Deubiquitinating enzymes regulate PARK2-mediated mitophagy
Identifieur interne : 000019 ( Pmc/Corpus ); précédent : 000018; suivant : 000020Deubiquitinating enzymes regulate PARK2-mediated mitophagy
Auteurs : Yuqing Wang ; Mauro Serricchio ; Miluska Jauregui ; Riya Shanbhag ; Tasha Stoltz ; Caitlin T. Di Paolo ; Peter K. Kim ; G Angus McquibbanSource :
- Autophagy [ 1554-8627 ] ; 2015.
Abstract
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.
Url:
DOI: 10.1080/15548627.2015.1034408
PubMed: 25915564
PubMed Central: 4502823
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PMC:4502823Le document en format XML
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<front><div type="abstract" xml:lang="en"><p>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.</p>
</div>
</front>
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<pmc article-type="brief-report"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Autophagy</journal-id>
<journal-id journal-id-type="iso-abbrev">Autophagy</journal-id>
<journal-id journal-id-type="pmc">KAUP</journal-id>
<journal-title-group><journal-title>Autophagy</journal-title>
</journal-title-group>
<issn pub-type="ppub">1554-8627</issn>
<issn pub-type="epub">1554-8635</issn>
<publisher><publisher-name>Taylor & Francis</publisher-name>
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<article-meta><article-id pub-id-type="pmid">25915564</article-id>
<article-id pub-id-type="pmc">4502823</article-id>
<article-id pub-id-type="publisher-id">1034408</article-id>
<article-id pub-id-type="doi">10.1080/15548627.2015.1034408</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Basic Brief Report</subject>
</subj-group>
</article-categories>
<title-group><article-title>Deubiquitinating enzymes regulate PARK2-mediated mitophagy</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Wang</surname>
<given-names>Yuqing</given-names>
</name>
<xref ref-type="aff" rid="af0001"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="af0002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Serricchio</surname>
<given-names>Mauro</given-names>
</name>
<xref ref-type="aff" rid="af0002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Jauregui</surname>
<given-names>Miluska</given-names>
</name>
<xref ref-type="aff" rid="af0001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Shanbhag</surname>
<given-names>Riya</given-names>
</name>
<xref ref-type="aff" rid="af0002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Stoltz</surname>
<given-names>Tasha</given-names>
</name>
<xref ref-type="aff" rid="af0001"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="af0002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Di Paolo</surname>
<given-names>Caitlin T</given-names>
</name>
<xref ref-type="aff" rid="af0001"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="af0002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kim</surname>
<given-names>Peter K</given-names>
</name>
<xref ref-type="aff" rid="af0001"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="af0002"><sup>2</sup>
</xref>
<xref ref-type="corresp" rid="an0001"><sup>*</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>McQuibban</surname>
<given-names>G Angus</given-names>
</name>
<xref ref-type="aff" rid="af0002"><sup>2</sup>
</xref>
<xref ref-type="corresp" rid="an0001"><sup>*</sup>
</xref>
</contrib>
<aff id="af0001"><label>1</label>
<institution>Cell Biology Program; The Hospital for Sick Children</institution>
; Toronto, ON<country>Canada</country>
</aff>
<aff id="af0002"><label>2</label>
<institution>Department of Biochemistry; University of Toronto</institution>
; Toronto, ON<country>Canada</country>
</aff>
</contrib-group>
<author-notes><corresp id="an0001"><label>*</label>
Correspondence to: Peter K Kim; Email: <email xlink:href="pkim@sickkids.ca">pkim@sickkids.ca</email>
; G Angus McQuibban; Email: <email xlink:href="angus.mcquibban@utoronto.ca">angus.mcquibban@utoronto.ca</email>
</corresp>
</author-notes>
<pub-date pub-type="epub"><day>27</day>
<month>4</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="collection"><month>4</month>
<year>2015</year>
</pub-date>
<volume>11</volume>
<issue>4</issue>
<fpage seq="3">595</fpage>
<lpage>606</lpage>
<history><date date-type="received"><day>10</day>
<month>6</month>
<year>2014</year>
</date>
<date date-type="rev-recd"><day>20</day>
<month>2</month>
<year>2015</year>
</date>
<date date-type="accepted"><day>26</day>
<month>2</month>
<year>2015</year>
</date>
</history>
<permissions><copyright-statement>© Taylor & Francis Group, LLC</copyright-statement>
<copyright-year>2015</copyright-year>
<copyright-holder>Taylor & Francis Group, LLC</copyright-holder>
</permissions>
<self-uri content-type="pdf" xlink:href="kaup-11-04-1034408.pdf"></self-uri>
<abstract><p>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.</p>
</abstract>
<kwd-group kwd-group-type="author"><title>Keywords</title>
<kwd>autophagy</kwd>
<kwd>deubiquitinating enzymes</kwd>
<kwd>mitochondrial dynamics</kwd>
<kwd>mitophagy</kwd>
<kwd>neurodegenerative diseases</kwd>
<kwd>PARK2</kwd>
<kwd>ubiquitin</kwd>
<kwd>USP30</kwd>
<kwd>USP35</kwd>
</kwd-group>
<counts><fig-count count="4"></fig-count>
<table-count count="0"></table-count>
<ref-count count="33"></ref-count>
<page-count count="12"></page-count>
</counts>
</article-meta>
</front>
</pmc>
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