Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment
Identifieur interne : 001401 ( Main/Exploration ); précédent : 001400; suivant : 001402Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment
Auteurs : Andrew W. Greene [Canada] ; Karl Grenier [Canada] ; Miguel A. Aguileta [Canada] ; Stephanie Muise [Canada] ; Rasoul Farazifard [Canada] ; M Emdadul Haque [Canada] ; Heidi M. Mcbride [Canada] ; David S. Park [Canada] ; Edward A. Fon [Canada]Source :
- EMBO reports [ 1469-221X ] ; 2012-04.
English descriptors
- KwdEn :
- ATP-Dependent Proteases (metabolism), Autophagy (drug effects), Carbonyl Cyanide m-Chlorophenyl Hydrazone (pharmacology), Endopeptidase Clp (metabolism), Gene Knockdown Techniques, HEK293 Cells, Humans, Metalloendopeptidases (metabolism), Mitochondria (drug effects), Mitochondria (metabolism), Molecular Weight, Peptide Fragments (metabolism), Proteasome Endopeptidase Complex (metabolism), Protein Kinases (metabolism), Protein Processing, Post-Translational (drug effects), Protein Transport (drug effects), RNA, Small Interfering (metabolism), Ubiquitin-Protein Ligases (metabolism).
- MESH :
- chemical , metabolism : ATP-Dependent Proteases, Endopeptidase Clp, Metalloendopeptidases, Peptide Fragments, Proteasome Endopeptidase Complex, Protein Kinases, RNA, Small Interfering, Ubiquitin-Protein Ligases.
- drug effects : Autophagy, Mitochondria, Protein Processing, Post-Translational, Protein Transport.
- metabolism : Mitochondria.
- chemical , pharmacology : Carbonyl Cyanide m-Chlorophenyl Hydrazone.
- Gene Knockdown Techniques, HEK293 Cells, Humans, Molecular Weight.
Abstract
Mutations in phosphatase and tensin homologue‐induced kinase 1 (PINK1) cause recessively inherited Parkinson's disease (PD), a neurodegenerative disorder linked to mitochondrial dysfunction. In healthy mitochondria, PINK1 is rapidly degraded in a process involving both mitochondrial proteases and the proteasome. However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD‐linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. Using an unbiased RNA‐mediated interference (RNAi)‐based screen, we identified four mitochondrial proteases, mitochondrial processing peptidase (MPP), presenilin‐associated rhomboid‐like protease (PARL), m‐AAA and ClpXP, involved in PINK1 degradation. We find that PINK1 turnover is particularly sensitive to even modest reductions in MPP levels. Moreover, PINK1 cleavage by MPP is coupled to import such that reducing MPP activity induces PINK1 accumulation at the mitochondrial surface, leading to Parkin recruitment and mitophagy. These results highlight a new role for MPP in PINK1 import and mitochondrial quality control via the PINK1–Parkin pathway.
Url:
DOI: 10.1038/embor.2012.14
Affiliations:
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In healthy mitochondria, PINK1 is rapidly degraded in a process involving both mitochondrial proteases and the proteasome. However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD‐linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. Using an unbiased RNA‐mediated interference (RNAi)‐based screen, we identified four mitochondrial proteases, mitochondrial processing peptidase (MPP), presenilin‐associated rhomboid‐like protease (PARL), m‐AAA and ClpXP, involved in PINK1 degradation. We find that PINK1 turnover is particularly sensitive to even modest reductions in MPP levels. Moreover, PINK1 cleavage by MPP is coupled to import such that reducing MPP activity induces PINK1 accumulation at the mitochondrial surface, leading to Parkin recruitment and mitophagy. These results highlight a new role for MPP in PINK1 import and mitochondrial quality control via the PINK1–Parkin pathway.</div></front></TEI><affiliations><list><country><li>Canada</li></country><region><li>Québec</li></region><settlement><li>Montréal</li></settlement><orgName><li>Université McGill</li></orgName></list><tree><country name="Canada"><region name="Québec"><name sortKey="Greene, Andrew W" sort="Greene, Andrew W" uniqKey="Greene A" first="Andrew W" last="Greene">Andrew W. Greene</name></region><name sortKey="Aguileta, Miguel A" sort="Aguileta, Miguel A" uniqKey="Aguileta M" first="Miguel A" last="Aguileta">Miguel A. Aguileta</name><name sortKey="Farazifard, Rasoul" sort="Farazifard, Rasoul" uniqKey="Farazifard R" first="Rasoul" last="Farazifard">Rasoul Farazifard</name><name sortKey="Fon, Edward A" sort="Fon, Edward A" uniqKey="Fon E" first="Edward A" last="Fon">Edward A. Fon</name><name sortKey="Fon, Edward A" sort="Fon, Edward A" uniqKey="Fon E" first="Edward A" last="Fon">Edward A. Fon</name><name sortKey="Grenier, Karl" sort="Grenier, Karl" uniqKey="Grenier K" first="Karl" last="Grenier">Karl Grenier</name><name sortKey="Haque, M Emdadul" sort="Haque, M Emdadul" uniqKey="Haque M" first="M Emdadul" last="Haque">M Emdadul Haque</name><name sortKey="Mcbride, Heidi M" sort="Mcbride, Heidi M" uniqKey="Mcbride H" first="Heidi M" last="Mcbride">Heidi M. Mcbride</name><name sortKey="Muise, Stephanie" sort="Muise, Stephanie" uniqKey="Muise S" first="Stephanie" last="Muise">Stephanie Muise</name><name sortKey="Park, David S" sort="Park, David S" uniqKey="Park D" first="David S" last="Park">David S. Park</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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