Parkin Mediates Proteasome-dependent Protein Degradation and Rupture of the Outer Mitochondrial Membrane

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2011 Apr 2

PMID 21454557

Citations 326

Authors

Saori R Yoshii

Chieko Kishi

Naotada Ishihara

Noboru Mizushima

Affiliations

Soon will be listed here.

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.

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References

Suzuki H, Maeda M, Mihara K . Characterization of rat TOM70 as a receptor of the preprotein translocase of the mitochondrial outer membrane. J Cell Sci. 2002; 115(Pt 9):1895-905. DOI: 10.1242/jcs.115.9.1895. View

Abou-Sleiman P, Muqit M, Wood N . Expanding insights of mitochondrial dysfunction in Parkinson's disease. Nat Rev Neurosci. 2006; 7(3):207-19. DOI: 10.1038/nrn1868. View

Neutzner A, Benard G, Youle R, Karbowski M . Role of the ubiquitin conjugation system in the maintenance of mitochondrial homeostasis. Ann N Y Acad Sci. 2008; 1147:242-53. DOI: 10.1196/annals.1427.012. View

Dickson D, Braak H, Duda J, Duyckaerts C, Gasser T, Halliday G . Neuropathological assessment of Parkinson's disease: refining the diagnostic criteria. Lancet Neurol. 2009; 8(12):1150-7. DOI: 10.1016/S1474-4422(09)70238-8. View

Narendra D, Jin S, Tanaka A, Suen D, Gautier C, Shen J . PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 2010; 8(1):e1000298. PMC: 2811155. DOI: 10.1371/journal.pbio.1000298. View

Poole A, Thomas R, Yu S, Vincow E, Pallanck L . The mitochondrial fusion-promoting factor mitofusin is a substrate of the PINK1/parkin pathway. PLoS One. 2010; 5(4):e10054. PMC: 2850930. DOI: 10.1371/journal.pone.0010054. View

Chan N, Salazar A, Pham A, Sweredoski M, Kolawa N, Graham R . Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy. Hum Mol Genet. 2011; 20(9):1726-37. PMC: 3071670. DOI: 10.1093/hmg/ddr048. View

Tanaka A, Cleland M, Xu S, Narendra D, Suen D, Karbowski M . Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J Cell Biol. 2010; 191(7):1367-80. PMC: 3010068. DOI: 10.1083/jcb.201007013. View

Okatsu K, Saisho K, Shimanuki M, Nakada K, Shitara H, Sou Y . p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria. Genes Cells. 2010; 15(8):887-900. PMC: 2970908. DOI: 10.1111/j.1365-2443.2010.01426.x. View

10.

Tanaka A . Parkin-mediated selective mitochondrial autophagy, mitophagy: Parkin purges damaged organelles from the vital mitochondrial network. FEBS Lett. 2010; 584(7):1386-92. PMC: 2843751. DOI: 10.1016/j.febslet.2010.02.060. View

11.

Gegg M, Cooper J, Chau K, Rojo M, Schapira A, Taanman J . Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. Hum Mol Genet. 2010; 19(24):4861-70. PMC: 3583518. DOI: 10.1093/hmg/ddq419. View

12.

Newman R, Mobascher A, Mangold U, Koike C, Diah S, Schmidt M . Antizyme targets cyclin D1 for degradation. A novel mechanism for cell growth repression. J Biol Chem. 2004; 279(40):41504-11. DOI: 10.1074/jbc.M407349200. View

13.

Yonashiro R, Ishido S, Kyo S, Fukuda T, Goto E, Matsuki Y . A novel mitochondrial ubiquitin ligase plays a critical role in mitochondrial dynamics. EMBO J. 2006; 25(15):3618-26. PMC: 1538564. DOI: 10.1038/sj.emboj.7601249. View

14.

Matsuda N, Sato S, Shiba K, Okatsu K, Saisho K, Gautier C . PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol. 2010; 189(2):211-21. PMC: 2856912. DOI: 10.1083/jcb.200910140. View

15.

Murakami Y, MATSUFUJI S, Kameji T, Hayashi S, Igarashi K, Tamura T . Ornithine decarboxylase is degraded by the 26S proteasome without ubiquitination. Nature. 1992; 360(6404):597-9. DOI: 10.1038/360597a0. View

16.

Suzuki H, OKAZAWA Y, Komiya T, Saeki K, Mekada E, Kitada S . Characterization of rat TOM40, a central component of the preprotein translocase of the mitochondrial outer membrane. J Biol Chem. 2000; 275(48):37930-6. DOI: 10.1074/jbc.M006558200. View

17.

Livnat-Levanon N, Glickman M . Ubiquitin-proteasome system and mitochondria - reciprocity. Biochim Biophys Acta. 2010; 1809(2):80-7. DOI: 10.1016/j.bbagrm.2010.07.005. View

18.

Hayashi-Nishino M, Fujita N, Noda T, Yamaguchi A, Yoshimori T, Yamamoto A . A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat Cell Biol. 2009; 11(12):1433-7. DOI: 10.1038/ncb1991. View

19.

Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T . The role of autophagy during the early neonatal starvation period. Nature. 2004; 432(7020):1032-6. DOI: 10.1038/nature03029. View

20.

Yoshimori T, YAMAGATA F, Yamamoto A, Mizushima N, Kabeya Y, Nara A . The mouse SKD1, a homologue of yeast Vps4p, is required for normal endosomal trafficking and morphology in mammalian cells. Mol Biol Cell. 2000; 11(2):747-63. PMC: 14807. DOI: 10.1091/mbc.11.2.747. View