The three ‘P’s of mitophagy: PARKIN, PINK1, and post-translational modifications
Identifieur interne : 000104 ( Pmc/Corpus ); précédent : 000103; suivant : 000105The three ‘P’s of mitophagy: PARKIN, PINK1, and post-translational modifications
Auteurs : Thomas M. Durcan ; Edward A. FonSource :
- Genes & Development [ 0890-9369 ] ; 2015.
Abstract
In this review, Durcan and Fon discuss how post-translational modifications are at the heart of how PARKIN and PINK1 function in mitochondrial quality control. They also ask how our current understanding of these proteins may impact the development of future therapies for Parkinson's disease.
Url:
DOI: 10.1101/gad.262758.115
PubMed: 25995186
PubMed Central: 4441056
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PMC:4441056Le document en format XML
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<series><title level="j">Genes & Development</title>
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<front><div type="abstract" xml:lang="en"><p>In this review, Durcan and Fon discuss how post-translational modifications are at the heart of how PARKIN and PINK1 function in mitochondrial quality control. They also ask how our current understanding of these proteins may impact the development of future therapies for Parkinson's disease.</p>
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<pmc article-type="review-article"><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">Genes Dev</journal-id>
<journal-id journal-id-type="iso-abbrev">Genes Dev</journal-id>
<journal-id journal-id-type="hwp">genesdev</journal-id>
<journal-id journal-id-type="pmc">genesdev</journal-id>
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<journal-title-group><journal-title>Genes & Development</journal-title>
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<issn pub-type="ppub">0890-9369</issn>
<issn pub-type="epub">1549-5477</issn>
<publisher><publisher-name>Cold Spring Harbor Laboratory Press</publisher-name>
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<article-id pub-id-type="medline">8711660</article-id>
<article-id pub-id-type="doi">10.1101/gad.262758.115</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Review</subject>
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<title-group><article-title>The three ‘P’s of mitophagy: PARKIN, PINK1, and post-translational modifications</article-title>
<alt-title alt-title-type="left-running">Durcan and Fon</alt-title>
<alt-title alt-title-type="right-running">Post-translational regulation of PARKIN and PINK1</alt-title>
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<contrib-group><contrib contrib-type="author"><name><surname>Durcan</surname>
<given-names>Thomas M.</given-names>
</name>
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<contrib contrib-type="author" corresp="yes"><name><surname>Fon</surname>
<given-names>Edward A.</given-names>
</name>
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<aff>McGill Parkinson's Program, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada</aff>
<author-notes><corresp>Corresponding author: <email>ted.fon@mcgill.ca</email>
</corresp>
</author-notes>
<pub-date pub-type="ppub"><day>15</day>
<month>5</month>
<year>2015</year>
</pub-date>
<volume>29</volume>
<issue>10</issue>
<fpage>989</fpage>
<lpage>999</lpage>
<permissions><copyright-statement><ext-link ext-link-type="uri" xlink:href="http://genesdev.cshlp.org/site/misc/terms.xhtml">© 2015 Durcan and Fon; Published by Cold Spring Harbor Laboratory Press</ext-link>
</copyright-statement>
<copyright-year>2015</copyright-year>
<license license-type="creative-commons" xlink:href="http://creativecommons.org/licenses/by-nc/4.0/"><license-p>This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see <ext-link ext-link-type="uri" xlink:href="http://genesdev.cshlp.org/site/misc/terms.xhtml">http://genesdev.cshlp.org/site/misc/terms.xhtml</ext-link>
). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/4.0/">http://creativecommons.org/licenses/by-nc/4.0/</ext-link>
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<abstract abstract-type="precis"><p>In this review, Durcan and Fon discuss how post-translational modifications are at the heart of how PARKIN and PINK1 function in mitochondrial quality control. They also ask how our current understanding of these proteins may impact the development of future therapies for Parkinson's disease.</p>
</abstract>
<abstract><p>Two Parkinson's disease (PD)-associated proteins, the mitochondrial kinase PINK1 and the E3-ubiquitin (Ub) ligase PARKIN, are central to mitochondrial quality control. In this pathway, PINK1 accumulates on defective mitochondria, eliciting the translocation of PARKIN from the cytosol to mediate the clearance of damaged mitochondria via autophagy (mitophagy). Throughout the different stages of mitophagy, post-translational modifications (PTMs) are critical for the regulation of PINK1 and PARKIN activity and function. Indeed, activation and recruitment of PARKIN onto damaged mitochondria involves PINK1-mediated phosphorylation of both PARKIN and Ub. Through a stepwise cascade, PARKIN is converted from an autoinhibited enzyme into an active phospho-Ub-dependent E3 ligase. Upon activation, PARKIN ubiquitinates itself in concert with many different mitochondrial substrates. The Ub conjugates attached to these substrates can in turn be phosphorylated by PINK1, which triggers further cycles of PARKIN recruitment and activation. This feed-forward amplification loop regulates both PARKIN activity and mitophagy. However, the precise steps and sequence of PTMs in this cascade are only now being uncovered. For instance, the Ub conjugates assembled by PARKIN consist predominantly of noncanonical K6-linked Ub chains. Moreover, these modifications are reversible and can be disassembled by deubiquitinating enzymes (DUBs), including Ub-specific protease 8 (USP8), USP15, and USP30. However, PINK1-mediated phosphorylation of Ub can impede the activity of these DUBs, adding a new layer of complexity to the regulation of PARKIN-mediated mitophagy by PTMs. It is therefore evident that further insight into how PTMs regulate the PINK1–PARKIN pathway will be critical for our understanding of mitochondrial quality control.</p>
</abstract>
<kwd-group><kwd>PARKIN</kwd>
<kwd>ubiquitin</kwd>
<kwd>deubiquitination</kwd>
<kwd>mitophagy</kwd>
<kwd>PINK1</kwd>
<kwd>phosphorylation</kwd>
</kwd-group>
<funding-group><award-group id="funding-1"><funding-source>Canadian Institutes of Health Research <named-content content-type="funder-id">http://dx.doi.org/10.13039/501100000024</named-content>
</funding-source>
</award-group>
<award-group id="funding-2"><funding-source>Fonds de Recherche du Québec-Santé <named-content content-type="funder-id">http://dx.doi.org/10.13039/501100000156</named-content>
</funding-source>
</award-group>
<award-group id="funding-3"><funding-source>Parkinson's Society of Canada <named-content content-type="funder-id">http://dx.doi.org/10.13039/501100000263</named-content>
</funding-source>
</award-group>
</funding-group>
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