Parkin Mediates Proteasome-dependent Protein Degradation and Rupture of the Outer Mitochondrial Membrane*♦
- From the ‡Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo 113-8519 and
- the §Department of Protein Biochemistry, Institute of Life Science, Kurume University, Kurume 839-0864, Japan
- ↵2 To whom correspondence should be addressed: Dept. of Physiology and Cell Biology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. Tel.: 81-3-5803-5158; Fax: 81-3-5803-0118; E-mail: nmizu.phy2{at}tmd.ac.jp.
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↵1 Both authors contributed equally to this work.
Abstract
Upon mitochondrial depolarization, Parkin, a Parkinson disease-related E3 ubiquitin ligase, translocates from the cytosol to mitochondria and promotes their degradation by mitophagy, a selective type of autophagy. Here, we report that in addition to mitophagy, Parkin mediates proteasome-dependent degradation of outer membrane proteins such as Tom20, Tom40, Tom70, and Omp25 of depolarized mitochondria. By contrast, degradation of the inner membrane and matrix proteins largely depends on mitophagy. Furthermore, Parkin induces rupture of the outer membrane of depolarized mitochondria, which also depends on proteasomal activity. Upon induction of mitochondrial depolarization, proteasomes are recruited to mitochondria in the perinuclear region. Neither proteasome-dependent degradation of outer membrane proteins nor outer membrane rupture is required for mitophagy. These results suggest that Parkin regulates degradation of outer and inner mitochondrial membrane proteins differently through proteasome- and mitophagy-dependent pathways.
Footnotes
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↵* This work was supported in part by grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (to N. I. and N. M.), the Takeda Science Foundation (to N. M.), and the Funding Program for Next Generation World-Leading Researchers (to N. I. and N. M.).
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↵♦ This article was selected as a Paper of the Week.
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The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.
- Received December 6, 2010.
- Revision received March 15, 2011.
- © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.
