Wang, Yuqing; Serricchio, Mauro; Jauregui, Miluska; Shanbhag, Riya; Stoltz, Tasha; Di Paolo, Caitlin T; Kim, Peter K; McQuibban, G Angus (2015). Deubiquitinating enzymes regulate PARK2-mediated mitophagy. Autophagy, 11(4), pp. 595-606. Taylor & Francis 10.1080/15548627.2015.1034408
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The selective degradation of mitochondria by the process of autophagy, termed mitophagy, is one of the major mechanisms of mitochondrial quality control. The best-studied mitophagy pathway is the one mediated by PINK1 and PARK2/Parkin. From recent studies it has become clear that ubiquitin-ligation plays a pivotal role and most of the focus has been on the role of ubiquitination of mitochondrial proteins in mitophagy. Even though ubiquitination is a reversible process, very little is known about the role of deubiquitinating enzymes (DUBs) in mitophagy. Here, we report that 2 mitochondrial DUBs, USP30 and USP35, regulate PARK2-mediated mitophagy. We show that USP30 and USP35 can delay PARK2-mediated mitophagy using a quantitative mitophagy assay. Furthermore, we show that USP30 delays mitophagy by delaying PARK2 recruitment to the mitochondria during mitophagy. USP35 does not delay PARK2 recruitment, suggesting that it regulates mitophagy through an alternative mechanism. Interestingly, USP35 only associates with polarized mitochondria, and rapidly translocates to the cytosol during CCCP-induced mitophagy. It is clear that PARK2-mediated mitophagy is regulated at many steps in this important quality control pathway. Taken together, these findings demonstrate an important role of mitochondrial-associated DUBs in mitophagy. Because defects in mitochondria quality control are implicated in many neurodegenerative disorders, our study provides clear rationales for the design and development of drugs for the therapeutic treatment of neurodegenerative diseases such as Parkinson and Alzheimer diseases.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine |
UniBE Contributor: |
Serricchio, Mauro |
Subjects: |
500 Science > 570 Life sciences; biology 600 Technology > 610 Medicine & health |
ISSN: |
1554-8627 |
Publisher: |
Taylor & Francis |
Projects: |
[UNSPECIFIED] PBBEP3_146277 |
Language: |
English |
Submitter: |
Mauro Serricchio |
Date Deposited: |
18 Nov 2019 12:49 |
Last Modified: |
05 Dec 2022 15:32 |
Publisher DOI: |
10.1080/15548627.2015.1034408 |
PubMed ID: |
25915564 |
Uncontrolled Keywords: |
CCCP Cer, cerulean DMSO, dimethyl sulfoxide DUB DsRed, Discosoma sp. red fluorescent protein GAPDH, glyceraldehyde 3-phosphate dehydrogenase GFP, green fluorescent protein HA, human influenza hemagglutinin MFN2, mitofusin 2 MTS OMM, outer mitochondrial membrane PARK2 PARK2, parkin RBR E3 ubiquitin protein ligase PINK1, PTEN-induced putative kinase 1 SYNJ2BP, synaptojanin 2 binding protein TOMM20, translocase of outer mitochondrial membrane 20 homolog (yeast) USP, ubiquitin specific peptidase USP30 USP35 autophagy carbonyl cyanide m-chlorophenylhydrazone deubiquitinating enzyme deubiquitinating enzymes l-USP35, long form of ubiquitin specific peptidase 35 mitochondrial dynamics mitochondrial targeting sequence mitophagy neurodegenerative diseases s-USP35, short form of ubiquitin specific peptidase 35 ubiquitin |
BORIS DOI: |
10.7892/boris.135039 |
URI: |
https://boris.unibe.ch/id/eprint/135039 |
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