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PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy

Parkinson's disease (PD) is a prevalent neurodegenerative disorder. Recent identification of genes linked to familial forms of PD such as Parkin and PINK1 (PTEN-induced putative kinase 1) has revealed that ubiquitylation and mitochondrial integrity are key factors in disease pathogenesis. Howev...

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Autores principales: Matsuda, Noriyuki, Sato, Shigeto, Shiba, Kahori, Okatsu, Kei, Saisho, Keiko, Gautier, Clement A., Sou, Yu-shin, Saiki, Shinji, Kawajiri, Sumihiro, Sato, Fumiaki, Kimura, Mayumi, Komatsu, Masaaki, Hattori, Nobutaka, Tanaka, Keiji
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2856912/
https://www.ncbi.nlm.nih.gov/pubmed/20404107
http://dx.doi.org/10.1083/jcb.200910140
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author Matsuda, Noriyuki
Sato, Shigeto
Shiba, Kahori
Okatsu, Kei
Saisho, Keiko
Gautier, Clement A.
Sou, Yu-shin
Saiki, Shinji
Kawajiri, Sumihiro
Sato, Fumiaki
Kimura, Mayumi
Komatsu, Masaaki
Hattori, Nobutaka
Tanaka, Keiji
author_facet Matsuda, Noriyuki
Sato, Shigeto
Shiba, Kahori
Okatsu, Kei
Saisho, Keiko
Gautier, Clement A.
Sou, Yu-shin
Saiki, Shinji
Kawajiri, Sumihiro
Sato, Fumiaki
Kimura, Mayumi
Komatsu, Masaaki
Hattori, Nobutaka
Tanaka, Keiji
author_sort Matsuda, Noriyuki
collection PubMed
description Parkinson's disease (PD) is a prevalent neurodegenerative disorder. Recent identification of genes linked to familial forms of PD such as Parkin and PINK1 (PTEN-induced putative kinase 1) has revealed that ubiquitylation and mitochondrial integrity are key factors in disease pathogenesis. However, the exact mechanism underlying the functional interplay between Parkin-catalyzed ubiquitylation and PINK1-regulated mitochondrial quality control remains an enigma. In this study, we show that PINK1 is rapidly and constitutively degraded under steady-state conditions in a mitochondrial membrane potential–dependent manner and that a loss in mitochondrial membrane potential stabilizes PINK1 mitochondrial accumulation. Furthermore, PINK1 recruits Parkin from the cytoplasm to mitochondria with low membrane potential to initiate the autophagic degradation of damaged mitochondria. Interestingly, the ubiquitin ligase activity of Parkin is repressed in the cytoplasm under steady-state conditions; however, PINK1-dependent mitochondrial localization liberates the latent enzymatic activity of Parkin. Some pathogenic mutations of PINK1 and Parkin interfere with the aforementioned events, suggesting an etiological importance. These results provide crucial insight into the pathogenic mechanisms of PD.
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spelling pubmed-28569122010-10-19 PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy Matsuda, Noriyuki Sato, Shigeto Shiba, Kahori Okatsu, Kei Saisho, Keiko Gautier, Clement A. Sou, Yu-shin Saiki, Shinji Kawajiri, Sumihiro Sato, Fumiaki Kimura, Mayumi Komatsu, Masaaki Hattori, Nobutaka Tanaka, Keiji J Cell Biol Research Articles Parkinson's disease (PD) is a prevalent neurodegenerative disorder. Recent identification of genes linked to familial forms of PD such as Parkin and PINK1 (PTEN-induced putative kinase 1) has revealed that ubiquitylation and mitochondrial integrity are key factors in disease pathogenesis. However, the exact mechanism underlying the functional interplay between Parkin-catalyzed ubiquitylation and PINK1-regulated mitochondrial quality control remains an enigma. In this study, we show that PINK1 is rapidly and constitutively degraded under steady-state conditions in a mitochondrial membrane potential–dependent manner and that a loss in mitochondrial membrane potential stabilizes PINK1 mitochondrial accumulation. Furthermore, PINK1 recruits Parkin from the cytoplasm to mitochondria with low membrane potential to initiate the autophagic degradation of damaged mitochondria. Interestingly, the ubiquitin ligase activity of Parkin is repressed in the cytoplasm under steady-state conditions; however, PINK1-dependent mitochondrial localization liberates the latent enzymatic activity of Parkin. Some pathogenic mutations of PINK1 and Parkin interfere with the aforementioned events, suggesting an etiological importance. These results provide crucial insight into the pathogenic mechanisms of PD. The Rockefeller University Press 2010-04-19 /pmc/articles/PMC2856912/ /pubmed/20404107 http://dx.doi.org/10.1083/jcb.200910140 Text en © 2010 Matsuda et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Matsuda, Noriyuki
Sato, Shigeto
Shiba, Kahori
Okatsu, Kei
Saisho, Keiko
Gautier, Clement A.
Sou, Yu-shin
Saiki, Shinji
Kawajiri, Sumihiro
Sato, Fumiaki
Kimura, Mayumi
Komatsu, Masaaki
Hattori, Nobutaka
Tanaka, Keiji
PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy
title PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy
title_full PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy
title_fullStr PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy
title_full_unstemmed PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy
title_short PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy
title_sort pink1 stabilized by mitochondrial depolarization recruits parkin to damaged mitochondria and activates latent parkin for mitophagy
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2856912/
https://www.ncbi.nlm.nih.gov/pubmed/20404107
http://dx.doi.org/10.1083/jcb.200910140
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