Journal of Bioenergetics and Biomembranes

, Volume 41, Issue 6, pp 473–479 | Cite as

Mitochondrial quality control: insights on how Parkinson’s disease related genes PINK1, parkin, and Omi/HtrA2 interact to maintain mitochondrial homeostasis

Article

Abstract

Alterations in mitochondrial homeostasis have been implicated in the etiology of Parkinson disease (PD) as demonstrated by human tissue studies, cell culture and in vivo genetic and toxin models. Mutations in the genes encoding PTEN-induced kinase 1 (PINK1), Omi/HtrA2 and parkin contribute to rare forms of parkinsonian neurodegeneration. Recently, each of these proteins has been shown to play a normal role in regulating mitochondrial structure, function, fission-fusion dynamics, or turnover (autophagy and biogenesis), promoting neuronal survival. Here, we review the biochemical mechanisms of mitochondrial protection conferred by each of these PD associated gene products in neurons, neuronal cell lines and other cell types. Potential molecular interactions and mitoprotective signaling pathways involving these three PD associated gene products are discussed in the context of mitochondrial quality control, in response to increasing levels of mitochondrial damage. We propose that PINK1, Omi/HtrA2 and parkin participate at different levels in mitochondrial quality control, converging through some overlapping and some distinct steps to maintain a common phenotype of healthy mitochondrial networks.

Keywords

Mitochondria Ser/thr kinases PINK1 Parkin Omi/HtrA2 Neurotoxin Autophagy Ubiquitin Neurodegeneration Oxidative stress Parkinson’s disease 

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References

  1. Betarbet R, Sherer TB, Di Monte DA, Greenamyre JT (2002) Mechanistic approaches to Parkinson’s disease pathogenesis. Brain Pathol 12:499–510CrossRefGoogle Scholar
  2. Biskup S, Moore DJ, Celsi F, Higashi S, West AB, Andrabi SA, Kurkinen K, Yu SW, Savitt JM, Waldvogel HJ, Faull RL, Emson PC, Torp R, Ottersen OP, Dawson TM, Dawson VL (2006) Localization of LRRK2 to membranous and vesicular structures in mammalian brain. Ann Neurol 60:557–569CrossRefGoogle Scholar
  3. 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 7:129–151CrossRefGoogle Scholar
  4. Cassarino DS, Parks JK, Parker WD Jr, Bennett JP Jr (1999) The parkinsonian neurotoxin MPP + opens the mitochondrial permeability transition pore and releases cytochrome c in isolated mitochondria via an oxidative mechanism. Biochim Biophys Acta 1453:49–62Google Scholar
  5. Chalovich EM, Zhu JH, Caltagarone J, Bowser R, Chu CT (2006) Functional repression of cAMP response element in 6-hydroxydopamine-treated neuronal cells. J Biol Chem 281:17870–17881CrossRefGoogle Scholar
  6. Cherra SJ, Chu CT (2008) Autophagy in neuroprotection and neurodegeneration: a question of balance. Future Neurol 3:309–323Google Scholar
  7. Chu CT (2009) Tickled PINK1: mitochondrial homeostasis and autophagy in recessive Parkinsonism. Biochim Biophys Acta.Google Scholar
  8. Cookson MR, Dauer W, Dawson T, Fon EA, Guo M, Shen J (2007) The roles of kinases in familial Parkinson’s disease. J Neurosci 27:11865–11868CrossRefGoogle Scholar
  9. Dagda RK, Zhu J, Kulich SM, Chu CT (2008) Mitochondrially localized ERK2 regulates mitophagy and autophagic cell stress: implications for Parkinson’s disease. Autophagy 4:770–782Google Scholar
  10. Dagda RK, Zhu J, Chu CT (2009a) Mitochondrial kinases in Parkinson’s disease: converging insights from neurotoxin and genetic models. Mitochondrion 9:289–298CrossRefGoogle Scholar
  11. Dagda RK, Cherra SJ 3rd, Kulich SM, Tandon A, Park D, Chu CT (2009b) Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J Biol Chem 284:13843–13855CrossRefGoogle Scholar
  12. Darios F, Corti O, Lucking CB, Hampe C, Muriel MP, Abbas N, Gu WJ, Hirsch EC, Rooney T, Ruberg M, Brice A (2003) Parkin prevents mitochondrial swelling and cytochrome c release in mitochondria-dependent cell death. Hum Mol Genet 12:517–526CrossRefGoogle Scholar
  13. 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 105:14503–14508CrossRefGoogle Scholar
  14. Devi L, Raghavendran V, Prabhu BM, Avadhani NG, Anandatheerthavarada HK (2008) Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. J Biol Chem 283:9089–9100CrossRefGoogle Scholar
  15. Exner N, Treske B, Paquet D, Holmstrom K, Schiesling C, Gispert S, Carballo-Carbajal I, Berg D, Hoepken HH, Gasser T, Kruger R, Winklhofer KF, Vogel F, Reichert AS, Auburger G, Kahle PJ, Schmid B, Haass C (2007) Loss-of-function of human PINK1 results in mitochondrial pathology and can be rescued by parkin. J Neurosci 27:12413–12418CrossRefGoogle Scholar
  16. 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 132:1613–1623CrossRefGoogle Scholar
  17. 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:e4756CrossRefGoogle Scholar
  18. Gomez-Lazaro M, Bonekamp NA, Galindo MF, Jordan J, Schrader M (2008) 6-Hydroxydopamine (6-OHDA) induces Drp1-dependent mitochondrial fragmentation in SH-SY5Y cells. Free Radic Biol Med 44:1960–1969CrossRefGoogle Scholar
  19. Hegde R, Srinivasula SM, Zhang Z, Wassell R, Mukattash R, Cilenti L, DuBois G, Lazebnik Y, Zervos AS, Fernandes-Alnemri T, Alnemri ES (2002) Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction. J Biol Chem 277:432–438CrossRefGoogle Scholar
  20. Heikkila RE, Cohen G (1973) 6-Hydroxydopamine: evidence for superoxide radical as an oxidative intermediate. Science 181:456–457CrossRefGoogle Scholar
  21. Jiang H, Ren Y, Zhao J, Feng J (2004) Parkin protects human dopaminergic neuroblastoma cells against dopamine-induced apoptosis. Hum Mol Genet 13:1745–1754CrossRefGoogle Scholar
  22. Karbowski M, Youle RJ (2003) Dynamics of mitochondrial morphology in healthy cells and during apoptosis. Cell Death Differ 10:870–880CrossRefGoogle Scholar
  23. Kim Y, Park J, Kim S, Song S, Kwon SK, Lee SH, Kitada T, Kim JM, Chung J (2008) PINK1 controls mitochondrial localization of Parkin through direct phosphorylation. Biochem Biophys Res Commun 377:975–980CrossRefGoogle Scholar
  24. Kulich SM, Horbinski C, Patel M, Chu CT (2007) 6-Hydroxydopamine induces mitochondrial ERK activation. Free Radic Biol Med 43:372–383CrossRefGoogle Scholar
  25. Kuroda Y, Mitsui T, Kunishige M, Shono M, Akaike M, Azuma H, Matsumoto T (2006) Parkin enhances mitochondrial biogenesis in proliferating cells. Hum Mol Genet 15:883–895CrossRefGoogle Scholar
  26. Li Z, Okamoto K, Hayashi Y, Sheng M (2004) The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 119:873–887CrossRefGoogle Scholar
  27. Liang CL, Wang TT, Luby-Phelps K, German DC (2007) Mitochondria mass is low in mouse substantia nigra dopamine neurons: implications for Parkinson’s disease. Exp Neurol 203:370–380CrossRefGoogle Scholar
  28. Lu B (2009) Mitochondrial dynamics and neurodegeneration. Curr Neurol Neurosci Rep 9:212–219CrossRefGoogle Scholar
  29. Lutz AK, Exner N, Fett ME, Schlehe JS, Kloos K, Lammermann K, Brunner B, Kurz-Drexler A, Vogel F, Reichert AS, Bouman L, Vogt-Weisenhorn D, Wurst W, Tatzelt J, Haass C, Winklhofer KF (2009) Loss of parkin or PINK1 function increases Drp1-dependent mitochondrial fragmentation. J Biol Chem 284:22938–22951CrossRefGoogle Scholar
  30. Martins LM, Morrison A, Klupsch K, Fedele V, Moisoi N, Teismann P, Abuin A, Grau E, Geppert M, Livi GP, Creasy CL, Martin A, Hargreaves I, Heales SJ, Okada H, Brandner S, Schulz JB, Mak T, Downward J (2004) Neuroprotective role of the Reaper-related serine protease HtrA2/Omi revealed by targeted deletion in mice. Mol Cell Biol 24:9848–9862CrossRefGoogle Scholar
  31. Mills RD, Sim CH, Mok SS, Mulhern TD, Culvenor JG, Cheng HC (2008) Biochemical aspects of the neuroprotective mechanism of PTEN-induced kinase-1 (PINK1). J Neurochem 105:18–33CrossRefGoogle Scholar
  32. Mortiboys H, Thomas KJ, Koopman WJ, Klaffke S, Abou-Sleiman P, Olpin S, Wood NW, Willems PH, Smeitink JA, Cookson MR, Bandmann O (2008) Mitochondrial function and morphology are impaired in parkin-mutant fibroblasts. Ann Neurol 64:555–565CrossRefGoogle Scholar
  33. Narendra D, Tanaka A, Suen DF, Youle RJ (2008) Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 183:795–803CrossRefGoogle Scholar
  34. Olzmann JA, Chin LS (2008) Parkin-mediated K63-linked polyubiquitination: a signal for targeting misfolded proteins to the aggresome-autophagy pathway. Autophagy 4:85–87Google Scholar
  35. Plowey ED, Cherra III SJ, Liu Y-J, Chu CT (2008) Role of autophagy in G2019SLRRK2-associated neurite shortening in differentiated SH-SY5Y cells. J Neurochem 105:1048–1056Google Scholar
  36. Plun-Favreau H, Klupsch K, Moisoi N, Gandhi S, Kjaer S, Frith D, Harvey K, Deas E, Harvey RJ, McDonald N, Wood NW, Martins LM, Downward J (2007) The mitochondrial protease HtrA2 is regulated by Parkinson’s disease-associated kinase PINK1. Nat Cell Biol 9:1243–1252CrossRefGoogle Scholar
  37. 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 105:1638–1643CrossRefGoogle Scholar
  38. Pridgeon JW, Olzmann JA, Chin LS, Li L (2007) PINK1 Protects against Oxidative Stress by Phosphorylating Mitochondrial Chaperone TRAP1. PLoS Biol 5:e172CrossRefGoogle Scholar
  39. Sandebring A, Thomas KJ, Beilina A, van der Brug M, Cleland MM, Ahmad R, Miller DW, Zambrano I, Cowburn RF, Behbahani H, Cedazo-Minguez A, Cookson MR (2009) Mitochondrial alterations in PINK1 deficient cells are influenced by calcineurin-dependent dephosphorylation of dynamin-related protein 1. PLoS ONE 4:e5701CrossRefGoogle Scholar
  40. Strauss KM, Martins LM, Plun-Favreau H, Marx FP, Kautzmann S, Berg D, Gasser T, Wszolek Z, Muller T, Bornemann A, Wolburg H, Downward J, Riess O, Schulz JB, Kruger R (2005) Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson’s disease. Hum Mol Genet 14:2099–2111CrossRefGoogle Scholar
  41. Tain LS, Chowdhury RB, Tao RN, Plun-Favreau H, Moisoi N, Martins LM, Downward J, Whitworth AJ, Tapon N (2009) Drosophila HtrA2 is dispensable for apoptosis but acts downstream of PINK1 independently from Parkin. Cell Death Differ 16:1118–1125CrossRefGoogle Scholar
  42. Tatsuta T (2009) Protein quality control in mitochondria. J Biochem 146:455–461CrossRefGoogle Scholar
  43. Tatsuta T, Langer T (2009) AAA proteases in mitochondria: diverse functions of membrane-bound proteolytic machines. Res Microbiol.Google Scholar
  44. Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD, Walzer G, Stiles L, Haigh SE, Katz S, Las G, Alroy J, Wu M, Py BF, Yuan J, Deeney JT, Corkey BE, Shirihai OS (2008) Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. Embo J 27:433–446CrossRefGoogle Scholar
  45. Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, Gonzalez-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304:1158–1160CrossRefGoogle Scholar
  46. van Loo G, van Gurp M, Depuydt B, Srinivasula SM, Rodriguez I, Alnemri ES, Gevaert K, Vandekerckhove J, Declercq W, Vandenabeele P (2002) The serine protease Omi/HtrA2 is released from mitochondria during apoptosis. Omi interacts with caspase-inhibitor XIAP and induces enhanced caspase activity. Cell Death Differ 9:20–26CrossRefGoogle Scholar
  47. 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 47:365–378CrossRefGoogle Scholar
  48. Whitworth AJ, Lee JR, Ho VM, Flick R, Chowdhury R, McQuibban GA (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 173CrossRefGoogle Scholar
  49. Wood-Kaczmar A, Gandhi S, Yao Z, Abramov AS, Miljan EA, Keen G, Stanyer L, Hargreaves I, Klupsch K, Deas E, Downward J, Mansfield L, Jat P, Taylor J, Heales S, Duchen MR, Latchman D, Tabrizi SJ, Wood NW (2008) PINK1 is necessary for long term survival and mitochondrial function in human dopaminergic neurons. PLoS ONE 3:e2455CrossRefGoogle Scholar
  50. Xiong H, Wang D, Chen L, Choo YS, Ma H, Tang C, Xia K, Jiang W, Ronai Z, Zhuang X, Zhang Z (2009) Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein degradation. J Clin Invest 119:650–660CrossRefGoogle Scholar
  51. Yun J, Cao JH, Dodson MW, Clark IE, Kapahi P, Chowdhury RB, Guo M (2008) Loss-of-function analysis suggests that Omi/HtrA2 is not an essential component of the PINK1/PARKIN pathway in vivo. J Neurosci 28:14500–14510CrossRefGoogle Scholar
  52. Zhu J-H, Kulich SM, Oury TD, Chu CT (2002) Cytoplasmic aggregates of phosphorylated extracellular signal-regulated kinase in Lewy body diseases. Am J Pathol 161:2087–2098Google Scholar
  53. Zhu JH, Horbinski C, Guo F, Watkins S, Uchiyama Y, Chu CT (2007) Regulation of autophagy by extracellular signal-regulated protein kinases during 1-methyl-4-phenylpyridinium-induced cell death. Am J Pathol 170:75–86CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  2. 2.Center for NeuroscienceUniversity of Pittsburgh School of MedicinePittsburghUSA
  3. 3.Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghUSA

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