008) Clinical and molecular characterisation of a Parkinson family with a novel PINK1 mutation. J Neurol 255:643–648PubMedCrossRefGoogle Scholar
  131. 131.
    Rogaeva E, Johnson J, Lang AE et al (2004) Analysis of the PINK1 gene in a large cohort of cases with Parkinson disease. Arch Neurol 61:1898–1904PubMedCrossRefGoogle Scholar
  132. 132.
    Gelmetti V, Ferraris A, Brusa L et al (2008) Late onset sporadic Parkinson’s disease caused by PINK1 mutations: clinical and functional study. Mov Disord 23:881–885PubMedCrossRefGoogle Scholar
  133. 133.
    Silvestri L, Caputo V, Bellacchio E et al (2005) Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism. Hum Mol Genet 14:3477–3492PubMedCrossRefGoogle Scholar
  134. 134.
    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 102:5703–5708PubMedCrossRefGoogle Scholar
  135. 135.
    Taymans JM, Van den Haute C, Baekelandt V (2006) Distribution of PINK1 and LRRK2 in rat and mouse brain. J Neurochem 98:951–961PubMedCrossRefGoogle Scholar
  136. 136.
    Gandhi S, Muqit MM, Stanyer L et al (2006) PINK1 protein in normal human brain and Parkinson’s disease. Brain 129:1720–1731PubMedCrossRefGoogle Scholar
  137. 137.
    Blackinton JG, Anvret A, Beilina A, Olson L, Cookson MR, Galter D (2007) Expression of PINK1 mRNA in human and rodent brain and in Parkinson’s disease. Brain Res 1184:10–16PubMedCrossRefGoogle Scholar
  138. 138.
    Takatori S, Ito G, Iwatsubo T (2008) Cytoplasmic localization and proteasomal degradation of N-terminally cleaved form of PINK1. Neurosci Lett 430:13–17PubMedCrossRefGoogle Scholar
  139. 139.
    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 17:602–616PubMedCrossRefGoogle Scholar
  140. 140.
    Lin W, Kang UJ (2008) Characterization of PINK1 processing, stability, and subcellular localization. J Neurochem 106:464–474PubMedCrossRefGoogle Scholar
  141. 141.
    Zhou C, Huang Y, Shao Y et al (2008) The kinase domain of mitochondrial PINK1 faces the cytoplasm. Proc Natl Acad Sci USA 105:12022–12027PubMedCrossRefGoogle Scholar
  142. 142.
    Pridgeon JW, Olzmann JA, Chin LS, Li L (2007) PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1. PLoS Biol 5:e172PubMedCrossRefGoogle Scholar
  143. 143.
    Moriwaki Y, Kim YJ, Ido Y et al (2008) L347P PINK1 mutant that fails to bind to Hsp90/Cdc37 chaperones is rapidly degraded in a proteasome-dependent manner. Neurosci Res 61:43–48PubMedCrossRefGoogle Scholar
  144. 144.
    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 9:1243–1252PubMedCrossRefGoogle Scholar
  145. 145.
    Kim Y, Park J, Kim S et al (2008) PINK1 controls mitochondrial localization of Parkin through direct phosphorylation. Biochem Biophys Res Commun 377:975–980PubMedCrossRefGoogle Scholar
  146. 146.
    Martins LM, Morrison A, Klupsch K et al (2004) Neuroprotective role of the reaper-related serine protease HtrA2/Omi revealed by targeted deletion in mice. Mol Cell Biol 24:9848–9862PubMedCrossRefGoogle Scholar
  147. 147.
    Xu L, Voloboueva LA, Ouyang Y, Emery JF, Giffard RG (2009) Overexpression of mitochondrial Hsp70/Hsp75 in rat brain protects mitochondria, reduces oxidative stress, and protects from focal ischemia. J Cereb Blood Flow Metab 29:365–374PubMedCrossRefGoogle Scholar
  148. 148.
    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 27:12413–12418PubMedCrossRefGoogle Scholar
  149. 149.
    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:e2455PubMedCrossRefGoogle Scholar
  150. 150.
    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:e5701PubMedCrossRefGoogle Scholar
  151. 151.
    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 33:627–638PubMedCrossRefGoogle Scholar
  152. 152.
    Dagda RK, Cherra SJ 3rd, Kulich SM, Tandon A, Park D, Chu CT (2009) Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J Biol Chem 284:13843–13855PubMedCrossRefGoogle Scholar
  153. 153.
    Gegg ME, Cooper JM, Schapira AH, Taanman JW (2009) Silencing of PINK1 expression affects mitochondrial DNA and oxidative phosphorylation in dopaminergic cells. PLoS ONE 4:e4756PubMedCrossRefGoogle Scholar
  154. 154.
    Haque ME, Thomas KJ, D’Souza C et al (2008) Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP. Proc Natl Acad Sci USA 105:1716–1721PubMedCrossRefGoogle Scholar
  155. 155.
    Deng H, Jankovic J, Guo Y, Xie W, Le W (2005) Small interfering RNA targeting the PINK1 induces apoptosis in dopaminergic cells SH-SY5Y. Biochem Biophys Res Commun 337:1133–1138PubMedCrossRefGoogle Scholar
  156. 156.
    Petit A, Kawarai T, Paitel E et al (2005) Wild-type PINK1 prevents basal and induced neuronal apoptosis, a protective effect abrogated by Parkinson disease-related mutations. J Biol Chem 280:34025–34032PubMedCrossRefGoogle Scholar
  157. 157.
    Lutz AK, Exner N, Fett ME et al (2009) Loss of parkin or PINK1 function increases DRP1-dependent mitochondrial fragmentation. J Biol Chem 284:22938–22951PubMedCrossRefGoogle Scholar
  158. 158.
    Liu W, Vives-Bauza C, Acin-Perez R et al (2009) PINK1 defect causes mitochondrial dysfunction, proteasomal deficit and alpha-synuclein aggregation in cell culture models of Parkinson’s disease. PLoS ONE 4:e4597PubMedCrossRefGoogle Scholar
  159. 159.
    Hoepken HH, Gispert S, Morales B et al (2007) Mitochondrial dysfunction, peroxidation damage and changes in glutathione metabolism in PARK6. Neurobiol Dis 25:401–411PubMedCrossRefGoogle Scholar
  160. 160.
    Piccoli C, Sardanelli A, Scrima R et al (2008) Mitochondrial respiratory dysfunction in familiar parkinsonism associated with pink1 mutation. Neurochem Res 33:2565–2574PubMedCrossRefGoogle Scholar
  161. 161.
    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 105:7070–7075PubMedCrossRefGoogle Scholar
  162. 162.
    Clark IE, Dodson MW, Jiang C et al (2006) Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441:1162–1166PubMedCrossRefGoogle Scholar
  163. 163.
    Park J, Lee SB, Lee S et al (2006) Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441:1157–1161PubMedCrossRefGoogle Scholar
  164. 164.
    Poole AC, Thomas RE, Andrews LA, McBride HM, Whitworth AJ, Pallanck LJ (2008) The PINK1/Parkin pathway regulates mitochondrial morphology. Proc Natl Acad Sci USA 105:1638–1643PubMedCrossRefGoogle Scholar
  165. 165.
    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 105:14503–14508PubMedCrossRefGoogle Scholar
  166. 166.
    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 104:11441–11446PubMedCrossRefGoogle Scholar
  167. 167.
    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 105:11364–11369PubMedCrossRefGoogle Scholar
  168. 168.
    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:e5777PubMedCrossRefGoogle Scholar
  169. 169.
    Gerencser AA, Nicholls DG (2008) Measurement of instantaneous velocity vectors of organelle transport: mitochondrial transport and bioenergetics in hippocampal neurons. Biophys J 95:3079–3099PubMedCrossRefGoogle Scholar
  170. 170.
    Miller KE, Sheetz MP (2004) Axonal mitochondrial transport and potential are correlated. J Cell Sci 117:2791–2804PubMedCrossRefGoogle Scholar
  171. 171.
    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 48:2045–2052PubMedCrossRefGoogle Scholar
  172. 172.
    John GB, Shang Y, Li L et al (2005) The mitochondrial inner membrane protein mitofilin controls cristae morphology. Mol Biol Cell 16:1543–1554PubMedCrossRefGoogle Scholar
  173. 173.
    Szabadkai G, Simoni AM, Chami M, Wieckowski MR, Youle RJ, Rizzuto R (2004) Drp-1-dependent division of the mitochondrial network blocks intraorganellar Ca2+ waves and protects against Ca2+-mediated apoptosis. Mol Cell 16:59–68PubMedCrossRefGoogle Scholar
  174. 174.
    Mei Y, Zhang Y, Yamamoto K, Xie W, Mak TW, You H (2009) FOXO3a-dependent regulation of Pink1 (Park6) mediates survival signaling in response to cytokine deprivation. Proc Natl Acad Sci USA 106:5153–5158PubMedCrossRefGoogle Scholar
  175. 175.
    Sedding DG (2008) FoxO transcription factors in oxidative stress response and ageing—a new fork on the way to longevity? Biol Chem 389:279–283PubMedCrossRefGoogle Scholar
  176. 176.
    Twig G, Elorza A, Molina AJ et al (2008) Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 27:433–446PubMedCrossRefGoogle Scholar
  177. 177.
    Benard G, Bellance N, James D et al (2007) Mitochondrial bioenergetics and structural network organization. J Cell Sci 120:838–848PubMedCrossRefGoogle Scholar
  178. 178.
    Parone PA, Da Cruz S, Tondera D et al (2008) Preventing mitochondrial fission impairs mitochondrial function and leads to loss of mitochondrial DNA. PLoS ONE 3:e3257PubMedCrossRefGoogle Scholar
  179. 179.
    Detmer SA, Chan DC (2007) Functions and dysfunctions of mitochondrial dynamics. Nat Rev Mol Cell Biol 8:870–879PubMedCrossRefGoogle Scholar
  180. 180.
    Amati-Bonneau P, Valentino ML, Reynier P et al (2008) OPA1 mutations induce mitochondrial DNA instability and optic atrophy ‘plus’ phenotypes. Brain 131:338–351PubMedCrossRefGoogle Scholar
  181. 181.
    Hudson G, Amati-Bonneau P, Blakely EL et al (2008) Mutation of OPA1 causes dominant optic atrophy with external ophthalmoplegia, ataxia, deafness and multiple mitochondrial DNA deletions: a novel disorder of mtDNA maintenance. Brain 131:329–337PubMedCrossRefGoogle Scholar
  182. 182.
    Chen H, McCaffery JM, Chan DC (2007) Mitochondrial fusion protects against neurodegeneration in the cerebellum. Cell 130:548–562PubMedCrossRefGoogle Scholar
  183. 183.
    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 103:10793–10798PubMedCrossRefGoogle Scholar
  184. 184.
    He C, Klionsky DJ (2009) Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 43:67–93PubMedCrossRefGoogle Scholar
  185. 185.
    Hara T, Nakamura K, Matsui M et al (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441:885–889PubMedCrossRefGoogle Scholar
  186. 186.
    Komatsu M, Waguri S, Chiba T et al (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441:880–884PubMedCrossRefGoogle Scholar
  187. 187.
    Narendra D, Tanaka A, Suen DF, Youle RJ (2008) Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 183:795–803PubMedCrossRefGoogle Scholar
  188. 188.
    McBride HM (2008) Parkin mitochondria in the autophagosome. J Cell Biol 183:757–759PubMedCrossRefGoogle Scholar
  189. 189.
    Narendra D, Tanaka A, Suen DF, Youle RJ (2009) Parkin-induced mitophagy in the pathogenesis of Parkinson disease. Autophagy 5:706–708PubMedCrossRefGoogle Scholar
  190. 190.
    Kim PK, Hailey DW, Mullen RT, Lippincott-Schwartz J (2008) Ubiquitin signals autophagic degradation of cytosolic proteins and peroxisomes. Proc Natl Acad Sci USA 105:20567–20574PubMedCrossRefGoogle Scholar
  191. 191.
    Irrcher I, Park DS (2009) Parkinson’s disease: to live or die by autophagy. Sci Signal 2:21Google Scholar
  192. 192.
    Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in lewy bodies. Nature 388:839–840PubMedCrossRefGoogle Scholar
  193. 193.
    Polymeropoulos MH, Lavedan C, Leroy E et al (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047PubMedCrossRefGoogle Scholar
  194. 194.
    Kruger R, Kuhn W, Muller T et al (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet 18:106–108PubMedCrossRefGoogle Scholar
  195. 195.
    Vogiatzi T, Xilouri M, Vekrellis K, Stefanis L (2008) Wild type alpha-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells. J Biol Chem 283:23542–23556PubMedCrossRefGoogle Scholar
  196. 196.
    Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D (2004) Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305:1292–1295PubMedCrossRefGoogle Scholar
  197. 197.
    Bonifati V, Rizzu P, van Baren MJ et al (2003) Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299:256–259PubMedCrossRefGoogle Scholar
  198. 198.
    Gonzalez-Polo R, Niso-Santano M, Moran JM et al (2009) Silencing DJ-1 reveals its contribution in paraquat-induced autophagy. J Neurochem 109:889–898PubMedCrossRefGoogle Scholar
  199. 199.
    Cuervo AM (2006) Autophagy in neurons: it is not all about food. Trends Mol Med 12:461–464PubMedCrossRefGoogle Scholar
  200. 200.
    Xiong H, Wang D, Chen L et al (2009) Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein degradation. J Clin Invest 119:650–660PubMedCrossRefGoogle Scholar
  201. 201.
    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 36:1007–1019PubMedCrossRefGoogle Scholar
  202. 202.
    Haywood AF, Staveley BE (2004) Parkin counteracts symptoms in a Drosophila model of Parkinson’s disease. BMC Neurosci 5:14PubMedCrossRefGoogle Scholar
  203. 203.
    Yasuda T, Miyachi S, Kitagawa R et al (2007) Neuronal specificity of alpha-synuclein toxicity and effect of Parkin co-expression in primates. Neuroscience 144:743–753PubMedCrossRefGoogle Scholar
  204. 204.
    Todd AM, Staveley BE (2008) Pink1 suppresses alpha-synuclein-induced phenotypes in a Drosophila model of Parkinson’s disease. Genome 51:1040–1046PubMedCrossRefGoogle Scholar
  205. 205.
    Marazziti D, Di Pietro C, Golini E, Mandillo S, Matteoni R, Tocchini-Valentini GP (2009) Induction of macroautophagy by overexpression of the Parkinson’s disease-associated GPR37 receptor. FASEB J 23:1978–1987PubMedCrossRefGoogle Scholar
  206. 206.
    Knott AB, Perkins G, Schwarzenbacher R, Bossy-Wetzel E (2008) Mitochondrial fragmentation in neurodegeneration. Nat Rev Neurosci 9:505–518PubMedCrossRefGoogle Scholar
  207. 207.
    Liang CL, Wang TT, Luby-Phelps K, German DC (2007) Mitochondria mass is low in mouse substantia nigra dopaminergic neurons: implications for Parkinson’s disease. Exp Neurol 203:370–380PubMedCrossRefGoogle Scholar
  208. 208.
    Berman SB, Hastings TG (1999) Dopamine oxidation alters mitochondrial respiration and induces permeability transition in brain mitochondria: implications for Parkinson’s disease. J Neurochem 73:1127–1137PubMedCrossRefGoogle Scholar
  209. 209.
    Premkumar A, Simantov R (2002) Mitochondrial voltage-dependent anion channel is involved in dopamine-induced apoptosis. J Neurochem 82:345–352PubMedCrossRefGoogle Scholar
  210. 210.
    Van Laar VS, Mishizen AJ, Cascio M, Hastings TG (2009) Proteomic identification of dopamine-conjugated proteins from isolated rat brain mitochondria and SH-SY5Y cells. Neurobiol Dis 34:487–500PubMedCrossRefGoogle Scholar
  211. 211.
    Czerniczyniec A, Bustamante J, Lores-Arnaiz S (2007) Dopamine enhances mtNOS activity: implications in mitochondrial function. Biochim Biophys Acta 1767:1118–1125PubMedCrossRefGoogle Scholar
  212. 212.
    Antunes F, Han D, Rettori D, Cadenas E (2002) Mitochondrial damage by nitric oxide is potentiated by dopamine in PC12 cells. Biochim Biophys Acta 1556:233–238PubMedCrossRefGoogle Scholar
  213. 213.
    Brenner-Lavie H, Klein E, Ben-Shachar D (2009) Mitochondrial complex I as a novel target for intraneuronal DA: modulation of respiration in intact cells. Biochem Pharmacol 78:85–95PubMedCrossRefGoogle Scholar
  214. 214.
    Chen S, Owens GC, Edelman DB (2008) Dopamine inhibits mitochondrial motility in hippocampal neurons. PLoS One 3:e2804PubMedCrossRefGoogle Scholar
  215. 215.
    Martinez-Vicente M, Talloczy Z, Kaushik S et al (2008) Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy. J Clin Invest 118:777–788PubMedGoogle Scholar
  216. 216.
    Gomez-Santos C, Ferrer I, Santidrian AF, Barrachina M, Gil J, Ambrosio S (2003) Dopamine induces autophagic cell death and alpha-synuclein increase in human neuroblastoma SH-SY5Y cells. J Neurosci Res 73:341–350PubMedCrossRefGoogle Scholar
  217. 217.
    LaVoie MJ, Ostaszewski BL, Weihofen A, Schlossmacher MG, Selkoe DJ (2005) Dopamine covalently modifies and functionally inactivates parkin. Nat Med 11:1214–1221PubMedCrossRefGoogle Scholar
  218. 218.
    Bender A, Krishnan KJ, Morris CM et al (2006) High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet 38:515–517PubMedCrossRefGoogle Scholar
  219. 219.
    Kraytsberg Y, Kudryavtseva E, McKee AC, Geula C, Kowall NW, Khrapko K (2006) Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat Genet 38:518–520PubMedCrossRefGoogle Scholar
  220. 220.
    Malena A, Loro E, Di Re M, Holt IJ, Vergani L (2009) Inhibition of mitochondrial fission favours mutant over wild-type mitochondrial DNA. Hum Mol Genet 18:3407–3416PubMedCrossRefGoogle Scholar
  221. 221.
    Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318:121–134PubMedCrossRefGoogle Scholar
  222. 222.
    Herzig S, Martinou JC (2008) Mitochondrial dynamics: to be in good shape to survive. Curr Mol Med 8:131–137PubMedCrossRefGoogle Scholar
  223. 223.
    Liesa M, Palacin M, Zorzano A (2009) Mitochondrial dynamics in mammalian health and disease. Physiol Rev 89:799–845PubMedCrossRefGoogle Scholar
  224. 224.
    Wang X, Su B, Lee HG et al (2009) Impaired balance of mitochondrial fission and fusion in Alzheimer’s disease. J Neurosci 29:9090–9103PubMedCrossRefGoogle Scholar
  225. 225.
    Reddy PH (2009) Amyloid beta, mitochondrial structural and functional dynamics in Alzheimer’s disease. Exp Neurol 218:286–292PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Anatomy and NeurobiologyUniversity of KentuckyLexingtonUSA

Personalised recommendations