The TOMM machinery is a molecular switch in PINK1 and PARK2/PARKIN-dependent mitochondrial clearance.
Identifieur interne : 000C14 ( Main/Exploration ); précédent : 000C13; suivant : 000C15The TOMM machinery is a molecular switch in PINK1 and PARK2/PARKIN-dependent mitochondrial clearance.
Auteurs : Giulia Bertolin [France] ; Rosa Ferrando-Miguel ; Maxime Jacoupy ; Sabine Traver ; Karl Grenier ; Andrew W. Greene ; Aurélien Dauphin ; François Waharte ; Aurélien Bayot ; Jean Salamero ; Anne Lombès ; Anne-Laure Bulteau ; Edward A. Fon ; Alexis Brice ; Olga CortiSource :
- Autophagy [ 1554-8635 ] ; 2013.
English descriptors
- KwdEn :
- Down-Regulation, HEK293 Cells, HeLa Cells, Humans, Membrane Transport Proteins (metabolism), Mitochondria (metabolism), Mitochondrial Degradation, Mitochondrial Membrane Transport Proteins (metabolism), Mitochondrial Membranes (metabolism), Models, Biological, Mutation (genetics), Parkinson Disease (genetics), Protein Binding, Protein Kinases (metabolism), Protein Transport, Signal Transduction, Ubiquitin-Protein Ligases (metabolism).
- MESH :
- chemical , metabolism : Membrane Transport Proteins, Mitochondrial Membrane Transport Proteins, Protein Kinases, Ubiquitin-Protein Ligases.
- genetics : Mutation, Parkinson Disease.
- metabolism : Mitochondria, Mitochondrial Membranes.
- Down-Regulation, HEK293 Cells, HeLa Cells, Humans, Mitochondrial Degradation, Models, Biological, Protein Binding, Protein Transport, Signal Transduction.
Abstract
Loss-of-function mutations in PARK2/PARKIN and PINK1 cause early-onset autosomal recessive Parkinson disease (PD). The cytosolic E3 ubiquitin-protein ligase PARK2 cooperates with the mitochondrial kinase PINK1 to maintain mitochondrial quality. A loss of mitochondrial transmembrane potential (ΔΨ) leads to the PINK1-dependent recruitment of PARK2 to the outer mitochondrial membrane (OMM), followed by the ubiquitination and proteasome-dependent degradation of OMM proteins, and by the autophagy-dependent clearance of mitochondrial remnants. We showed here that blockade of mitochondrial protein import triggers the recruitment of PARK2, by PINK1, to the TOMM machinery. PD-causing PARK2 mutations weakened or disrupted the molecular interaction between PARK2 and specific TOMM subunits: the surface receptor, TOMM70A, and the channel protein, TOMM40. The downregulation of TOMM40 or its associated core subunit, TOMM22, was sufficient to trigger OMM protein clearance in the absence of PINK1 or PARK2. However, PARK2 was required to promote the degradation of whole organelles by autophagy. Furthermore, the overproduction of TOMM22 or TOMM40 reversed mitochondrial clearance promoted by PINK1 and PARK2 after ΔΨ loss. These results indicated that the TOMM machinery is a key molecular switch in the mitochondrial clearance program controlled by the PINK1-PARK2 pathway. Loss of functional coupling between mitochondrial protein import and the neuroprotective degradation of dysfunctional mitochondria may therefore be a primary pathogenic mechanism in autosomal recessive PD.
DOI: 10.4161/auto.25884
PubMed: 24149440
Affiliations:
Links toward previous steps (curation, corpus...)
- to stream PubMed, to step Corpus: 000665
- to stream PubMed, to step Curation: 000637
- to stream PubMed, to step Checkpoint: 000637
- to stream Ncbi, to step Merge: 001239
- to stream Ncbi, to step Curation: 001239
- to stream Ncbi, to step Checkpoint: 001239
- to stream Main, to step Merge: 000C35
- to stream Main, to step Curation: 000C14
Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">The TOMM machinery is a molecular switch in PINK1 and PARK2/PARKIN-dependent mitochondrial clearance.</title><author><name sortKey="Bertolin, Giulia" sort="Bertolin, Giulia" uniqKey="Bertolin G" first="Giulia" last="Bertolin">Giulia Bertolin</name><affiliation wicri:level="1"><nlm:affiliation>Inserm; U 975; CRICM; Hôpital de la Pitié-Salpêtrière; Paris, France; UPMC; Université Paris 06; UMR_S975; Paris, France; CNRS; UMR 7225; Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm; U 975; CRICM; Hôpital de la Pitié-Salpêtrière; Paris, France; UPMC; Université Paris 06; UMR_S975; Paris, France; CNRS; UMR 7225; Paris</wicri:regionArea><wicri:noRegion>France; CNRS; UMR 7225; Paris</wicri:noRegion><wicri:noRegion>France; CNRS; UMR 7225; Paris</wicri:noRegion></affiliation></author><author><name sortKey="Ferrando Miguel, Rosa" sort="Ferrando Miguel, Rosa" uniqKey="Ferrando Miguel R" first="Rosa" last="Ferrando-Miguel">Rosa Ferrando-Miguel</name></author><author><name sortKey="Jacoupy, Maxime" sort="Jacoupy, Maxime" uniqKey="Jacoupy M" first="Maxime" last="Jacoupy">Maxime Jacoupy</name></author><author><name sortKey="Traver, Sabine" sort="Traver, Sabine" uniqKey="Traver S" first="Sabine" last="Traver">Sabine Traver</name></author><author><name sortKey="Grenier, Karl" sort="Grenier, Karl" uniqKey="Grenier K" first="Karl" last="Grenier">Karl Grenier</name></author><author><name sortKey="Greene, Andrew W" sort="Greene, Andrew W" uniqKey="Greene A" first="Andrew W" last="Greene">Andrew W. Greene</name></author><author><name sortKey="Dauphin, Aurelien" sort="Dauphin, Aurelien" uniqKey="Dauphin A" first="Aurélien" last="Dauphin">Aurélien Dauphin</name></author><author><name sortKey="Waharte, Francois" sort="Waharte, Francois" uniqKey="Waharte F" first="François" last="Waharte">François Waharte</name></author><author><name sortKey="Bayot, Aurelien" sort="Bayot, Aurelien" uniqKey="Bayot A" first="Aurélien" last="Bayot">Aurélien Bayot</name></author><author><name sortKey="Salamero, Jean" sort="Salamero, Jean" uniqKey="Salamero J" first="Jean" last="Salamero">Jean Salamero</name></author><author><name sortKey="Lombes, Anne" sort="Lombes, Anne" uniqKey="Lombes A" first="Anne" last="Lombès">Anne Lombès</name></author><author><name sortKey="Bulteau, Anne Laure" sort="Bulteau, Anne Laure" uniqKey="Bulteau A" first="Anne-Laure" last="Bulteau">Anne-Laure Bulteau</name></author><author><name sortKey="Fon, Edward A" sort="Fon, Edward A" uniqKey="Fon E" first="Edward A" last="Fon">Edward A. Fon</name></author><author><name sortKey="Brice, Alexis" sort="Brice, Alexis" uniqKey="Brice A" first="Alexis" last="Brice">Alexis Brice</name></author><author><name sortKey="Corti, Olga" sort="Corti, Olga" uniqKey="Corti O" first="Olga" last="Corti">Olga Corti</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2013">2013</date><idno type="RBID">pubmed:24149440</idno><idno type="pmid">24149440</idno><idno type="doi">10.4161/auto.25884</idno><idno type="wicri:Area/PubMed/Corpus">000665</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000665</idno><idno type="wicri:Area/PubMed/Curation">000637</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000637</idno><idno type="wicri:Area/PubMed/Checkpoint">000637</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000637</idno><idno type="wicri:Area/Ncbi/Merge">001239</idno><idno type="wicri:Area/Ncbi/Curation">001239</idno><idno type="wicri:Area/Ncbi/Checkpoint">001239</idno><idno type="wicri:Area/Main/Merge">000C35</idno><idno type="wicri:Area/Main/Curation">000C14</idno><idno type="wicri:Area/Main/Exploration">000C14</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">The TOMM machinery is a molecular switch in PINK1 and PARK2/PARKIN-dependent mitochondrial clearance.</title><author><name sortKey="Bertolin, Giulia" sort="Bertolin, Giulia" uniqKey="Bertolin G" first="Giulia" last="Bertolin">Giulia Bertolin</name><affiliation wicri:level="1"><nlm:affiliation>Inserm; U 975; CRICM; Hôpital de la Pitié-Salpêtrière; Paris, France; UPMC; Université Paris 06; UMR_S975; Paris, France; CNRS; UMR 7225; Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm; U 975; CRICM; Hôpital de la Pitié-Salpêtrière; Paris, France; UPMC; Université Paris 06; UMR_S975; Paris, France; CNRS; UMR 7225; Paris</wicri:regionArea><wicri:noRegion>France; CNRS; UMR 7225; Paris</wicri:noRegion><wicri:noRegion>France; CNRS; UMR 7225; Paris</wicri:noRegion></affiliation></author><author><name sortKey="Ferrando Miguel, Rosa" sort="Ferrando Miguel, Rosa" uniqKey="Ferrando Miguel R" first="Rosa" last="Ferrando-Miguel">Rosa Ferrando-Miguel</name></author><author><name sortKey="Jacoupy, Maxime" sort="Jacoupy, Maxime" uniqKey="Jacoupy M" first="Maxime" last="Jacoupy">Maxime Jacoupy</name></author><author><name sortKey="Traver, Sabine" sort="Traver, Sabine" uniqKey="Traver S" first="Sabine" last="Traver">Sabine Traver</name></author><author><name sortKey="Grenier, Karl" sort="Grenier, Karl" uniqKey="Grenier K" first="Karl" last="Grenier">Karl Grenier</name></author><author><name sortKey="Greene, Andrew W" sort="Greene, Andrew W" uniqKey="Greene A" first="Andrew W" last="Greene">Andrew W. Greene</name></author><author><name sortKey="Dauphin, Aurelien" sort="Dauphin, Aurelien" uniqKey="Dauphin A" first="Aurélien" last="Dauphin">Aurélien Dauphin</name></author><author><name sortKey="Waharte, Francois" sort="Waharte, Francois" uniqKey="Waharte F" first="François" last="Waharte">François Waharte</name></author><author><name sortKey="Bayot, Aurelien" sort="Bayot, Aurelien" uniqKey="Bayot A" first="Aurélien" last="Bayot">Aurélien Bayot</name></author><author><name sortKey="Salamero, Jean" sort="Salamero, Jean" uniqKey="Salamero J" first="Jean" last="Salamero">Jean Salamero</name></author><author><name sortKey="Lombes, Anne" sort="Lombes, Anne" uniqKey="Lombes A" first="Anne" last="Lombès">Anne Lombès</name></author><author><name sortKey="Bulteau, Anne Laure" sort="Bulteau, Anne Laure" uniqKey="Bulteau A" first="Anne-Laure" last="Bulteau">Anne-Laure Bulteau</name></author><author><name sortKey="Fon, Edward A" sort="Fon, Edward A" uniqKey="Fon E" first="Edward A" last="Fon">Edward A. Fon</name></author><author><name sortKey="Brice, Alexis" sort="Brice, Alexis" uniqKey="Brice A" first="Alexis" last="Brice">Alexis Brice</name></author><author><name sortKey="Corti, Olga" sort="Corti, Olga" uniqKey="Corti O" first="Olga" last="Corti">Olga Corti</name></author></analytic><series><title level="j">Autophagy</title><idno type="eISSN">1554-8635</idno><imprint><date when="2013" type="published">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Down-Regulation</term><term>HEK293 Cells</term><term>HeLa Cells</term><term>Humans</term><term>Membrane Transport Proteins (metabolism)</term><term>Mitochondria (metabolism)</term><term>Mitochondrial Degradation</term><term>Mitochondrial Membrane Transport Proteins (metabolism)</term><term>Mitochondrial Membranes (metabolism)</term><term>Models, Biological</term><term>Mutation (genetics)</term><term>Parkinson Disease (genetics)</term><term>Protein Binding</term><term>Protein Kinases (metabolism)</term><term>Protein Transport</term><term>Signal Transduction</term><term>Ubiquitin-Protein Ligases (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Membrane Transport Proteins</term><term>Mitochondrial Membrane Transport Proteins</term><term>Protein Kinases</term><term>Ubiquitin-Protein Ligases</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Mutation</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Mitochondria</term><term>Mitochondrial Membranes</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Down-Regulation</term><term>HEK293 Cells</term><term>HeLa Cells</term><term>Humans</term><term>Mitochondrial Degradation</term><term>Models, Biological</term><term>Protein Binding</term><term>Protein Transport</term><term>Signal Transduction</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Loss-of-function mutations in PARK2/PARKIN and PINK1 cause early-onset autosomal recessive Parkinson disease (PD). The cytosolic E3 ubiquitin-protein ligase PARK2 cooperates with the mitochondrial kinase PINK1 to maintain mitochondrial quality. A loss of mitochondrial transmembrane potential (ΔΨ) leads to the PINK1-dependent recruitment of PARK2 to the outer mitochondrial membrane (OMM), followed by the ubiquitination and proteasome-dependent degradation of OMM proteins, and by the autophagy-dependent clearance of mitochondrial remnants. We showed here that blockade of mitochondrial protein import triggers the recruitment of PARK2, by PINK1, to the TOMM machinery. PD-causing PARK2 mutations weakened or disrupted the molecular interaction between PARK2 and specific TOMM subunits: the surface receptor, TOMM70A, and the channel protein, TOMM40. The downregulation of TOMM40 or its associated core subunit, TOMM22, was sufficient to trigger OMM protein clearance in the absence of PINK1 or PARK2. However, PARK2 was required to promote the degradation of whole organelles by autophagy. Furthermore, the overproduction of TOMM22 or TOMM40 reversed mitochondrial clearance promoted by PINK1 and PARK2 after ΔΨ loss. These results indicated that the TOMM machinery is a key molecular switch in the mitochondrial clearance program controlled by the PINK1-PARK2 pathway. Loss of functional coupling between mitochondrial protein import and the neuroprotective degradation of dysfunctional mitochondria may therefore be a primary pathogenic mechanism in autosomal recessive PD.</div></front></TEI><affiliations><list><country><li>France</li></country></list><tree><noCountry><name sortKey="Bayot, Aurelien" sort="Bayot, Aurelien" uniqKey="Bayot A" first="Aurélien" last="Bayot">Aurélien Bayot</name><name sortKey="Brice, Alexis" sort="Brice, Alexis" uniqKey="Brice A" first="Alexis" last="Brice">Alexis Brice</name><name sortKey="Bulteau, Anne Laure" sort="Bulteau, Anne Laure" uniqKey="Bulteau A" first="Anne-Laure" last="Bulteau">Anne-Laure Bulteau</name><name sortKey="Corti, Olga" sort="Corti, Olga" uniqKey="Corti O" first="Olga" last="Corti">Olga Corti</name><name sortKey="Dauphin, Aurelien" sort="Dauphin, Aurelien" uniqKey="Dauphin A" first="Aurélien" last="Dauphin">Aurélien Dauphin</name><name sortKey="Ferrando Miguel, Rosa" sort="Ferrando Miguel, Rosa" uniqKey="Ferrando Miguel R" first="Rosa" last="Ferrando-Miguel">Rosa Ferrando-Miguel</name><name sortKey="Fon, Edward A" sort="Fon, Edward A" uniqKey="Fon E" first="Edward A" last="Fon">Edward A. Fon</name><name sortKey="Greene, Andrew W" sort="Greene, Andrew W" uniqKey="Greene A" first="Andrew W" last="Greene">Andrew W. Greene</name><name sortKey="Grenier, Karl" sort="Grenier, Karl" uniqKey="Grenier K" first="Karl" last="Grenier">Karl Grenier</name><name sortKey="Jacoupy, Maxime" sort="Jacoupy, Maxime" uniqKey="Jacoupy M" first="Maxime" last="Jacoupy">Maxime Jacoupy</name><name sortKey="Lombes, Anne" sort="Lombes, Anne" uniqKey="Lombes A" first="Anne" last="Lombès">Anne Lombès</name><name sortKey="Salamero, Jean" sort="Salamero, Jean" uniqKey="Salamero J" first="Jean" last="Salamero">Jean Salamero</name><name sortKey="Traver, Sabine" sort="Traver, Sabine" uniqKey="Traver S" first="Sabine" last="Traver">Sabine Traver</name><name sortKey="Waharte, Francois" sort="Waharte, Francois" uniqKey="Waharte F" first="François" last="Waharte">François Waharte</name></noCountry><country name="France"><noRegion><name sortKey="Bertolin, Giulia" sort="Bertolin, Giulia" uniqKey="Bertolin G" first="Giulia" last="Bertolin">Giulia Bertolin</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Sante/explor/ParkinsonFranceV1/Data/Main/Exploration
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000C14 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 000C14 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Sante
|area= ParkinsonFranceV1
|flux= Main
|étape= Exploration
|type= RBID
|clé= pubmed:24149440
|texte= The TOMM machinery is a molecular switch in PINK1 and PARK2/PARKIN-dependent mitochondrial clearance.
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Exploration/RBID.i -Sk "pubmed:24149440" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd \
| NlmPubMed2Wicri -a ParkinsonFranceV1
| This area was generated with Dilib version V0.6.29. |  |