PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1
Identifieur interne : 000609 ( Main/Exploration ); précédent : 000608; suivant : 000610PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1
Auteurs : Sven Geisler [Allemagne] ; Kira M. Holmstrm [Allemagne] ; Diana Skujat [Allemagne] ; Fabienne C. Fiesel [Allemagne] ; Oliver C. Rothfuss [Allemagne] ; Philipp J. Kahle [Allemagne] ; Wolfdieter Springer [Allemagne]Source :
- Nature Cell Biology [ 1465-7392 ] ; 2010-02.
Abstract
Parkinson's disease is the most common neurodegenerative movement disorder. Mutations in PINK1 and PARKIN are the most frequent causes of recessive Parkinson's disease. However, their molecular contribution to pathogenesis remains unclear. Here, we reveal important mechanistic steps of a PINK1/Parkin-directed pathway linking mitochondrial damage, ubiquitylation and autophagy in non-neuronal and neuronal cells. PINK1 kinase activity and its mitochondrial localization sequence are prerequisites to induce translocation of the E3 ligase Parkin to depolarized mitochondria. Subsequently, Parkin mediates the formation of two distinct poly-ubiquitin chains, linked through Lys 63 and Lys 27. In addition, the autophagic adaptor p62/SQSTM1 is recruited to mitochondrial clusters and is essential for the clearance of mitochondria. Strikingly, we identified VDAC1 (voltage-dependent anion channel 1) as a target for Parkin-mediated Lys 27 poly-ubiquitylation and mitophagy. Moreover, pathogenic Parkin mutations interfere with distinct steps of mitochondrial translocation, ubiquitylation and/or final clearance through mitophagy. Thus, our data provide functional links between PINK1, Parkin and the selective autophagy of mitochondria, which is implicated in the pathogenesis of Parkinson's disease.
Url:
DOI: 10.1038/ncb2012
Affiliations:
Links toward previous steps (curation, corpus...)
Le document en format XML
<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1</title><author><name sortKey="Geisler, Sven" sort="Geisler, Sven" uniqKey="Geisler S" first="Sven" last="Geisler">Sven Geisler</name></author><author><name sortKey="Holmstrm, Kira M" sort="Holmstrm, Kira M" uniqKey="Holmstrm K" first="Kira M." last="Holmstrm">Kira M. Holmstrm</name></author><author><name sortKey="Skujat, Diana" sort="Skujat, Diana" uniqKey="Skujat D" first="Diana" last="Skujat">Diana Skujat</name></author><author><name sortKey="Fiesel, Fabienne C" sort="Fiesel, Fabienne C" uniqKey="Fiesel F" first="Fabienne C." last="Fiesel">Fabienne C. Fiesel</name></author><author><name sortKey="Rothfuss, Oliver C" sort="Rothfuss, Oliver C" uniqKey="Rothfuss O" first="Oliver C." last="Rothfuss">Oliver C. Rothfuss</name></author><author><name sortKey="Kahle, Philipp J" sort="Kahle, Philipp J" uniqKey="Kahle P" first="Philipp J." last="Kahle">Philipp J. Kahle</name></author><author><name sortKey="Springer, Wolfdieter" sort="Springer, Wolfdieter" uniqKey="Springer W" first="Wolfdieter" last="Springer">Wolfdieter Springer</name></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:E72E4B527D49D59B81805111805E67D4E130EA4A</idno><date when="2010" year="2010">2010</date><idno type="doi">10.1038/ncb2012</idno><idno type="url">https://api.istex.fr/document/E72E4B527D49D59B81805111805E67D4E130EA4A/fulltext/pdf</idno><idno type="wicri:Area/Main/Corpus">000F97</idno><idno type="wicri:Area/Main/Curation">000E12</idno><idno type="wicri:Area/Main/Exploration">000609</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1</title><author><name sortKey="Geisler, Sven" sort="Geisler, Sven" uniqKey="Geisler S" first="Sven" last="Geisler">Sven Geisler</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Laboratory of Functional Neurogenetics, Otfried-Mller-Strasse 27, 72076 Tbingen</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Tübingen</settlement></placeName></affiliation><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tbingen, Otfried-Mller-Strasse 27, 72076 Tbingen</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Tübingen</settlement></placeName></affiliation></author><author><name sortKey="Holmstrm, Kira M" sort="Holmstrm, Kira M" uniqKey="Holmstrm K" first="Kira M." last="Holmstrm">Kira M. Holmstrm</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Laboratory of Functional Neurogenetics, Otfried-Mller-Strasse 27, 72076 Tbingen</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Tübingen</settlement></placeName></affiliation><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tbingen, Otfried-Mller-Strasse 27, 72076 Tbingen</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Tübingen</settlement></placeName></affiliation></author><author><name sortKey="Skujat, Diana" sort="Skujat, Diana" uniqKey="Skujat D" first="Diana" last="Skujat">Diana Skujat</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Laboratory of Functional Neurogenetics, Otfried-Mller-Strasse 27, 72076 Tbingen</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Tübingen</settlement></placeName></affiliation><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tbingen, Otfried-Mller-Strasse 27, 72076 Tbingen</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Tübingen</settlement></placeName></affiliation></author><author><name sortKey="Fiesel, Fabienne C" sort="Fiesel, Fabienne C" uniqKey="Fiesel F" first="Fabienne C." last="Fiesel">Fabienne C. Fiesel</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Laboratory of Functional Neurogenetics, Otfried-Mller-Strasse 27, 72076 Tbingen</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Tübingen</settlement></placeName></affiliation><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tbingen, Otfried-Mller-Strasse 27, 72076 Tbingen</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Tübingen</settlement></placeName></affiliation></author><author><name sortKey="Rothfuss, Oliver C" sort="Rothfuss, Oliver C" uniqKey="Rothfuss O" first="Oliver C." last="Rothfuss">Oliver C. Rothfuss</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tbingen, Otfried-Mller-Strasse 27, 72076 Tbingen</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Tübingen</settlement></placeName></affiliation></author><author><name sortKey="Kahle, Philipp J" sort="Kahle, Philipp J" uniqKey="Kahle P" first="Philipp J." last="Kahle">Philipp J. Kahle</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Laboratory of Functional Neurogenetics, Otfried-Mller-Strasse 27, 72076 Tbingen</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Tübingen</settlement></placeName></affiliation><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tbingen, Otfried-Mller-Strasse 27, 72076 Tbingen</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Tübingen</settlement></placeName></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Allemagne</country></affiliation></author><author><name sortKey="Springer, Wolfdieter" sort="Springer, Wolfdieter" uniqKey="Springer W" first="Wolfdieter" last="Springer">Wolfdieter Springer</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Laboratory of Functional Neurogenetics, Otfried-Mller-Strasse 27, 72076 Tbingen</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Tübingen</settlement></placeName></affiliation><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tbingen, Otfried-Mller-Strasse 27, 72076 Tbingen</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Tübingen</settlement></placeName></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Allemagne</country></affiliation></author></analytic><monogr></monogr><series><title level="j">Nature Cell Biology</title><idno type="ISSN">1465-7392</idno><idno type="eISSN">1476-4679</idno><imprint><publisher>Nature Publishing Group</publisher><date type="published" when="2010-02">2010-02</date><biblScope unit="volume">12</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="119">119</biblScope><biblScope unit="page" to="131">131</biblScope></imprint><idno type="ISSN">1465-7392</idno></series><idno type="istex">E72E4B527D49D59B81805111805E67D4E130EA4A</idno><idno type="DOI">10.1038/ncb2012</idno><idno type="ArticleID">ncb2012</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1465-7392</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="eng">Parkinson's disease is the most common neurodegenerative movement disorder. Mutations in PINK1 and PARKIN are the most frequent causes of recessive Parkinson's disease. However, their molecular contribution to pathogenesis remains unclear. Here, we reveal important mechanistic steps of a PINK1/Parkin-directed pathway linking mitochondrial damage, ubiquitylation and autophagy in non-neuronal and neuronal cells. PINK1 kinase activity and its mitochondrial localization sequence are prerequisites to induce translocation of the E3 ligase Parkin to depolarized mitochondria. Subsequently, Parkin mediates the formation of two distinct poly-ubiquitin chains, linked through Lys 63 and Lys 27. In addition, the autophagic adaptor p62/SQSTM1 is recruited to mitochondrial clusters and is essential for the clearance of mitochondria. Strikingly, we identified VDAC1 (voltage-dependent anion channel 1) as a target for Parkin-mediated Lys 27 poly-ubiquitylation and mitophagy. Moreover, pathogenic Parkin mutations interfere with distinct steps of mitochondrial translocation, ubiquitylation and/or final clearance through mitophagy. Thus, our data provide functional links between PINK1, Parkin and the selective autophagy of mitochondria, which is implicated in the pathogenesis of Parkinson's disease.</div></front></TEI><affiliations><list><country><li>Allemagne</li></country><region><li>Bade-Wurtemberg</li><li>District de Tübingen</li></region><settlement><li>Tübingen</li></settlement></list><tree><country name="Allemagne"><region name="Bade-Wurtemberg"><name sortKey="Geisler, Sven" sort="Geisler, Sven" uniqKey="Geisler S" first="Sven" last="Geisler">Sven Geisler</name></region><name sortKey="Fiesel, Fabienne C" sort="Fiesel, Fabienne C" uniqKey="Fiesel F" first="Fabienne C." last="Fiesel">Fabienne C. Fiesel</name><name sortKey="Fiesel, Fabienne C" sort="Fiesel, Fabienne C" uniqKey="Fiesel F" first="Fabienne C." last="Fiesel">Fabienne C. Fiesel</name><name sortKey="Geisler, Sven" sort="Geisler, Sven" uniqKey="Geisler S" first="Sven" last="Geisler">Sven Geisler</name><name sortKey="Holmstrm, Kira M" sort="Holmstrm, Kira M" uniqKey="Holmstrm K" first="Kira M." last="Holmstrm">Kira M. Holmstrm</name><name sortKey="Holmstrm, Kira M" sort="Holmstrm, Kira M" uniqKey="Holmstrm K" first="Kira M." last="Holmstrm">Kira M. Holmstrm</name><name sortKey="Kahle, Philipp J" sort="Kahle, Philipp J" uniqKey="Kahle P" first="Philipp J." last="Kahle">Philipp J. Kahle</name><name sortKey="Kahle, Philipp J" sort="Kahle, Philipp J" uniqKey="Kahle P" first="Philipp J." last="Kahle">Philipp J. Kahle</name><name sortKey="Kahle, Philipp J" sort="Kahle, Philipp J" uniqKey="Kahle P" first="Philipp J." last="Kahle">Philipp J. Kahle</name><name sortKey="Rothfuss, Oliver C" sort="Rothfuss, Oliver C" uniqKey="Rothfuss O" first="Oliver C." last="Rothfuss">Oliver C. Rothfuss</name><name sortKey="Skujat, Diana" sort="Skujat, Diana" uniqKey="Skujat D" first="Diana" last="Skujat">Diana Skujat</name><name sortKey="Skujat, Diana" sort="Skujat, Diana" uniqKey="Skujat D" first="Diana" last="Skujat">Diana Skujat</name><name sortKey="Springer, Wolfdieter" sort="Springer, Wolfdieter" uniqKey="Springer W" first="Wolfdieter" last="Springer">Wolfdieter Springer</name><name sortKey="Springer, Wolfdieter" sort="Springer, Wolfdieter" uniqKey="Springer W" first="Wolfdieter" last="Springer">Wolfdieter Springer</name><name sortKey="Springer, Wolfdieter" sort="Springer, Wolfdieter" uniqKey="Springer W" first="Wolfdieter" last="Springer">Wolfdieter Springer</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Sante/explor/ParkinsonV1/Data/Main/Exploration
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000609 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 000609 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Sante
|area= ParkinsonV1
|flux= Main
|étape= Exploration
|type= RBID
|clé= ISTEX:E72E4B527D49D59B81805111805E67D4E130EA4A
|texte= PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1
}}
| This area was generated with Dilib version V0.6.23. |  |