Genome-wide RNAi screen identifies ATPase inhibitory factor 1 (ATPIF1) as essential for PARK2 recruitment and mitophagy.
Identifieur interne : 000D67 ( Main/Exploration ); précédent : 000D66; suivant : 000D68Genome-wide RNAi screen identifies ATPase inhibitory factor 1 (ATPIF1) as essential for PARK2 recruitment and mitophagy.
Auteurs : Valerie Lefebvre ; Qiujiang Du ; Stephen Baird ; Andy Cheuk-Him Ng ; Mirna Nascimento ; Michelangelo Campanella ; Heidi M. Mcbride ; Robert A. ScreatonSource :
- Autophagy [ 1554-8635 ] ; 2013.
English descriptors
- KwdEn :
- MESH :
- chemical , metabolism : Proteins, Ubiquitin-Protein Ligases.
- Electron Transport, Genome, Human, HeLa Cells, Humans, Membrane Potential, Mitochondrial, Mitochondrial Degradation, RNA Interference.
Abstract
Mitochondrial dysfunction is a hallmark of aging and numerous human diseases, including Parkinson disease (PD). Multiple homeostatic mechanisms exist to ensure mitochondrial integrity, including the selective autophagic program mitophagy, that is activated during starvation or in response to mitochondrial dysfunction. Following prolonged loss of potential across the inner mitochondrial membrane (ΔΨ), PTEN-induced putative kinase 1 (PINK1) and the E3-ubiquitin ligase PARK2 work in the same pathway to trigger mitophagy of dysfunctional mitochondria. Mutations in PINK1 and PARK2, as well as PARK7/DJ-1, underlie autosomal recessive Parkinsonism and impair mitochondrial function and morphology. In a genome-wide RNAi screen searching for genes that are required for PARK2 translocation to the mitochondria, we identified ATPase inhibitory factor 1 (ATPIF1/IF1) as essential for PARK2 recruitment and mitophagy in cultured cells. During uncoupling, ATPIF1 promotes collapse of ΔΨ and activation of the PINK-PARK2 mitophagy pathway by blocking the ATPase activity of the F 1-Fo ATP synthase. Restoration of ATPIF1 in Rho0 cells, which lack mtDNA and a functional electron transport chain, lowers ΔΨ and triggers PARK2 recruitment. Our findings identified ATPIF1 and the ATP synthase as novel components of the PINK1-PARK2 mitophagy pathway and provide genetic evidence that loss of ΔΨ is an essential trigger for mitophagy.
DOI: 10.4161/auto.25413
PubMed: 24005319
Affiliations:
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Mcbride</name></author><author><name sortKey="Screaton, Robert A" sort="Screaton, Robert A" uniqKey="Screaton R" first="Robert A" last="Screaton">Robert A. Screaton</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2013">2013</date><idno type="RBID">pubmed:24005319</idno><idno type="pmid">24005319</idno><idno type="doi">10.4161/auto.25413</idno><idno type="wicri:Area/PubMed/Corpus">000839</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000839</idno><idno type="wicri:Area/PubMed/Curation">000839</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000839</idno><idno type="wicri:Area/PubMed/Checkpoint">000839</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000839</idno><idno type="wicri:Area/Ncbi/Merge">001557</idno><idno type="wicri:Area/Ncbi/Curation">001557</idno><idno type="wicri:Area/Ncbi/Checkpoint">001557</idno><idno type="wicri:Area/Main/Merge">000D78</idno><idno type="wicri:Area/Main/Curation">000D67</idno><idno type="wicri:Area/Main/Exploration">000D67</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Genome-wide RNAi screen identifies ATPase inhibitory factor 1 (ATPIF1) as essential for PARK2 recruitment and mitophagy.</title><author><name sortKey="Lefebvre, Valerie" sort="Lefebvre, Valerie" uniqKey="Lefebvre V" first="Valerie" last="Lefebvre">Valerie Lefebvre</name><affiliation><nlm:affiliation>Children's Hospital of Eastern Ontario Research Institute; Ottawa, ON Canada; Department of Cellular and Molecular Medicine; University of Ottawa; Ottawa, ON Canada.</nlm:affiliation><wicri:noCountry code="subField">ON Canada</wicri:noCountry></affiliation></author><author><name sortKey="Du, Qiujiang" sort="Du, Qiujiang" uniqKey="Du Q" first="Qiujiang" last="Du">Qiujiang Du</name></author><author><name sortKey="Baird, Stephen" sort="Baird, Stephen" uniqKey="Baird S" first="Stephen" last="Baird">Stephen Baird</name></author><author><name sortKey="Ng, Andy Cheuk Him" sort="Ng, Andy Cheuk Him" uniqKey="Ng A" first="Andy Cheuk-Him" last="Ng">Andy Cheuk-Him Ng</name></author><author><name sortKey="Nascimento, Mirna" sort="Nascimento, Mirna" uniqKey="Nascimento M" first="Mirna" last="Nascimento">Mirna Nascimento</name></author><author><name sortKey="Campanella, Michelangelo" sort="Campanella, Michelangelo" uniqKey="Campanella M" first="Michelangelo" last="Campanella">Michelangelo Campanella</name></author><author><name sortKey="Mcbride, Heidi M" sort="Mcbride, Heidi M" uniqKey="Mcbride H" first="Heidi M" last="Mcbride">Heidi M. Mcbride</name></author><author><name sortKey="Screaton, Robert A" sort="Screaton, Robert A" uniqKey="Screaton R" first="Robert A" last="Screaton">Robert A. Screaton</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>Electron Transport</term><term>Genome, Human</term><term>HeLa Cells</term><term>Humans</term><term>Membrane Potential, Mitochondrial</term><term>Mitochondrial Degradation</term><term>Proteins (metabolism)</term><term>RNA Interference</term><term>Ubiquitin-Protein Ligases (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Proteins</term><term>Ubiquitin-Protein Ligases</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Electron Transport</term><term>Genome, Human</term><term>HeLa Cells</term><term>Humans</term><term>Membrane Potential, Mitochondrial</term><term>Mitochondrial Degradation</term><term>RNA Interference</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Mitochondrial dysfunction is a hallmark of aging and numerous human diseases, including Parkinson disease (PD). Multiple homeostatic mechanisms exist to ensure mitochondrial integrity, including the selective autophagic program mitophagy, that is activated during starvation or in response to mitochondrial dysfunction. Following prolonged loss of potential across the inner mitochondrial membrane (ΔΨ), PTEN-induced putative kinase 1 (PINK1) and the E3-ubiquitin ligase PARK2 work in the same pathway to trigger mitophagy of dysfunctional mitochondria. Mutations in PINK1 and PARK2, as well as PARK7/DJ-1, underlie autosomal recessive Parkinsonism and impair mitochondrial function and morphology. In a genome-wide RNAi screen searching for genes that are required for PARK2 translocation to the mitochondria, we identified ATPase inhibitory factor 1 (ATPIF1/IF1) as essential for PARK2 recruitment and mitophagy in cultured cells. During uncoupling, ATPIF1 promotes collapse of ΔΨ and activation of the PINK-PARK2 mitophagy pathway by blocking the ATPase activity of the F 1-Fo ATP synthase. Restoration of ATPIF1 in Rho0 cells, which lack mtDNA and a functional electron transport chain, lowers ΔΨ and triggers PARK2 recruitment. Our findings identified ATPIF1 and the ATP synthase as novel components of the PINK1-PARK2 mitophagy pathway and provide genetic evidence that loss of ΔΨ is an essential trigger for mitophagy.</div></front></TEI><affiliations><list></list><tree><noCountry><name sortKey="Baird, Stephen" sort="Baird, Stephen" uniqKey="Baird S" first="Stephen" last="Baird">Stephen Baird</name><name sortKey="Campanella, Michelangelo" sort="Campanella, Michelangelo" uniqKey="Campanella M" first="Michelangelo" last="Campanella">Michelangelo Campanella</name><name sortKey="Du, Qiujiang" sort="Du, Qiujiang" uniqKey="Du Q" first="Qiujiang" last="Du">Qiujiang Du</name><name sortKey="Lefebvre, Valerie" sort="Lefebvre, Valerie" uniqKey="Lefebvre V" first="Valerie" last="Lefebvre">Valerie Lefebvre</name><name sortKey="Mcbride, Heidi M" sort="Mcbride, Heidi M" uniqKey="Mcbride H" first="Heidi M" last="Mcbride">Heidi M. Mcbride</name><name sortKey="Nascimento, Mirna" sort="Nascimento, Mirna" uniqKey="Nascimento M" first="Mirna" last="Nascimento">Mirna Nascimento</name><name sortKey="Ng, Andy Cheuk Him" sort="Ng, Andy Cheuk Him" uniqKey="Ng A" first="Andy Cheuk-Him" last="Ng">Andy Cheuk-Him Ng</name><name sortKey="Screaton, Robert A" sort="Screaton, Robert A" uniqKey="Screaton R" first="Robert A" last="Screaton">Robert A. Screaton</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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