Parkin maintains mitochondrial levels of the protective Parkinson's disease-related enzyme 17-β hydroxysteroid dehydrogenase type 10
Identifieur interne : 000172 ( Pmc/Checkpoint ); précédent : 000171; suivant : 000173Parkin maintains mitochondrial levels of the protective Parkinson's disease-related enzyme 17-β hydroxysteroid dehydrogenase type 10
Auteurs : G. Bertolin [France] ; M. Jacoupy [France] ; S. Traver [France] ; R. Ferrando-Miguel [France] ; T. Saint Georges [France] ; K. Grenier [Canada] ; H. Ardila-Osorio [France] ; M-P Muriel [France] ; H. Takahashi [Japon] ; A J Lees [Royaume-Uni] ; C. Gautier [France] ; D. Guedin [France] ; F. Coge [France] ; E A Fon [Canada] ; A. Brice [France] ; O. Corti [France]Source :
- Cell Death and Differentiation [ 1350-9047 ] ; 2015.
Abstract
Mutations of the
Url:
DOI: 10.1038/cdd.2014.224
PubMed: 25591737
PubMed Central: 4563777
Affiliations:
Links toward previous steps (curation, corpus...)
Links to Exploration step
PMC:4563777Le document en format XML
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hydroxysteroid dehydrogenase type 10</title>
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<author><name sortKey="Ferrando Miguel, R" sort="Ferrando Miguel, R" uniqKey="Ferrando Miguel R" first="R" last="Ferrando-Miguel">R. Ferrando-Miguel</name>
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<author><name sortKey="Saint Georges, T" sort="Saint Georges, T" uniqKey="Saint Georges T" first="T" last="Saint Georges">T. Saint Georges</name>
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<author><name sortKey="Grenier, K" sort="Grenier, K" uniqKey="Grenier K" first="K" last="Grenier">K. Grenier</name>
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<country xml:lang="fr">Canada</country>
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<author><name sortKey="Ardila Osorio, H" sort="Ardila Osorio, H" uniqKey="Ardila Osorio H" first="H" last="Ardila-Osorio">H. Ardila-Osorio</name>
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<country xml:lang="fr">France</country>
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<country xml:lang="fr">France</country>
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<author><name sortKey="Muriel, M P" sort="Muriel, M P" uniqKey="Muriel M" first="M-P" last="Muriel">M-P Muriel</name>
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<country xml:lang="fr">France</country>
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<author><name sortKey="Takahashi, H" sort="Takahashi, H" uniqKey="Takahashi H" first="H" last="Takahashi">H. Takahashi</name>
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<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Lees, A J" sort="Lees, A J" uniqKey="Lees A" first="A J" last="Lees">A J Lees</name>
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<country xml:lang="fr">France</country>
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<author><name sortKey="Guedin, D" sort="Guedin, D" uniqKey="Guedin D" first="D" last="Guedin">D. Guedin</name>
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<country xml:lang="fr">France</country>
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<author><name sortKey="Coge, F" sort="Coge, F" uniqKey="Coge F" first="F" last="Coge">F. Coge</name>
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<country xml:lang="fr">France</country>
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<author><name sortKey="Fon, E A" sort="Fon, E A" uniqKey="Fon E" first="E A" last="Fon">E A Fon</name>
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<country xml:lang="fr">Canada</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Brice, A" sort="Brice, A" uniqKey="Brice A" first="A" last="Brice">A. Brice</name>
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</nlm:aff>
<country xml:lang="fr">France</country>
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<author><name sortKey="Corti, O" sort="Corti, O" uniqKey="Corti O" first="O" last="Corti">O. Corti</name>
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</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>CNRS, UMR 7225</institution>
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</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127</institution>
, 75013 Paris,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Institut du Cerveau et de la Moelle épinière, ICM</institution>
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</nlm:aff>
<country xml:lang="fr">France</country>
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</titleStmt>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Parkin maintains mitochondrial levels of the protective Parkinson's disease-related enzyme 17-<italic>β</italic>
hydroxysteroid dehydrogenase type 10</title>
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</nlm:aff>
<country xml:lang="fr">France</country>
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</nlm:aff>
<country xml:lang="fr">France</country>
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<author><name sortKey="Traver, S" sort="Traver, S" uniqKey="Traver S" first="S" last="Traver">S. Traver</name>
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<author><name sortKey="Ferrando Miguel, R" sort="Ferrando Miguel, R" uniqKey="Ferrando Miguel R" first="R" last="Ferrando-Miguel">R. Ferrando-Miguel</name>
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<author><name sortKey="Saint Georges, T" sort="Saint Georges, T" uniqKey="Saint Georges T" first="T" last="Saint Georges">T. Saint Georges</name>
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<author><name sortKey="Grenier, K" sort="Grenier, K" uniqKey="Grenier K" first="K" last="Grenier">K. Grenier</name>
<affiliation wicri:level="1"><nlm:aff id="aff6"><institution>McGill Parkinson Program, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University</institution>
, Montreal, Quebec,<country>Canada</country>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Ardila Osorio, H" sort="Ardila Osorio, H" uniqKey="Ardila Osorio H" first="H" last="Ardila-Osorio">H. Ardila-Osorio</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Inserm, U1127</institution>
, 75013 Paris,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>CNRS, UMR 7225</institution>
, 75013 Paris,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127</institution>
, 75013 Paris,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Institut du Cerveau et de la Moelle épinière, ICM</institution>
, 75013 Paris,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Muriel, M P" sort="Muriel, M P" uniqKey="Muriel M" first="M-P" last="Muriel">M-P Muriel</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Inserm, U1127</institution>
, 75013 Paris,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>CNRS, UMR 7225</institution>
, 75013 Paris,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127</institution>
, 75013 Paris,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Institut du Cerveau et de la Moelle épinière, ICM</institution>
, 75013 Paris,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Takahashi, H" sort="Takahashi, H" uniqKey="Takahashi H" first="H" last="Takahashi">H. Takahashi</name>
<affiliation wicri:level="1"><nlm:aff id="aff7"><institution>Department of Pathology, Brain Research Institute, University of Niigata</institution>
, Niigata,<country>Japan</country>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Lees, A J" sort="Lees, A J" uniqKey="Lees A" first="A J" last="Lees">A J Lees</name>
<affiliation wicri:level="1"><nlm:aff id="aff8"><institution>Reta Lila Weston Institute for Neurological Studies, Institute of Neurology, University College London</institution>
, London,<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Gautier, C" sort="Gautier, C" uniqKey="Gautier C" first="C" last="Gautier">C. Gautier</name>
<affiliation wicri:level="1"><nlm:aff id="aff9"><institution>Laboratoire Chémogénétique Servier-Diverchim, Institut du Cerveau et de la Moelle épinière, ICM</institution>
, Paris,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Guedin, D" sort="Guedin, D" uniqKey="Guedin D" first="D" last="Guedin">D. Guedin</name>
<affiliation wicri:level="1"><nlm:aff id="aff9"><institution>Laboratoire Chémogénétique Servier-Diverchim, Institut du Cerveau et de la Moelle épinière, ICM</institution>
, Paris,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Coge, F" sort="Coge, F" uniqKey="Coge F" first="F" last="Coge">F. Coge</name>
<affiliation wicri:level="1"><nlm:aff id="aff9"><institution>Laboratoire Chémogénétique Servier-Diverchim, Institut du Cerveau et de la Moelle épinière, ICM</institution>
, Paris,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Fon, E A" sort="Fon, E A" uniqKey="Fon E" first="E A" last="Fon">E A Fon</name>
<affiliation wicri:level="1"><nlm:aff id="aff6"><institution>McGill Parkinson Program, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University</institution>
, Montreal, Quebec,<country>Canada</country>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Brice, A" sort="Brice, A" uniqKey="Brice A" first="A" last="Brice">A. Brice</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Inserm, U1127</institution>
, 75013 Paris,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>CNRS, UMR 7225</institution>
, 75013 Paris,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127</institution>
, 75013 Paris,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Institut du Cerveau et de la Moelle épinière, ICM</institution>
, 75013 Paris,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Corti, O" sort="Corti, O" uniqKey="Corti O" first="O" last="Corti">O. Corti</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Inserm, U1127</institution>
, 75013 Paris,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>CNRS, UMR 7225</institution>
, 75013 Paris,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127</institution>
, 75013 Paris,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Institut du Cerveau et de la Moelle épinière, ICM</institution>
, 75013 Paris,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series><title level="j">Cell Death and Differentiation</title>
<idno type="ISSN">1350-9047</idno>
<idno type="eISSN">1476-5403</idno>
<imprint><date when="2015">2015</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>Mutations of the <italic>PARK2</italic>
and <italic>PINK1</italic>
genes, encoding the cytosolic E3 ubiquitin-protein ligase Parkin and the mitochondrial serine/threonine kinase PINK1, respectively, cause autosomal recessive early-onset Parkinson's disease (PD). Parkin and PINK1 cooperate in a biochemical mitochondrial quality control pathway regulating mitochondrial morphology, dynamics and clearance. This study identifies the multifunctional PD-related mitochondrial matrix enzyme 17-<italic>β</italic>
hydroxysteroid dehydrogenase type 10 (HSD17B10) as a new Parkin substrate. Parkin overproduction in cells increased mitochondrial HSD17B10 abundance by a mechanism involving ubiquitin chain extension, whereas <italic>PARK2</italic>
downregulation or deficiency caused mitochondrial HSD17B10 depletion in cells and mice. HSD17B10 levels were also found to be low in the brains of PD patients with <italic>PARK2</italic>
mutations. Confocal and Förster resonance energy transfer (FRET) microscopy revealed that HSD17B10 recruited Parkin to the translocase of the outer membrane (TOM), close to PINK1, both in functional mitochondria and after the collapse of mitochondrial membrane potential (ΔΨm). PD-causing <italic>PARK2</italic>
mutations impaired interaction with HSD17B10 and the HSD17B10-dependent mitochondrial translocation of Parkin. HSD17B10 overproduction promoted mitochondrial elongation and mitigated CCCP-induced mitochondrial degradation independently of enzymatic activity. These effects were abolished by overproduction of the fission-promiting dynamin-related protein 1 (Drp1). By contrast, siRNA-mediated <italic>HSD17B10</italic>
silencing enhanced mitochondrial fission and mitophagy. These findings suggest that the maintenance of appropriate mitochondrial HSD17B10 levels is one of the mechanisms by which Parkin preserves mitochondrial quality. The loss of this protective mechanism may contribute to mitochondrial dysfunction and neuronal degeneration in autosomal recessive PD.</p>
</div>
</front>
</TEI>
<pmc article-type="research-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">Cell Death Differ</journal-id>
<journal-id journal-id-type="iso-abbrev">Cell Death Differ</journal-id>
<journal-title-group><journal-title>Cell Death and Differentiation</journal-title>
</journal-title-group>
<issn pub-type="ppub">1350-9047</issn>
<issn pub-type="epub">1476-5403</issn>
<publisher><publisher-name>Nature Publishing Group</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">25591737</article-id>
<article-id pub-id-type="pmc">4563777</article-id>
<article-id pub-id-type="pii">cdd2014224</article-id>
<article-id pub-id-type="doi">10.1038/cdd.2014.224</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Original Paper</subject>
</subj-group>
</article-categories>
<title-group><article-title>Parkin maintains mitochondrial levels of the protective Parkinson's disease-related enzyme 17-<italic>β</italic>
hydroxysteroid dehydrogenase type 10</article-title>
<alt-title alt-title-type="running">Parkin regulates mitochondrial HSD17B10 levels</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Bertolin</surname>
<given-names>G</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
<xref ref-type="aff" rid="aff3">3</xref>
<xref ref-type="aff" rid="aff4">4</xref>
<xref ref-type="author-notes" rid="note1"><sup>10</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Jacoupy</surname>
<given-names>M</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
<xref ref-type="aff" rid="aff3">3</xref>
<xref ref-type="aff" rid="aff4">4</xref>
<xref ref-type="author-notes" rid="note1"><sup>10</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Traver</surname>
<given-names>S</given-names>
</name>
<xref ref-type="aff" rid="aff5">5</xref>
<xref ref-type="author-notes" rid="note1"><sup>10</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ferrando-Miguel</surname>
<given-names>R</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
<xref ref-type="aff" rid="aff3">3</xref>
<xref ref-type="aff" rid="aff4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Saint Georges</surname>
<given-names>T</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
<xref ref-type="aff" rid="aff3">3</xref>
<xref ref-type="aff" rid="aff4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Grenier</surname>
<given-names>K</given-names>
</name>
<xref ref-type="aff" rid="aff6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ardila-Osorio</surname>
<given-names>H</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
<xref ref-type="aff" rid="aff3">3</xref>
<xref ref-type="aff" rid="aff4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Muriel</surname>
<given-names>M-P</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
<xref ref-type="aff" rid="aff3">3</xref>
<xref ref-type="aff" rid="aff4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Takahashi</surname>
<given-names>H</given-names>
</name>
<xref ref-type="aff" rid="aff7">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lees</surname>
<given-names>A J</given-names>
</name>
<xref ref-type="aff" rid="aff8">8</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gautier</surname>
<given-names>C</given-names>
</name>
<xref ref-type="aff" rid="aff9">9</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Guedin</surname>
<given-names>D</given-names>
</name>
<xref ref-type="aff" rid="aff9">9</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Coge</surname>
<given-names>F</given-names>
</name>
<xref ref-type="aff" rid="aff9">9</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Fon</surname>
<given-names>E A</given-names>
</name>
<xref ref-type="aff" rid="aff6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Brice</surname>
<given-names>A</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
<xref ref-type="aff" rid="aff3">3</xref>
<xref ref-type="aff" rid="aff4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Corti</surname>
<given-names>O</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
<xref ref-type="aff" rid="aff3">3</xref>
<xref ref-type="aff" rid="aff4">4</xref>
<xref ref-type="corresp" rid="caf1">*</xref>
</contrib>
<aff id="aff1"><label>1</label>
<institution>Inserm, U1127</institution>
, 75013 Paris,<country>France</country>
</aff>
<aff id="aff2"><label>2</label>
<institution>CNRS, UMR 7225</institution>
, 75013 Paris,<country>France</country>
</aff>
<aff id="aff3"><label>3</label>
<institution>Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127</institution>
, 75013 Paris,<country>France</country>
</aff>
<aff id="aff4"><label>4</label>
<institution>Institut du Cerveau et de la Moelle épinière, ICM</institution>
, 75013 Paris,<country>France</country>
</aff>
<aff id="aff5"><label>5</label>
<institution>CHU Montpellier, Institute for Research in Biotherapy, Saint-Eloi Hospital</institution>
, Montpellier,<country>France</country>
</aff>
<aff id="aff6"><label>6</label>
<institution>McGill Parkinson Program, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University</institution>
, Montreal, Quebec,<country>Canada</country>
</aff>
<aff id="aff7"><label>7</label>
<institution>Department of Pathology, Brain Research Institute, University of Niigata</institution>
, Niigata,<country>Japan</country>
</aff>
<aff id="aff8"><label>8</label>
<institution>Reta Lila Weston Institute for Neurological Studies, Institute of Neurology, University College London</institution>
, London,<country>UK</country>
</aff>
<aff id="aff9"><label>9</label>
<institution>Laboratoire Chémogénétique Servier-Diverchim, Institut du Cerveau et de la Moelle épinière, ICM</institution>
, Paris,<country>France</country>
</aff>
</contrib-group>
<author-notes><corresp id="caf1"><label>*</label>
<institution>Molecular Basis, Physiopathology and Treatment of Neurodegenerative Diseases; Institut du Cerveau et de la Moelle épinière, Pitié-Salpêtrière Hospital</institution>
, 75013 Paris, <country>France</country>
. Tel: +33 15 72 74 651; Fax: +33 15 72 74 795. E-mail: <email>olga.corti@upmc.fr</email>
</corresp>
<fn fn-type="present-address" id="note1"><label>10</label>
<p>These authors contributed equally to this work.</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><month>10</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="epub"><day>16</day>
<month>01</month>
<year>2015</year>
</pub-date>
<volume>22</volume>
<issue>10</issue>
<fpage>1563</fpage>
<lpage>1576</lpage>
<history><date date-type="received"><day>29</day>
<month>10</month>
<year>2013</year>
</date>
<date date-type="rev-recd"><day>08</day>
<month>10</month>
<year>2014</year>
</date>
<date date-type="accepted"><day>25</day>
<month>11</month>
<year>2014</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2015 Macmillan Publishers Limited</copyright-statement>
<copyright-year>2015</copyright-year>
<copyright-holder>Macmillan Publishers Limited</copyright-holder>
</permissions>
<abstract><p>Mutations of the <italic>PARK2</italic>
and <italic>PINK1</italic>
genes, encoding the cytosolic E3 ubiquitin-protein ligase Parkin and the mitochondrial serine/threonine kinase PINK1, respectively, cause autosomal recessive early-onset Parkinson's disease (PD). Parkin and PINK1 cooperate in a biochemical mitochondrial quality control pathway regulating mitochondrial morphology, dynamics and clearance. This study identifies the multifunctional PD-related mitochondrial matrix enzyme 17-<italic>β</italic>
hydroxysteroid dehydrogenase type 10 (HSD17B10) as a new Parkin substrate. Parkin overproduction in cells increased mitochondrial HSD17B10 abundance by a mechanism involving ubiquitin chain extension, whereas <italic>PARK2</italic>
downregulation or deficiency caused mitochondrial HSD17B10 depletion in cells and mice. HSD17B10 levels were also found to be low in the brains of PD patients with <italic>PARK2</italic>
mutations. Confocal and Förster resonance energy transfer (FRET) microscopy revealed that HSD17B10 recruited Parkin to the translocase of the outer membrane (TOM), close to PINK1, both in functional mitochondria and after the collapse of mitochondrial membrane potential (ΔΨm). PD-causing <italic>PARK2</italic>
mutations impaired interaction with HSD17B10 and the HSD17B10-dependent mitochondrial translocation of Parkin. HSD17B10 overproduction promoted mitochondrial elongation and mitigated CCCP-induced mitochondrial degradation independently of enzymatic activity. These effects were abolished by overproduction of the fission-promiting dynamin-related protein 1 (Drp1). By contrast, siRNA-mediated <italic>HSD17B10</italic>
silencing enhanced mitochondrial fission and mitophagy. These findings suggest that the maintenance of appropriate mitochondrial HSD17B10 levels is one of the mechanisms by which Parkin preserves mitochondrial quality. The loss of this protective mechanism may contribute to mitochondrial dysfunction and neuronal degeneration in autosomal recessive PD.</p>
</abstract>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>Canada</li>
<li>France</li>
<li>Japon</li>
<li>Royaume-Uni</li>
</country>
</list>
<tree><country name="France"><noRegion><name sortKey="Bertolin, G" sort="Bertolin, G" uniqKey="Bertolin G" first="G" last="Bertolin">G. Bertolin</name>
</noRegion>
<name sortKey="Ardila Osorio, H" sort="Ardila Osorio, H" uniqKey="Ardila Osorio H" first="H" last="Ardila-Osorio">H. Ardila-Osorio</name>
<name sortKey="Ardila Osorio, H" sort="Ardila Osorio, H" uniqKey="Ardila Osorio H" first="H" last="Ardila-Osorio">H. Ardila-Osorio</name>
<name sortKey="Ardila Osorio, H" sort="Ardila Osorio, H" uniqKey="Ardila Osorio H" first="H" last="Ardila-Osorio">H. Ardila-Osorio</name>
<name sortKey="Ardila Osorio, H" sort="Ardila Osorio, H" uniqKey="Ardila Osorio H" first="H" last="Ardila-Osorio">H. Ardila-Osorio</name>
<name sortKey="Bertolin, G" sort="Bertolin, G" uniqKey="Bertolin G" first="G" last="Bertolin">G. Bertolin</name>
<name sortKey="Bertolin, G" sort="Bertolin, G" uniqKey="Bertolin G" first="G" last="Bertolin">G. Bertolin</name>
<name sortKey="Bertolin, G" sort="Bertolin, G" uniqKey="Bertolin G" first="G" last="Bertolin">G. Bertolin</name>
<name sortKey="Brice, A" sort="Brice, A" uniqKey="Brice A" first="A" last="Brice">A. Brice</name>
<name sortKey="Brice, A" sort="Brice, A" uniqKey="Brice A" first="A" last="Brice">A. Brice</name>
<name sortKey="Brice, A" sort="Brice, A" uniqKey="Brice A" first="A" last="Brice">A. Brice</name>
<name sortKey="Brice, A" sort="Brice, A" uniqKey="Brice A" first="A" last="Brice">A. Brice</name>
<name sortKey="Coge, F" sort="Coge, F" uniqKey="Coge F" first="F" last="Coge">F. Coge</name>
<name sortKey="Corti, O" sort="Corti, O" uniqKey="Corti O" first="O" last="Corti">O. Corti</name>
<name sortKey="Corti, O" sort="Corti, O" uniqKey="Corti O" first="O" last="Corti">O. Corti</name>
<name sortKey="Corti, O" sort="Corti, O" uniqKey="Corti O" first="O" last="Corti">O. Corti</name>
<name sortKey="Corti, O" sort="Corti, O" uniqKey="Corti O" first="O" last="Corti">O. Corti</name>
<name sortKey="Ferrando Miguel, R" sort="Ferrando Miguel, R" uniqKey="Ferrando Miguel R" first="R" last="Ferrando-Miguel">R. Ferrando-Miguel</name>
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<name sortKey="Ferrando Miguel, R" sort="Ferrando Miguel, R" uniqKey="Ferrando Miguel R" first="R" last="Ferrando-Miguel">R. Ferrando-Miguel</name>
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<name sortKey="Jacoupy, M" sort="Jacoupy, M" uniqKey="Jacoupy M" first="M" last="Jacoupy">M. Jacoupy</name>
<name sortKey="Jacoupy, M" sort="Jacoupy, M" uniqKey="Jacoupy M" first="M" last="Jacoupy">M. Jacoupy</name>
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<name sortKey="Muriel, M P" sort="Muriel, M P" uniqKey="Muriel M" first="M-P" last="Muriel">M-P Muriel</name>
<name sortKey="Saint Georges, T" sort="Saint Georges, T" uniqKey="Saint Georges T" first="T" last="Saint Georges">T. Saint Georges</name>
<name sortKey="Saint Georges, T" sort="Saint Georges, T" uniqKey="Saint Georges T" first="T" last="Saint Georges">T. Saint Georges</name>
<name sortKey="Saint Georges, T" sort="Saint Georges, T" uniqKey="Saint Georges T" first="T" last="Saint Georges">T. Saint Georges</name>
<name sortKey="Saint Georges, T" sort="Saint Georges, T" uniqKey="Saint Georges T" first="T" last="Saint Georges">T. Saint Georges</name>
<name sortKey="Traver, S" sort="Traver, S" uniqKey="Traver S" first="S" last="Traver">S. Traver</name>
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<country name="Canada"><noRegion><name sortKey="Grenier, K" sort="Grenier, K" uniqKey="Grenier K" first="K" last="Grenier">K. Grenier</name>
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<name sortKey="Fon, E A" sort="Fon, E A" uniqKey="Fon E" first="E A" last="Fon">E A Fon</name>
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<country name="Japon"><noRegion><name sortKey="Takahashi, H" sort="Takahashi, H" uniqKey="Takahashi H" first="H" last="Takahashi">H. Takahashi</name>
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<country name="Royaume-Uni"><noRegion><name sortKey="Lees, A J" sort="Lees, A J" uniqKey="Lees A" first="A J" last="Lees">A J Lees</name>
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</record>
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