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Acta Neuropathologica
Published in: Acta Neuropathologica 2/2012

01-02-2012 | Review

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

Authors: Anna Pilsl, Konstanze F. Winklhofer

Published in: Acta Neuropathologica | Issue 2/2012

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Abstract

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.
Literature
1.
Abou-Sleiman PM, Muqit MM, Wood NW (2006) Expanding insights of mitochondrial dysfunction in Parkinson’s disease. Nat Rev Neurosci 7:207–219PubMed
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 26:211–215PubMed
3.
Behrends C, Harper JW (2011) Constructing and decoding unconventional ubiquitin chains. Nat Struct Mol Biol 18:520–528PubMed
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 102:5703–5708PubMed
5.
Benard G, Karbowski M (2009) Mitochondrial fusion and division: regulation and role in cell viability. Semin Cell Dev Biol 20:365–374PubMed
6.
Berger AK, Cortese GP, Amodeo KD et al (2009) Parkin selectively alters the intrinsic threshold for mitochondrial cytochrome c release. Hum Mol Genet 18:4317–4328PubMed
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 7:129–151PubMed
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 18:769–782PubMed
9.
Braak H, Del Tredici K, Rub U et al (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211PubMed
10.
Bueler H (2010) Mitochondrial dynamics, cell death and the pathogenesis of Parkinson’s disease. Apoptosis 15:1336–1353PubMed
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 40:1048–1060PubMed
12.
Burke RE, Dauer WT, Vonsattel JP (2008) A critical evaluation of the Braak staging scheme for Parkinson’s disease. Ann Neurol 64:485–491PubMed
13.
Caughey B, Lansbury PT (2003) Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci 26:267–298PubMed
14.
Cerveny KL, Jensen RE (2003) The WD-repeats of Net2p interact with Dnm1p and Fis1p to regulate division of mitochondria. Mol Biol Cell 14:4126–4139PubMed
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 102:10345–10350PubMed
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 20:1726–1737PubMed
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 57:348–351PubMed
18.
Chen H, Chan DC (2009) Mitochondrial dynamics—fusion, fission, movement, and mitophagy—in neurodegenerative diseases. Hum Mol Genet 18:R169–R176PubMed
19.
Chen H, Chomyn A, Chan DC (2005) Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J Biol Chem 280:26185–26192PubMed
20.
Chen H, McCaffery JM, Chan DC (2007) Mitochondrial fusion protects against neurodegeneration in the cerebellum. Cell 130:548–562PubMed
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 141:280–289PubMed
22.
Chu CT (2010) A pivotal role for PINK1 and autophagy in mitochondrial quality control: implications for Parkinson disease. Hum Mol Genet 19:R28–R37PubMed
23.
Chung KK, Thomas B, Li X et al (2004) S-nitrosylation of parkin regulates ubiquitination and compromises parkin’s protective function. Science 304:1328–1331PubMed
24.
Clark IE, Dodson MW, Jiang C et al (2006) Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441:1162–1166PubMed
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 285:11740–11752PubMed
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 284:13843–13855PubMed
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 12:517–526PubMed
28.
Davis GC, Williams AC, Markey SP et al (1979) Chronic Parkinsonism secondary to intravenous injection of meperidine analogues. Psychiatry Res 1:249–254PubMed
29.
Dawson TM, Dawson VL (2010) The role of parkin in familial and sporadic Parkinson’s disease. Mov Disord 25(Suppl 1):S32–S39PubMed
30.
Dawson TM, Ko HS, Dawson VL (2010) Genetic animal models of Parkinson’s disease. Neuron 66:646–661PubMed
31.
Deas E, Plun-Favreau H, Gandhi S et al (2011) PINK1 cleavage at position A103 by the mitochondrial protease PARL. Hum Mol Genet 20:867–879PubMed
32.
Deas E, Plun-Favreau H, Wood NW (2009) PINK1 function in health and disease. EMBO Mol Med 1:152–165PubMed
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 26:207–210PubMed
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 105:14503–14508PubMed
35.
Detmer SA, Chan DC (2007) Functions and dysfunctions of mitochondrial dynamics. Nat Rev Mol Cell Biol 8:870–879PubMed
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 285:27879–27890PubMed
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 104:1325–1330PubMed
38.
Eskelinen EL, Saftig P (2009) Autophagy: a lysosomal degradation pathway with a central role in health and disease. Biochim Biophys Acta 1793:664–673PubMed
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 27:12413–12418PubMed
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 8:834–842PubMed
41.
Fett ME, Pilsl A, Paquet D et al (2010) Parkin is protective against proteotoxic stress in a transgenic zebrafish model. PLoS One 5:e11783PubMed
42.
Forno LS (1996) Neuropathology of Parkinson’s disease. J Neuropathol Exp Neurol 55:259–272PubMed
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 33:627–638PubMed
44.
Garcia-Arencibia M, Hochfeld WE, Toh PP, Rubinsztein DC (2010) Autophagy, a guardian against neurodegeneration. Semin Cell Dev Biol 21:691–698PubMed
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 105:11364–11369PubMed
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 19:4861–4870PubMed
47.
Geisler S, Holmstrom KM, Skujat D et al (2010) PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol 12:119–131PubMed
48.
Geisler S, Holmstrom KM, Treis A et al (2010) The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations. Autophagy 6:871–878PubMed
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:e5777PubMed
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 118:636–645PubMed
51.
Gomes LC, Di Benedetto G, Scorrano L (2011) During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 13:589–598PubMed
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 100:4078–4083PubMed
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 219:266–273PubMed
54.
Grunewald A, Voges L, Rakovic A et al (2010) Mutant Parkin impairs mitochondrial function and morphology in human fibroblasts. PLoS One 5:e12962PubMed
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 105:1716–1721PubMed
56.
Hardy J (2010) Genetic analysis of pathways to Parkinson disease. Neuron 68:201–206PubMed
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 19:254–265PubMed
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 105:1700–1715PubMed
59.
Henchcliffe C, Beal MF (2008) Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis. Nat Clin Pract Neurol 4:600–609PubMed
60.
Henn IH, Bouman L, Schlehe JS et al (2007) Parkin mediates neuroprotection through activation of IkappaB kinase/nuclear factor-kappaB signaling. J Neurosci 27:1868–1878PubMed
61.
Higashi Y, Asanuma M, Miyazaki I et al (2004) Parkin attenuates manganese-induced dopaminergic cell death. J Neurochem 89:1490–1497PubMed
62.
Hoepken HH, Gispert S, Morales B et al (2007) Mitochondrial dysfunction, peroxidation damage and changes in glutathione metabolism in PARK6. Neurobiol Dis 25:401–411PubMed
63.
Hoppins S, Nunnari J (2009) The molecular mechanism of mitochondrial fusion. Biochim Biophys Acta 1793:20–26PubMed
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 284:14978–14986PubMed
65.
Ikeda F, Dikic I (2008) Atypical ubiquitin chains: new molecular signals ‘Protein Modifications: Beyond the Usual Suspects’ review series. EMBO Rep 9:536–542PubMed
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 275:35661–35664PubMed
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 11:958–966PubMed
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 82:2173–2177PubMed
69.
Jiang H, Ren Y, Zhao J, Feng J (2004) Parkin protects human dopaminergic neuroblastoma cells against dopamine-induced apoptosis. Hum Mol Genet 13:1745–1754PubMed
70.
Jin SM, Lazarou M, Wang C et al (2010) Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J Cell Biol 191:933–942PubMed
71.
Karbowski M, Youle RJ (2011) Regulating mitochondrial outer membrane proteins by ubiquitination and proteasomal degradation. Curr Opin Cell Biol 23:476–482PubMed
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 115:727–738PubMed
73.
Kawajiri S, Saiki S, Sato S, Hattori N (2011) Genetic mutations and functions of PINK1. Trends Pharmacol Sci 32:573–580PubMed
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 584:1073–1079PubMed
75.
Kim Y, Park J, Kim S et al (2008) PINK1 controls mitochondrial localization of Parkin through direct phosphorylation. Biochem Biophys Res Commun 377:975–980PubMed
76.
Kirkin V, McEwan DG, Novak I, Dikic I (2009) A role for ubiquitin in selective autophagy. Mol Cell 34:259–269PubMed
77.
Kitada T, Asakawa S, Hattori N et al (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605–608PubMed
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 104:11441–11446PubMed
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 111:696–702PubMed
80.
Knott AB, Bossy-Wetzel E (2008) Impairing the mitochondrial fission and fusion balance: a new mechanism of neurodegeneration. Ann N Y Acad Sci 1147:283–292PubMed
81.
Knott AB, Perkins G, Schwarzenbacher R, Bossy-Wetzel E (2008) Mitochondrial fragmentation in neurodegeneration. Nat Rev Neurosci 9:505–518PubMed
82.
Komander D (2009) The emerging complexity of protein ubiquitination. Biochem Soc Trans 37:937–953PubMed
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 14:504–506PubMed
84.
Kraft C, Peter M, Hofmann K (2010) Selective autophagy: ubiquitin-mediated recognition and beyond. Nat Cell Biol 12:836–841PubMed
85.
Lamark T, Kirkin V, Dikic I, Johansen T (2009) NBR1 and p62 as cargo receptors for selective autophagy of ubiquitinated targets. Cell Cycle 8:1986–1990PubMed
86.
Landes T, Leroy I, Bertholet A et al (2010) OPA1 (dys)functions. Semin Cell Dev Biol 21:593–598PubMed
87.
Lang AE, Obeso JA (2004) Challenges in Parkinson’s disease: restoration of the nigrostriatal dopamine system is not enough. Lancet Neurol 3:309–316PubMed
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 309:310PubMed
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 46:598–605PubMed
90.
LaVoie MJ, Cortese GP, Ostaszewski BL, Schlossmacher MG (2007) The effects of oxidative stress on parkin and other E3 ligases. J Neurochem 103:2354–2368PubMed
91.
LaVoie MJ, Ostaszewski BL, Weihofen A, Schlossmacher MG, Selkoe DJ (2005) Dopamine covalently modifies and functionally inactivates parkin. Nat Med 11:1214–1221PubMed
92.
Lee JY, Koga H, Kawaguchi Y et al (2010) HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy. EMBO J 29:969–980PubMed
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 189:671–679PubMed
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 15:5001–5011PubMed
95.
Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132:27–42PubMed
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 14:501–503PubMed
97.
Lin W, Kang UJ (2008) Characterization of PINK1 processing, stability, and subcellular localization. J Neurochem 106:464–474PubMed
98.
Lin W, Kang UJ (2010) Structural determinants of PINK1 topology and dual subcellular distribution. BMC Cell Biol 11:90PubMed
99.
Livnat-Levanon N, Glickman MH (2011) Ubiquitin-proteasome system and mitochondria—reciprocity. Biochim Biophys Acta 1809:80–87PubMed
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 101:17510–17515PubMed
101.
Lutz AK, Exner N, Fett ME et al (2009) Loss of parkin or PINK1 function increases Drp1-dependent mitochondrial fragmentation. J Biol Chem 284:22938–22951PubMed
102.
Magen I, Chesselet MF (2010) Genetic mouse models of Parkinson’s disease The state of the art. Prog Brain Res 184:53–87PubMed
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 120:1707–1716PubMed
104.
Markey SP, Johannessen JN, Chiueh CC, Burns RS, Herkenham MA (1984) Intraneuronal generation of a pyridinium metabolite may cause drug-induced parkinsonism. Nature 311:464–467PubMed
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: null
106.
Martinelli P, Rugarli EI (2010) Emerging roles of mitochondrial proteases in neurodegeneration. Biochim Biophys Acta 1797:1–10PubMed
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 189:211–221PubMed
108.
Mattson MP, Gleichmann M, Cheng A (2008) Mitochondria in neuroplasticity and neurological disorders. Neuron 60:748–766PubMed
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 117:856–867PubMed
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 14:507–509PubMed
111.
Miller KE, Sheetz MP (2004) Axonal mitochondrial transport and potential are correlated. J Cell Sci 117:2791–2804PubMed
112.
Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451:1069–1075PubMed
113.
Moore DJ (2006) Parkin: a multifaceted ubiquitin ligase. Biochem Soc Trans 34:749–753PubMed
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 1:99–111PubMed
115.
Mortiboys H, Thomas KJ, Koopman WJ et al (2008) Mitochondrial function and morphology are impaired in parkin-mutant fibroblasts. Ann Neurol 64:555–565PubMed
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 13:117–135PubMed
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 7:934–940PubMed
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 6:1090–1106PubMed
119.
Narendra D, Tanaka A, Suen DF, Youle RJ (2008) Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 183:795–803PubMed
120.
Narendra DP, Jin SM, Tanaka A et al (2010) PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol 8:e1000298PubMed
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 36:2503–2508PubMed
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 31:763–780PubMed
123.
Obeso JA, Rodriguez-Oroz MC, Goetz CG et al (2010) Missing pieces in the Parkinson’s disease puzzle. Nat Med 16:653–661PubMed
124.
Okatsu K, Saisho K, Shimanuki M et al (2010) p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria. Genes Cells 15:887–900PubMed
125.
Palacino JJ, Sagi D, Goldberg MS et al (2004) Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem 279:18614–18622PubMed
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 378:518–523PubMed
127.
Park J, Lee SB, Lee S et al (2006) Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441:1157–1161PubMed
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 36:1007–1019PubMed
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 9:1243–1252PubMed
130.
Poole AC, Thomas RE, Andrews LA et al (2008) The PINK1/Parkin pathway regulates mitochondrial morphology. Proc Natl Acad Sci USA 105:1638–1643PubMed
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:e10054PubMed
132.
Pridgeon JW, Olzmann JA, Chin LS, Li L (2007) PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1. PLoS Biol 5:e172PubMed
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 93:4565–4571PubMed
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 108:10190–10195PubMed
135.
Rodgers JT, Lerin C, Gerhart-Hines Z, Puigserver P (2008) Metabolic adaptations through the PGC-1 alpha and SIRT1 pathways. FEBS Lett 582:46–53PubMed
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 281:12809–12816PubMed
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:e5701PubMed
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 41:1303–1307PubMed
139.
Scarpulla RC (2011) Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta 1813:1269–1278PubMed
140.
Schapira AH (2008) Mitochondria in the aetiology and pathogenesis of Parkinson’s disease. Lancet Neurol 7:97–109PubMed
141.
Schapira AH, Cooper JM, Dexter D et al (1989) Mitochondrial complex I deficiency in Parkinson’s disease. Lancet 1:1269PubMed
142.
Schlehe JS, Lutz AK, Pilsl A et al (2008) Aberrant folding of pathogenic Parkin mutants: aggregation versus degradation. J Biol Chem 283:13771–13779PubMed
143.
Schon EA, Przedborski S (2011) Mitochondria: the next (neurode)generation. Neuron 70:1033–1053PubMed
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 31:5970–5976PubMed
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 19:352–363PubMed
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 20:1966–1974PubMed
147.
Shiba K, Arai T, Sato S et al (2009) Parkin stabilizes PINK1 through direct interaction. Biochem Biophys Res Commun 383:331–335PubMed
148.
Shin JH, Ko HS, Kang H et al (2011) PARIS (ZNF746) repression of PGC-1alpha contributes to neurodegeneration in Parkinson’s disease. Cell 144:689–702PubMed
149.
Shulman JM, De Jager PL, Feany MB (2011) Parkinson’s disease: genetics and pathogenesis. Annu Rev Pathol 6:193–222PubMed
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 14:3477–3492PubMed
151.
Simon-Sanchez J, Schulte C, Bras JM et al (2009) Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet 41:1308–1312PubMed
152.
Soubannier V, McBride HM (2009) Positioning mitochondrial plasticity within cellular signaling cascades. Biochim Biophys Acta 1793:154–170PubMed
153.
Spillantini MG, Schmidt ML, Lee VM et al (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840PubMed
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 37:735–749PubMed
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 108:12937–12942PubMed
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 16:1118–1125PubMed
157.
Takatori S, Ito G, Iwatsubo T (2008) Cytoplasmic localization and proteasomal degradation of N-terminally cleaved form of PINK1. Neurosci Lett 430:13–17PubMed
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 118:484–488PubMed
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 191:1367–1380PubMed
160.
Tatsuta T, Langer T (2008) Quality control of mitochondria: protection against neurodegeneration and ageing. EMBO J 27:306–314PubMed
161.
Terzioglu M, Galter D (2008) Parkinson’s disease: genetic versus toxin-induced rodent models. Febs J 275:1384–1391PubMed
162.
Thomas KJ, Cookson MR (2009) The role of PTEN-induced kinase 1 in mitochondrial dysfunction and dynamics. Int J Biochem Cell Biol 41:2025–2035PubMed
163.
Tondera D, Grandemange S, Jourdain A et al (2009) SLP-2 is required for stress-induced mitochondrial hyperfusion. EMBO J 28:1589–1600PubMed
164.
Twig G, Elorza A, Molina AJ et al (2008) Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 27:433–446PubMed
165.
Ulusoy A, Kirik D (2008) Can overexpression of parkin provide a novel strategy for neuroprotection in Parkinson’s disease? Exp Neurol 212:258–260PubMed
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 40:421–432PubMed
167.
Valente EM, Abou-Sleiman PM, Caputo V et al (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304:1158–1160PubMed
168.
Van Humbeeck C, Cornelissen T, Hofkens H et al (2011) Parkin interacts with ambra1 to induce mitophagy. J Neurosci 31:10249–10261PubMed
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 20:927–940PubMed
170.
Van Laar VS, Berman SB (2009) Mitochondrial dynamics in Parkinson’s disease. Exp Neurol 218:247–256PubMed
171.
Vila M, Ramonet D, Perier C (2008) Mitochondrial alterations in Parkinson’s disease: new clues. J Neurochem 107:317–328PubMed
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 107:378–383PubMed
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 72:57–71PubMed
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 14:3885–3897PubMed
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 286:11649–11658PubMed
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 17:602–616PubMed
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 48:2045–2052PubMed
178.
Wenz T (2009) PGC-1alpha activation as a therapeutic approach in mitochondrial disease. IUBMB Life 61:1051–1062PubMed
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 173PubMed
180.
Winklhofer KF (2007) The parkin protein as a therapeutic target in Parkinson’s disease. Expert Opin Ther Targets 11:1543–1552PubMed
181.
Winklhofer KF, Haass C (2010) Mitochondrial dysfunction in Parkinson’s disease. Biochim Biophys Acta 1802:29–44PubMed
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 278:47199–47208PubMed
183.
Winklhofer KF, Tatzelt J, Haass C (2008) The two faces of protein misfolding: gain- and loss-of-function in neurodegenerative diseases. EMBO J 27:336–349PubMed
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 282:12310–12318PubMed
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:e2455PubMed
186.
Yamaguchi R, Perkins G (2009) Dynamics of mitochondrial structure during apoptosis and the enigma of Opa1. Biochim Biophys Acta 1787:963–972PubMed
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 103:10793–10798PubMed
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 105:7070–7075PubMed
189.
Yang Z, Klionsky DJ (2010) Eaten alive: a history of macroautophagy. Nat Cell Biol 12:814–822PubMed
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 101:10810–10814PubMed
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 286:19630–19640PubMed
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 28:14500–14510PubMed
193.
Zhou C, Huang Y, Shao Y et al (2008) The kinase domain of mitochondrial PINK1 faces the cytoplasm. Proc Natl Acad Sci USA 105:12022–12027PubMed
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 3:242–250PubMed
195.
Ziviani E, Tao RN, Whitworth AJ (2010) Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin. Proc Natl Acad Sci USA 107:5018–5023PubMed
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 36:449–451PubMed
Metadata
Title
Parkin, PINK1 and mitochondrial integrity: emerging concepts of mitochondrial dysfunction in Parkinson’s disease
Authors
Anna Pilsl
Konstanze F. Winklhofer
Publication date
01-02-2012
Publisher
Springer-Verlag
Published in
Acta Neuropathologica / Issue 2/2012
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-011-0902-3

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