PINK1 is selectively stabilized on impaired mitochondria to activate Parkin
Derek P Narendra, Seok Min Jin, Atsushi Tanaka, Der-Fen Suen, Clement A Gautier, Jie Shen, Mark R Cookson, Richard J Youle, Derek P Narendra, Seok Min Jin, Atsushi Tanaka, Der-Fen Suen, Clement A Gautier, Jie Shen, Mark R Cookson, Richard J Youle
Abstract
Loss-of-function mutations in PINK1 and Parkin cause parkinsonism in humans and mitochondrial dysfunction in model organisms. Parkin is selectively recruited from the cytosol to damaged mitochondria to trigger their autophagy. How Parkin recognizes damaged mitochondria, however, is unknown. Here, we show that expression of PINK1 on individual mitochondria is regulated by voltage-dependent proteolysis to maintain low levels of PINK1 on healthy, polarized mitochondria, while facilitating the rapid accumulation of PINK1 on mitochondria that sustain damage. PINK1 accumulation on mitochondria is both necessary and sufficient for Parkin recruitment to mitochondria, and disease-causing mutations in PINK1 and Parkin disrupt Parkin recruitment and Parkin-induced mitophagy at distinct steps. These findings provide a biochemical explanation for the genetic epistasis between PINK1 and Parkin in Drosophila melanogaster. In addition, they support a novel model for the negative selection of damaged mitochondria, in which PINK1 signals mitochondrial dysfunction to Parkin, and Parkin promotes their elimination.
Conflict of interest statement
The authors have declared that no competing interests exist.
Figures
References
- Schapira A. H. Molecular and clinical pathways to neuroprotection of dopaminergic drugs in Parkinson disease. Neurology. 2009;72:S44–50.
- Soong N. W, Hinton D. R, Cortopassi G, Arnheim N. Mosaicism for a specific somatic mitochondrial DNA mutation in adult human brain. Nat Genet. 1992;2:318–323.
- Schapira A. H. Mitochondria in the aetiology and pathogenesis of Parkinson's disease. Lancet Neurol. 2008;7:97–109.
- Bender A, Krishnan K. J, Morris C. M, Taylor G. A, Reeve A. K, et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet. 2006;38:515–517.
- Kraytsberg Y, Kudryavtseva E, McKee A. C, Geula C, Kowall N. W, et al. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat Genet. 2006;38:518–520.
- Baloh R. H, Salavaggione E, Milbrandt J, Pestronk A. Familial parkinsonism and ophthalmoplegia from a mutation in the mitochondrial DNA helicase twinkle. Arch Neurol. 2007;64:998–1000.
- Luoma P, Melberg A, Rinne J. O, Kaukonen J. A, Nupponen N. N, et al. Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study. Lancet. 2004;364:875–882.
- Ekstrand M. I, Terzioglu M, Galter D, Zhu S, Hofstetter C, et al. Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proc Natl Acad Sci U S A. 2007;104:1325–1330.
- Langston J. W, Ballard P, Tetrud J. W, Irwin I. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science. 1983;219:979–980.
- Betarbet R, Sherer T. B, MacKenzie G, Garcia-Osuna M, Panov A. V, et al. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci. 2000;3:1301–1306.
- Yang Y, Gehrke S, Imai Y, Huang Z, Ouyang Y, et al. 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. 2006;103:10793–10798.
- Clark I. E, Dodson M. W, Jiang C, Cao J. H, Huh J. R, et al. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature. 2006;441:1162–1166.
- Park J, Lee S. B, Lee S, Kim Y, Song S, et al. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature. 2006;441:1157–1161.
- Greene J. C, Whitworth A. J, Kuo I, Andrews L. A, Feany M. B, et al. Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc Natl Acad Sci U S A. 2003;100:4078–4083.
- Whitworth A. J, Theodore D. A, Greene J. C, Benes H, Wes P. D, et al. Increased glutathione S-transferase activity rescues dopaminergic neuron loss in a Drosophila model of Parkinson's disease. Proc Natl Acad Sci U S A. 2005;102:8024–8029.
- Gautier C. A, Kitada T, Shen J. Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress. Proc Natl Acad Sci U S A. 2008;105:11364–11369.
- Palacino J. J, Sagi D, Goldberg M. S, Krauss S, Motz C, et al. Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem. 2004;279:18614–18622.
- Mortiboys H, Thomas K. J, Koopman W. J, Klaffke S, Abou-Sleiman P, et al. Mitochondrial function and morphology are impaired in parkin-mutant fibroblasts. Ann Neurol. 2008;64:555–565.
- Muftuoglu M, Elibol B, Dalmizrak O, Ercan A, Kulaksiz G, et al. Mitochondrial complex I and IV activities in leukocytes from patients with parkin mutations. Mov Disord. 2004;19:544–548.
- Exner N, Treske B, Paquet D, Holmstrom K, Schiesling C, et al. Loss-of-function of human PINK1 results in mitochondrial pathology and can be rescued by parkin. J Neurosci. 2007;27:12413–12418.
- Narendra D, Tanaka A, Suen D. F, Youle R. J. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol. 2008;183:795–803.
- Zhou C, Huang Y, Shao Y, May J, Prou D, et al. The kinase domain of mitochondrial PINK1 faces the cytoplasm. Proc Natl Acad Sci U S A. 2008;105:12022–12027.
- Eguchi Y, Shimizu S, Tsujimoto Y. Intracellular ATP levels determine cell death fate by apoptosis or necrosis. Cancer Res. 1997;57:1835–1840.
- Budd S. L, Nicholls D. G. A reevaluation of the role of mitochondria in neuronal Ca2+ homeostasis. J Neurochem. 1996;66:403–411.
- Chen H, Chomyn A, Chan D. C. Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J Biol Chem. 2005;280:26185–26192.
- Cocheme H. M, Murphy M. P. Complex I is the major site of mitochondrial superoxide production by paraquat. J Biol Chem. 2008;283:1786–1798.
- Kim Y, Park J, Kim S, Song S, Kwon S. K, et al. PINK1 controls mitochondrial localization of Parkin through direct phosphorylation. Biochem Biophys Res Commun. 2008;377:975–980.
- Beilina A, Van Der Brug M, Ahmad R, Kesavapany S, Miller D. W, et al. Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability. Proc Natl Acad Sci U S A. 2005;102:5703–5708.
- Xiong H, Wang D, Chen L, Choo Y. S, Ma H, et al. Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein degradation. J Clin Invest. 2009;119:650–660.
- Lin W, Kang U. J. Characterization of PINK1 processing, stability, and subcellular localization. J Neurochem. 2008;106:464–474.
- Whitworth A. J, Lee J. R, Ho V. M, Flick R, Chowdhury R, et al. Rhomboid-7 and HtrA2/Omi act in a common pathway with the Parkinson's disease factors Pink1 and Parkin. Dis Model Mech. 2008;1:168–174; discussion 173.
- Dagda R. K, Cherra S. J, 3rd, Kulich S. M, Tandon A, Park D, et al. Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J Biol Chem. 2009;284:13843–13855.
- Weihofen A, Thomas K. J, Ostaszewski B. L, Cookson M. R, Selkoe D. J. Pink1 Forms a Multiprotein Complex with Miro and Milton, Linking Pink1 Function to Mitochondrial Trafficking (dagger). Biochemistry. 2009;48:2045–2052.
- Sandebring A, Thomas K. J, Beilina A, van der Brug M, Cleland M. M, et al. Mitochondrial alterations in PINK1 deficient cells are influenced by calcineurin-dependent dephosphorylation of dynamin-related protein 1. PLoS One. 2009;4:e5701. doi: .
- Rodriguez-Enriquez S, Kim I, Currin R. T, Lemasters J. J. Tracker dyes to probe mitochondrial autophagy (mitophagy) in rat hepatocytes. Autophagy. 2006;2:39–46.
- Kundu M, Lindsten T, Yang C. Y, Wu J, Zhao F, et al. Ulk1 plays a critical role in the autophagic clearance of mitochondria and ribosomes during reticulocyte maturation. Blood. 2008;112:1493–1502.
- Li B, Holloszy J. O, Semenkovich C. F. Respiratory uncoupling induces delta-aminolevulinate synthase expression through a nuclear respiratory factor-1-dependent mechanism in HeLa cells. J Biol Chem. 1999;274:17534–17540.
- Rossmeisl M, Barbatelli G, Flachs P, Brauner P, Zingaretti M. C, et al. Expression of the uncoupling protein 1 from the aP2 gene promoter stimulates mitochondrial biogenesis in unilocular adipocytes in vivo. Eur J Biochem. 2002;269:19–28.
- Haque M. E, Thomas K. J, D'Souza C, Callaghan S, Kitada T, et al. Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP. Proc Natl Acad Sci U S A. 2008;105:1716–1721.
- Belshaw P. J, Ho S. N, Crabtree G. R, Schreiber S. L. Controlling protein association and subcellular localization with a synthetic ligand that induces heterodimerization of proteins. Proc Natl Acad Sci U S A. 1996;93:4604–4607.
- Hristova V. A, Beasley S. A, Rylett R. J, Shaw G. S. Identification of a novel Zn2+-binding domain in the autosomal recessive juvenile parkinson's related E3 ligase parkin. J Biol Chem. 2009;284:14978–14986.
- Abou-Sleiman P. M, Muqit M. M, McDonald N. Q, Yang Y. X, Gandhi S, et al. A heterozygous effect for PINK1 mutations in Parkinson's disease? Ann Neurol. 2006;60:414–419.
- Eisenhaber B, Chumak N, Eisenhaber F, Hauser M. T. The ring between ring fingers (RBR) protein family. Genome Biol. 2007;8:209.
- Beasley S. A, Hristova V. A, Shaw G. S. Structure of the Parkin in-between-ring domain provides insights for E3-ligase dysfunction in autosomal recessive Parkinson's disease. Proc Natl Acad Sci U S A. 2007;104:3095–3100.
- Capili A. D, Edghill E. L, Wu K, Borden K. L. Structure of the C-terminal RING finger from a RING-IBR-RING/TRIAD motif reveals a novel zinc-binding domain distinct from a RING. J Mol Biol. 2004;340:1117–1129.
- Fallon L, Belanger C. M, Corera A. T, Kontogiannea M, Regan-Klapisz E, et al. A regulated interaction with the UIM protein Eps15 implicates parkin in EGF receptor trafficking and PI(3)K-Akt signalling. Nat Cell Biol. 2006;8:834–842.
- Hurley J. H, Lee S, Prag G. Ubiquitin-binding domains. Biochem J. 2006;399:361–372.
- Griparic L, Kanazawa T, van der Bliek A. M. Regulation of the mitochondrial dynamin-like protein Opa1 by proteolytic cleavage. J Cell Biol. 2007;178:757–764.
- Safadi S. S, Shaw G. S. A disease state mutation unfolds the parkin ubiquitin-like domain. Biochemistry. 2007;46:14162–14169.
- Abbas N, Lucking C. B, Ricard S, Durr A, Bonifati V, et al. 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. 1999;8:567–574.
- Gandhi S, Wood-Kaczmar A, Yao Z, Plun-Favreau H, Deas E, et al. PINK1-associated Parkinson's disease is caused by neuronal vulnerability to calcium-induced cell death. Mol Cell. 2009;33:627–638.
- Yun J, Cao J. H, Dodson M. W, Clark I. E, Kapahi P, et al. Loss-of-function analysis suggests that Omi/HtrA2 is not an essential component of the PINK1/PARKIN pathway in vivo. J Neurosci. 2008;28:14500–14510.
- Tain L. S, Chowdhury R. B, Tao R. N, Plun-Favreau H, Moisoi N, et al. Drosophila HtrA2 is dispensable for apoptosis but acts downstream of PINK1 independently from Parkin. Cell Death Differ. 2009;16:1118–1125.
- Kanki T, Wang K, Cao Y, Baba M, Klionsky D. J. Atg32 is a mitochondrial protein that confers selectivity during mitophagy. Dev Cell. 2009;17:98–109.
- Okamoto K, Kondo-Okamoto N, Ohsumi Y. Mitochondria-anchored receptor Atg32 mediates degradation of mitochondria via selective autophagy. Dev Cell. 2009;17:87–97.
- Chan C. S, Guzman J. N, Ilijic E, Mercer J. N, Rick C, et al. ‘Rejuvenation’ protects neurons in mouse models of Parkinson's disease. Nature. 2007;447:1081–1086.
- Kitada T, Pisani A, Porter D. R, Yamaguchi H, Tscherter A, et al. Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proc Natl Acad Sci U S A. 2007;104:11441–11446.
- Cipolat S, Rudka T, Hartmann D, Costa V, Serneels L, et al. Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling. Cell. 2006;126:163–175.
Source: PubMed