References 1. Cookson MR (2005) The biochemistry of Parkinson’s disease. Annu Rev Biochem 74: 29–52. 2. Przedborski S, Ischiropoulos H (2005) Reactive oxygen and nitrogen species: weapons of neuronal destruction in models of Parkinson’s disease. Antioxid Redox Signal 7: 685–693. 3. Canet-Aviles RM, Wilson MA, Miller DW, Ahmad R, McLendon C, et al. (2004) The Parkinson’s disease protein DJ-1 is neuroprotective due to cysteine- sulfinic acid-driven mitochondrial localization. Proc Natl Acad Sci U S A 101: 9103–9108. 4. 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: 799–811. 5. Palacino JJ, Sagi D, Goldberg MS, Krauss S, Motz C, et al. (2004) Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem 279: 18614–18622. 6. Darios F, Corti O, Lucking CB, Hampe C, Muriel MP, et al. (2003) Parkin prevents mitochondrial swelling and cytochrome c release in mitochondria- dependent cell death. Hum Mol Genet 12: 517–526. 7. Narendra D, Tanaka A, Suen DF, Youle RJ (2008) Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 183: 795–803. 8. Clark IE, Dodson MW, Jiang C, Cao JH, Huh JR, et al. (2006) Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441: 1162–1166. 9. Park J, Lee SB, Lee S, Kim Y, Song S, et al. (2006) Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441: 1157–1161. 10. Yang Y, Gehrke S, Imai Y, Huang Z, Ouyang 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 U S A 103: 10793–10798. 11. Hoepken HH, Gispert S, Morales B, Wingerter O, Del Turco D, et al. (2006) Mitochondrial dysfunction, peroxidation damage and changes in glutathione metabolism in PARK6. Neurobiol Dis. 12. Exner N, Treske B, Paquet D, Holmstrom K, Schiesling C, et al. (2007) Loss-of- function of human PINK1 results in mitochondrial pathology and can be rescued by parkin. J Neurosci 27: 12413–12418. 13. Mortiboys H, Thomas KJ, Koopman WJ, Klaffke S, Abou-Sleiman P, et al. (2008) Mitochondrial function and morphology are impaired in parkin-mutant fibroblasts. Ann Neurol 64: 555–565. 14. Wood-Kaczmar A, Gandhi S, Yao Z, Abramov AS, Miljan EA, et al. (2008) PINK1 is necessary for long term survival and mitochondrial function in human dopaminergic neurons. PLoS ONE 3: e2455. 15. Dagda RK, Cherra SJ 3rd, Kulich SM, Tandon A, Park D, et al. (2009) Loss of pink1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J Biol Chem. 16. Gandhi S, Wood-Kaczmar A, Yao Z, Plun-Favreau H, Deas E, et al. (2009) PINK1-associated Parkinson’s disease is caused by neuronal vulnerability to calcium-induced cell death. Mol Cell 33: 627–638. 17. Kitada T, Pisani A, Porter DR, Yamaguchi H, Tscherter A, et al. (2007) Impaired dopamine release and synaptic plasticity in the striatum of PINK1- deficient mice. Proc Natl Acad Sci U S A 104: 11441–11446. 18. Gautier CA, Kitada T, Shen J (2008) Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress. Proc Natl Acad Sci U S A 105: 11364–11369. 19. Liu W, Vives-Bauza C, Acin-Perez R, Yamamoto A, Tan Y, 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: e4597. 20. 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: e4756. 21. Chan DC (2006) Mitochondrial fusion and fission in mammals. Annu Rev Cell Dev Biol 22: 79–99. 22. Poole AC, Thomas RE, Andrews LA, McBride HM, Whitworth AJ, et al. (2008) The PINK1/Parkin pathway regulates mitochondrial morphology. Proc Natl Acad Sci U S A 105: 1638–1643. 23. Yang Y, Ouyang Y, Yang L, Beal MF, McQuibban A, et al. (2008) Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery. Proc Natl Acad Sci U S A 105: 7070–7075. 24. Ichishita R, Tanaka K, Sugiura Y, Sayano T, Mihara K, et al. (2008) An RNAi Screen for Mitochondrial Proteins Required to Maintain the Morphology of the Organelle in Caenorhabditis elegans. J Biochem 143: 449–454. 25. Barsoum MJ, Yuan H, Gerencser AA, Liot G, Kushnareva Y, et al. (2006) Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons. Embo J 25: 3900–3911. 26. Mills RD, Sim CH, Mok SS, Mulhern TD, Culvenor JG, et al. (2008) Biochemical aspects of the neuroprotective mechanism of PTEN-induced kinase-1 (PINK1). J Neurochem 105: 18–33. 27. Pridgeon JW, Olzmann JA, Chin LS, Li L (2007) PINK1 Protects against Oxidative Stress by Phosphorylating Mitochondrial Chaperone TRAP1. PLoS Biol 5: e172. PINK1 and Drp1 28. Plun-Favreau H, Klupsch K, Moisoi N, Gandhi S, Kjaer S, et al. (2007) The mitochondrial protease HtrA2 is regulated by Parkinson’s disease-associated kinase PINK1. Nat Cell Biol 9: 1243–1252. 29. Beilina A, Van Der Brug M, Ahmad R, Kesavapany S, Miller DW, et al. (2005) Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability. Proc Natl Acad Sci U S A 102: 5703–5708. 30. 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: 1133–1138. 31. Petit A, Kawarai T, Paitel E, Sanjo N, Maj M, 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: 34025–34032. 32. Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, et al. (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304: 1158–1160. 33. Haque ME, Thomas KJ, D’Souza C, Callaghan S, Kitada T, et al. (2008) Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP. Proc Natl Acad Sci U S A 105: 1716–1721. 34. Benard G, Bellance N, James D, Parrone P, Fernandez H, et al. (2007) Mitochondrial bioenergetics and structural network organization. J Cell Sci 120: 838–848. 35. Plecita-Hlavata L, Lessard M, Santorova J, Bewersdorf J, Jezek P (2008) Mitochondrial oxidative phosphorylation and energetic status are reflected by morphology of mitochondrial network in INS-1E and HEP-G2 cells viewed by 4Pi microscopy. Biochim Biophys Acta 1777: 834–846. 36. 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 U S A 105: 14503–14508. 37. Karbowski M, Jeong SY, Youle RJ (2004) Endophilin B1 is required for the maintenance of mitochondrial morphology. J Cell Biol 166: 1027–1039. 38. Stojanovski D, Koutsopoulos OS, Okamoto K, Ryan MT (2004) Levels of human Fis1 at the mitochondrial outer membrane regulate mitochondrial morphology. J Cell Sci 117: 1201–1210. 39. 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: 1178–1188. 40. Chang CR, Blackstone C (2007) Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology. J Biol Chem 282: 21583–21587. 41. 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. 42. Han XJ, Lu YF, Li SA, Kaitsuka T, Sato Y, et al. (2008) CaM kinase Ialpha- induced phosphorylation of Drp1 regulates mitochondrial morphology. J Cell Biol 182: 573–585. 43. 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: 11521–11529. 44. Rahman-Roblick R, Hellman U, Becker S, Bader FG, Auer G, et al. (2008) Proteomic identification of p53-dependent protein phosphorylation. Oncogene. 45. Detmer SA, Chan DC (2007) Functions and dysfunctions of mitochondrial dynamics. Nat Rev Mol Cell Biol 8: 870–879. 46. Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD, et al. (2008) Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 27: 433–446. 47. Nowikovsky K, Reipert S, Devenish RJ, Schweyen RJ (2007) Mdm38 protein depletion causes loss of mitochondrial K+/H+ exchange activity, osmotic swelling and mitophagy. Cell Death Differ 14: 1647–1656. 48. Priault M, Salin B, Schaeffer J, Vallette FM, di Rago JP, et al. (2005) Impairing the bioenergetic status and the biogenesis of mitochondria triggers mitophagy in yeast. Cell Death Differ 12: 1613–1621. 49. Twig G, Hyde B, Shirihai OS (2008) Mitochondrial fusion, fission and autophagy as a quality control axis: the bioenergetic view. Biochim Biophys Acta 1777: 1092–1097. 50. Babcock DF, Herrington J, Goodwin PC, Park YB, Hille B (1997) Mitochondrial participation in the intracellular Ca2+ network. J Cell Biol 136: 833–844. 51. Herrington J, Park YB, Babcock DF, Hille B (1996) Dominant role of mitochondria in clearance of large Ca2+ loads from rat adrenal chromaffin cells. Neuron 16: 219–228. 52. Ishii K, Hirose K, Iino M (2006) Ca2+ shuttling between endoplasmic reticulum and mitochondria underlying Ca2+ oscillations. EMBO Rep 7: 390–396. 53. de Brito OM, Scorrano L (2008) Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456: 605–610. 54. Marongiu R, Spencer B, Crews L, Adame A, Patrick C, et al. (2009) Mutant Pink1 induces mitochondrial dysfunction in a neuronal cell model of Parkinson’s disease by disturbing calcium flux. J Neurochem. 55. Cereghetti GM, Stangherlin A, Martins de Brito O, Chang CR, Blackstone C, et al. (2008) Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria. Proc Natl Acad Sci U S A 105: 15803–15808. PLoS ONE | www.plosone.org 17 May 2009 | Volume 4 | Issue 5 | e5701