Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy
Identifieur interne : 001277 ( Main/Corpus ); précédent : 001276; suivant : 001278Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy
Auteurs : Matthew E. Gegg ; J. Mark Cooper ; Kai-Yin Chau ; Manuel Rojo ; Anthony H. V. Schapira ; Jan-Willem TaanmanSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2010-12-15.
Abstract
Mitochondrial dysfunction and perturbed degradation of proteins have been implicated in Parkinson's disease (PD) pathogenesis. Mutations in the Parkin and PINK1 genes are a cause of familial PD. PINK1 is a putative kinase associated with mitochondria, and loss of PINK1 expression leads to mitochondrial dysfunction, which increases with time. Parkin is suggested to be downstream of PINK1 and also mediates the removal of damaged mitochondria by macroautophagy (mitophagy). We investigated whether mitochondrial dysfunction in dopaminergic SH-SY5Y cells following decreased PINK1 expression by RNAi may in part be due to the inhibition of mitophagy. Reduced flux through the macroautophagy pathway was found to be coincident with the inhibition of ATP synthesis following 12 days of PINK1 silencing. Overexpression of parkin in these cells restored both autophagic flux and ATP synthesis. Overexpression and RNAi studies also indicated that PINK1 and parkin were required for mitophagy following CCCP-induced mitochondrial damage. The ubiquitination of several mitochondrial proteins, including mitofusin 1 and mitofusin 2, were detected within 3 h of CCCP treatment. These post-translational modifications were reduced following the silencing of parkin or PINK1. The ubiquitination of mitochondrial proteins appears to identify mitochondria for degradation and facilitate mitophagy. PINK1 and parkin are thus required for the removal of damaged mitochondria in dopaminergic cells, and inhibition of this pathway may lead to the accumulation of defective mitochondria which may contribute to PD pathogenesis.
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DOI: 10.1093/hmg/ddq419
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Mutations in the Parkin and PINK1 genes are a cause of familial PD. PINK1 is a putative kinase associated with mitochondria, and loss of PINK1 expression leads to mitochondrial dysfunction, which increases with time. Parkin is suggested to be downstream of PINK1 and also mediates the removal of damaged mitochondria by macroautophagy (mitophagy). We investigated whether mitochondrial dysfunction in dopaminergic SH-SY5Y cells following decreased PINK1 expression by RNAi may in part be due to the inhibition of mitophagy. Reduced flux through the macroautophagy pathway was found to be coincident with the inhibition of ATP synthesis following 12 days of PINK1 silencing. Overexpression of parkin in these cells restored both autophagic flux and ATP synthesis. Overexpression and RNAi studies also indicated that PINK1 and parkin were required for mitophagy following CCCP-induced mitochondrial damage. The ubiquitination of several mitochondrial proteins, including mitofusin 1 and mitofusin 2, were detected within 3 h of CCCP treatment. These post-translational modifications were reduced following the silencing of parkin or PINK1. The ubiquitination of mitochondrial proteins appears to identify mitochondria for degradation and facilitate mitophagy. PINK1 and parkin are thus required for the removal of damaged mitochondria in dopaminergic cells, and inhibition of this pathway may lead to the accumulation of defective mitochondria which may contribute to PD pathogenesis.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Matthew E. Gegg</name><affiliations><json:string>Department of Clinical Neurosciences, Institute of Neurology, University College London, London, UK and</json:string><json:string>E-mail: m.gegg@medsch.ucl.ac.uk</json:string></affiliations></json:item><json:item><name>J. Mark Cooper</name><affiliations><json:string>Department of Clinical Neurosciences, Institute of Neurology, University College London, London, UK and</json:string></affiliations></json:item><json:item><name>Kai-Yin Chau</name><affiliations><json:string>Department of Clinical Neurosciences, Institute of Neurology, University College London, London, UK and</json:string></affiliations></json:item><json:item><name>Manuel Rojo</name><affiliations><json:string>Institut de Biochimie et Gntique Cellulaires (IBGC), UMR5095 CNRS Universit Victor Segalen, Bordeaux, France</json:string></affiliations></json:item><json:item><name>Anthony H.V. Schapira</name><affiliations><json:string>Department of Clinical Neurosciences, Institute of Neurology, University College London, London, UK and</json:string></affiliations></json:item><json:item><name>Jan-Willem Taanman</name><affiliations><json:string>Department of Clinical Neurosciences, Institute of Neurology, University College London, London, UK and</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>ARTICLES</value></json:item></subject><language><json:string>eng</json:string></language><abstract>Mitochondrial dysfunction and perturbed degradation of proteins have been implicated in Parkinson's disease (PD) pathogenesis. Mutations in the Parkin and PINK1 genes are a cause of familial PD. PINK1 is a putative kinase associated with mitochondria, and loss of PINK1 expression leads to mitochondrial dysfunction, which increases with time. Parkin is suggested to be downstream of PINK1 and also mediates the removal of damaged mitochondria by macroautophagy (mitophagy). We investigated whether mitochondrial dysfunction in dopaminergic SH-SY5Y cells following decreased PINK1 expression by RNAi may in part be due to the inhibition of mitophagy. Reduced flux through the macroautophagy pathway was found to be coincident with the inhibition of ATP synthesis following 12 days of PINK1 silencing. Overexpression of parkin in these cells restored both autophagic flux and ATP synthesis. Overexpression and RNAi studies also indicated that PINK1 and parkin were required for mitophagy following CCCP-induced mitochondrial damage. The ubiquitination of several mitochondrial proteins, including mitofusin 1 and mitofusin 2, were detected within 3 h of CCCP treatment. These post-translational modifications were reduced following the silencing of parkin or PINK1. 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Mutations in the Parkin and PINK1 genes are a cause of familial PD. PINK1 is a putative kinase associated with mitochondria, and loss of PINK1 expression leads to mitochondrial dysfunction, which increases with time. Parkin is suggested to be downstream of PINK1 and also mediates the removal of damaged mitochondria by macroautophagy (mitophagy). We investigated whether mitochondrial dysfunction in dopaminergic SH-SY5Y cells following decreased PINK1 expression by RNAi may in part be due to the inhibition of mitophagy. Reduced flux through the macroautophagy pathway was found to be coincident with the inhibition of ATP synthesis following 12 days of PINK1 silencing. Overexpression of parkin in these cells restored both autophagic flux and ATP synthesis. Overexpression and RNAi studies also indicated that PINK1 and parkin were required for mitophagy following CCCP-induced mitochondrial damage. The ubiquitination of several mitochondrial proteins, including mitofusin 1 and mitofusin 2, were detected within 3 h of CCCP treatment. These post-translational modifications were reduced following the silencing of parkin or PINK1. The ubiquitination of mitochondrial proteins appears to identify mitochondria for degradation and facilitate mitophagy. PINK1 and parkin are thus required for the removal of damaged mitochondria in dopaminergic cells, and inhibition of this pathway may lead to the accumulation of defective mitochondria which may contribute to PD pathogenesis.</p></abstract></profileDesc><revisionDesc><change when="2010-09-24">Created</change><change when="2010-12-15">Published</change><change xml:id="refBibs-istex" who="#ISTEX-API" when="2016-3-15">References added</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/9C42399B53A08875EE8719EB4A64EEE3D49238AD/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article"><front><journal-meta><journal-id journal-id-type="publisher-id">hmg</journal-id><journal-id journal-id-type="hwp">hmg</journal-id><journal-title>Human Molecular Genetics</journal-title><issn pub-type="ppub">0964-6906</issn><issn pub-type="epub">1460-2083</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.1093/hmg/ddq419</article-id><article-id pub-id-type="publisher-id">ddq419</article-id><article-categories><subj-group subj-group-type="heading"><subject>ARTICLES</subject></subj-group></article-categories><title-group><article-title>Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Gegg</surname><given-names>Matthew E.</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib><contrib contrib-type="author"><name><surname>Cooper</surname><given-names>J. Mark</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Chau</surname><given-names>Kai-Yin</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Rojo</surname><given-names>Manuel</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Schapira</surname><given-names>Anthony H.V.</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Taanman</surname><given-names>Jan-Willem</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib></contrib-group><aff id="af1"><label>1</label><addr-line>Department of Clinical Neurosciences</addr-line>, <institution>Institute of Neurology, University College</institution> <addr-line>London, London</addr-line>, <country>UK</country> and</aff><aff id="af2"><label>2</label><addr-line>Institut de Biochimie et Génétique Cellulaires (IBGC)</addr-line>, <institution>UMR5095 CNRS – Université Victor Segalen</institution>, <addr-line>Bordeaux</addr-line>, <country>France</country></aff><author-notes><corresp id="cor1"><label>*</label>To whom correspondence should be addressed at: Department of Clinical Neurosciences, Institute of Neurology, University College London, Rowland Hill Street, London NW3 2PF, UK. Tel: <phone>+44 2077940500</phone>; Fax: <fax>+44 2074726829</fax>; Email: <email>m.gegg@medsch.ucl.ac.uk</email></corresp></author-notes><pub-date pub-type="ppub"><day>15</day><month>12</month><year>2010</year></pub-date><pub-date pub-type="epub"><day>24</day><month>9</month><year>2010</year></pub-date><volume>19</volume><issue>24</issue><fpage>4861</fpage><lpage>4870</lpage><history><date date-type="received"><day>16</day><month>7</month><year>2010</year></date><date date-type="rev-recd"><day>20</day><month>9</month><year>2010</year></date><date date-type="accepted"><day>20</day><month>9</month><year>2010</year></date></history><permissions><copyright-statement>© The Author 2010. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</copyright-statement><copyright-year>2010</copyright-year></permissions><self-uri content-type="pdf" xlink:href="ddq419.pdf"></self-uri><abstract><p>Mitochondrial dysfunction and perturbed degradation of proteins have been implicated in Parkinson's disease (PD) pathogenesis. Mutations in the <italic>Parkin</italic> and <italic>PINK1</italic> genes are a cause of familial PD. PINK1 is a putative kinase associated with mitochondria, and loss of PINK1 expression leads to mitochondrial dysfunction, which increases with time. Parkin is suggested to be downstream of PINK1 and also mediates the removal of damaged mitochondria by macroautophagy (mitophagy). We investigated whether mitochondrial dysfunction in dopaminergic SH-SY5Y cells following decreased PINK1 expression by RNAi may in part be due to the inhibition of mitophagy. Reduced flux through the macroautophagy pathway was found to be coincident with the inhibition of ATP synthesis following 12 days of PINK1 silencing. Overexpression of parkin in these cells restored both autophagic flux and ATP synthesis. Overexpression and RNAi studies also indicated that PINK1 and parkin were required for mitophagy following CCCP-induced mitochondrial damage. The ubiquitination of several mitochondrial proteins, including mitofusin 1 and mitofusin 2, were detected within 3 h of CCCP treatment. These post-translational modifications were reduced following the silencing of parkin or PINK1. The ubiquitination of mitochondrial proteins appears to identify mitochondria for degradation and facilitate mitophagy. PINK1 and parkin are thus required for the removal of damaged mitochondria in dopaminergic cells, and inhibition of this pathway may lead to the accumulation of defective mitochondria which may contribute to PD pathogenesis.</p></abstract></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy</title></titleInfo><name type="personal"><namePart type="given">Matthew E.</namePart><namePart type="family">Gegg</namePart><affiliation></affiliation><affiliation>E-mail: m.gegg@medsch.ucl.ac.uk</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">J. Mark</namePart><namePart type="family">Cooper</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kai-Yin</namePart><namePart type="family">Chau</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Manuel</namePart><namePart type="family">Rojo</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Anthony H.V.</namePart><namePart type="family">Schapira</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jan-Willem</namePart><namePart type="family">Taanman</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2010-12-15</dateIssued><dateCreated encoding="w3cdtf">2010-09-24</dateCreated><copyrightDate encoding="w3cdtf">2010</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>Mitochondrial dysfunction and perturbed degradation of proteins have been implicated in Parkinson's disease (PD) pathogenesis. Mutations in the Parkin and PINK1 genes are a cause of familial PD. PINK1 is a putative kinase associated with mitochondria, and loss of PINK1 expression leads to mitochondrial dysfunction, which increases with time. Parkin is suggested to be downstream of PINK1 and also mediates the removal of damaged mitochondria by macroautophagy (mitophagy). We investigated whether mitochondrial dysfunction in dopaminergic SH-SY5Y cells following decreased PINK1 expression by RNAi may in part be due to the inhibition of mitophagy. Reduced flux through the macroautophagy pathway was found to be coincident with the inhibition of ATP synthesis following 12 days of PINK1 silencing. Overexpression of parkin in these cells restored both autophagic flux and ATP synthesis. Overexpression and RNAi studies also indicated that PINK1 and parkin were required for mitophagy following CCCP-induced mitochondrial damage. The ubiquitination of several mitochondrial proteins, including mitofusin 1 and mitofusin 2, were detected within 3 h of CCCP treatment. These post-translational modifications were reduced following the silencing of parkin or PINK1. The ubiquitination of mitochondrial proteins appears to identify mitochondria for degradation and facilitate mitophagy. PINK1 and parkin are thus required for the removal of damaged mitochondria in dopaminergic cells, and inhibition of this pathway may lead to the accumulation of defective mitochondria which may contribute to PD pathogenesis.</abstract><relatedItem type="host"><titleInfo><title>Human Molecular Genetics</title></titleInfo><genre type="Journal">journal</genre><identifier type="ISSN">0964-6906</identifier><identifier type="eISSN">1460-2083</identifier><identifier type="PublisherID">hmg</identifier><identifier type="PublisherID-hwp">hmg</identifier><part><date>2010</date><detail type="volume"><caption>vol.</caption><number>19</number></detail><detail type="issue"><caption>no.</caption><number>24</number></detail><extent unit="pages"><start>4861</start><end>4870</end></extent></part></relatedItem><identifier type="istex">9C42399B53A08875EE8719EB4A64EEE3D49238AD</identifier><identifier type="DOI">10.1093/hmg/ddq419</identifier><identifier type="href">ddq419.pdf</identifier><identifier type="ArticleID">ddq419</identifier><accessCondition type="use and reproduction" contentType="copyright">The Author 2010. Published by Oxford University Press. All rights reserved. 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