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PNAS 107 (1): 378-383

Copyright © 2010 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / NEUROSCIENCE

PINK1-dependent recruitment of Parkin to mitochondria in mitophagy

Cristofol Vives-Bauzaa,1, Chun Zhoua,1, Yong Huanga,1, Mei Cuib, Rosa L.A. de Vriesa, Jiho Kimc, Jessica Maya, Maja Aleksandra Tocilescua, Wencheng Liud, Han Seok Koe,f, Jordi Magranéd, Darren J. Mooree,f,2, Valina L. Dawsone,f,g,h, Regis Grailhec, Ted M. Dawsone,f,h, Chenjian Lid, Kim Tieub, and Serge Przedborskia,i,j,3

Departments of aNeurology and iPathology and Cell Biology and the jCenter for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032; bDepartment of Neurology, Center for Translational Medicine, University of Rochester, Rochester, NY 14642; c Institut Pasteur Korea, Gyeonggi-do 463-400, Republic of Korea; dDepartment of Neurology and Neurosciences, Weill Medical College of Cornell University, New York, NY 10065; eNeuroRegeneration and Stem Cell Programs, Institute for Cell Engineering, Departments of fNeurology and gPhysiology, and the hSolomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205

Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved November 9, 2009 (received for review September 29, 2009)

Abstract: Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and PARK2/Parkin mutations cause autosomal recessive forms of Parkinson's disease. Upon a loss of mitochondrial membrane potential ({Delta}{Psi}m) in human cells, cytosolic Parkin has been reported to be recruited to mitochondria, which is followed by a stimulation of mitochondrial autophagy. Here, we show that the relocation of Parkin to mitochondria induced by a collapse of {Delta}{Psi}m relies on PINK1 expression and that overexpression of WT but not of mutated PINK1 causes Parkin translocation to mitochondria, even in cells with normal {Delta}{Psi}m. We also show that once at the mitochondria, Parkin is in close proximity to PINK1, but we find no evidence that Parkin catalyzes PINK1 ubiquitination or that PINK1 phosphorylates Parkin. However, co-overexpression of Parkin and PINK1 collapses the normal tubular mitochondrial network into mitochondrial aggregates and/or large perinuclear clusters, many of which are surrounded by autophagic vacuoles. Our results suggest that Parkin, together with PINK1, modulates mitochondrial trafficking, especially to the perinuclear region, a subcellular area associated with autophagy. Thus by impairing this process, mutations in either Parkin or PINK1 may alter mitochondrial turnover which, in turn, may cause the accumulation of defective mitochondria and, ultimately, neurodegeneration in Parkinson's disease.

Key Words: autophagy • Parkinson's disease • phosphatase and tensin homolog-induced putative kinase 1

Author contributions: C.V.-B., C.Z., Y.H., and S.P. designed research; C.V.-B., C.Z., Y.H., M.C., R.L.A.d.V., J.K., J. May, M.A.T., W.L., H.S.K., J. Magrané, and R.G. performed research; D.J.M., V.L.D., T.M.D., C.L., and K.T. contributed new reagents/analytic tools; C.V.-B., C.Z., Y.H., and S.P. analyzed data; and C.V.-B., C.Z., Y.H., and S.P. wrote the paper.

1C.V.-B., C.Z., and Y.H. contributed equally to this work.

2Present address: Laboratory of Molecular Neurodegenerative Research, Brain Mind Institute, Ecole Polytechnique Federale de Lausanne, Lausanne, CH 1015, Switzerland.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0911187107/DCSupplemental.

3To whom correspondence should be addressed at: BB–302, Columbia University, 650 West 168th Street, New York, NY 10032. E–mail: SP30{at}Columbia.edu.

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Perturbations in Mitochondrial Dynamics Induced by Human Mutant PINK1 Can Be Rescued by the Mitochondrial Division Inhibitor mdivi-1.
M. Cui, X. Tang, W. V. Christian, Y. Yoon, and K. Tieu (2010)
J. Biol. Chem. 285, 11740-11752
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Drosophila Parkin requires PINK1 for mitochondrial translocation and ubiquitinates Mitofusin.
E. Ziviani, R. N. Tao, and A. J. Whitworth (2010)
PNAS 107, 5018-5023
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