PINK1 is Selectively Stabilized on Impaired Mitochondria to Activate Parkin

Overview

Journal PLoS Biol

Specialty Biology

Date 2010 Feb 4

PMID 20126261

Citations 1494

Authors

Derek P Narendra

Seok Min Jin

Atsushi Tanaka

Der-Fen Suen

Clement A Gautier

Jie Shen

Mark R Cookson

Richard J Youle

Affiliations

Soon will be listed here.

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.

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References

Yang Y, Gehrke S, Imai Y, Huang Z, Ouyang Y, Wang J . 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(28):10793-8. PMC: 1502310. DOI: 10.1073/pnas.0602493103. View

Rossmeisl M, Barbatelli G, Flachs P, Brauner P, Zingaretti M, Marelli M . Expression of the uncoupling protein 1 from the aP2 gene promoter stimulates mitochondrial biogenesis in unilocular adipocytes in vivo. Eur J Biochem. 2002; 269(1):19-28. DOI: 10.1046/j.0014-2956.2002.02627.x. View

Schapira A . Mitochondria in the aetiology and pathogenesis of Parkinson's disease. Lancet Neurol. 2007; 7(1):97-109. DOI: 10.1016/S1474-4422(07)70327-7. View

Kundu M, Lindsten T, Yang C, Wu J, Zhao F, Zhang J . Ulk1 plays a critical role in the autophagic clearance of mitochondria and ribosomes during reticulocyte maturation. Blood. 2008; 112(4):1493-502. PMC: 2515143. DOI: 10.1182/blood-2008-02-137398. View

Palacino J, Sagi D, Goldberg M, Krauss S, Motz C, Wacker M . Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem. 2004; 279(18):18614-22. DOI: 10.1074/jbc.M401135200. View

Hristova V, Beasley S, Rylett R, Shaw G . Identification of a novel Zn2+-binding domain in the autosomal recessive juvenile Parkinson-related E3 ligase parkin. J Biol Chem. 2009; 284(22):14978-86. PMC: 2685680. DOI: 10.1074/jbc.M808700200. View

Exner N, Treske B, Paquet D, Holmstrom K, Schiesling C, Gispert S . Loss-of-function of human PINK1 results in mitochondrial pathology and can be rescued by parkin. J Neurosci. 2007; 27(45):12413-8. PMC: 6673250. DOI: 10.1523/JNEUROSCI.0719-07.2007. View

Zhou C, Huang Y, Shao Y, May J, Prou D, Perier C . The kinase domain of mitochondrial PINK1 faces the cytoplasm. Proc Natl Acad Sci U S A. 2008; 105(33):12022-7. PMC: 2575334. DOI: 10.1073/pnas.0802814105. View

Greene J, Whitworth A, Kuo I, Andrews L, Feany M, Pallanck L . Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc Natl Acad Sci U S A. 2003; 100(7):4078-83. PMC: 153051. DOI: 10.1073/pnas.0737556100. View

10.

Beilina A, van der Brug M, Ahmad R, Kesavapany S, Miller D, Petsko G . 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(16):5703-8. PMC: 556294. DOI: 10.1073/pnas.0500617102. View

11.

Yun J, Cao J, Dodson M, Clark I, Kapahi P, Chowdhury R . Loss-of-function analysis suggests that Omi/HtrA2 is not an essential component of the PINK1/PARKIN pathway in vivo. J Neurosci. 2009; 28(53):14500-10. PMC: 2718055. DOI: 10.1523/JNEUROSCI.5141-08.2008. View

12.

Rodriguez-Enriquez S, Kim I, Currin R, Lemasters J . Tracker dyes to probe mitochondrial autophagy (mitophagy) in rat hepatocytes. Autophagy. 2006; 2(1):39-46. PMC: 4007489. DOI: 10.4161/auto.2229. View

13.

Chen H, Chomyn A, Chan D . Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J Biol Chem. 2005; 280(28):26185-92. DOI: 10.1074/jbc.M503062200. View

14.

Lin W, Kang U . Characterization of PINK1 processing, stability, and subcellular localization. J Neurochem. 2008; 106(1):464-74. PMC: 3638740. DOI: 10.1111/j.1471-4159.2008.05398.x. View

15.

Bender A, Krishnan K, Morris C, Taylor G, Reeve A, Perry R . High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet. 2006; 38(5):515-7. DOI: 10.1038/ng1769. View

16.

Budd S, Nicholls D . A reevaluation of the role of mitochondria in neuronal Ca2+ homeostasis. J Neurochem. 1996; 66(1):403-11. DOI: 10.1046/j.1471-4159.1996.66010403.x. View

17.

Weihofen A, Thomas K, Ostaszewski B, Cookson M, Selkoe D . Pink1 forms a multiprotein complex with Miro and Milton, linking Pink1 function to mitochondrial trafficking. Biochemistry. 2009; 48(9):2045-52. PMC: 2693257. DOI: 10.1021/bi8019178. View

18.

Griparic L, Kanazawa T, van der Bliek A . Regulation of the mitochondrial dynamin-like protein Opa1 by proteolytic cleavage. J Cell Biol. 2007; 178(5):757-64. PMC: 2064541. DOI: 10.1083/jcb.200704112. View

19.

Whitworth A, Theodore D, Greene J, Benes H, Wes P, Pallanck L . 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(22):8024-9. PMC: 1142368. DOI: 10.1073/pnas.0501078102. View

20.

Whitworth A, Lee J, Ho V, Flick R, Chowdhury R, McQuibban G . Rhomboid-7 and HtrA2/Omi act in a common pathway with the Parkinson's disease factors Pink1 and Parkin. Dis Model Mech. 2008; 1(2-3):168-74. PMC: 2562193. DOI: 10.1242/dmm.000109. View