PINK1 is selectively stabilized on impaired mitochondria to activate Parkin.

Loss-of-function mutations in PINK1 and Parkin cause parkinsonism in humans and mitochondrial dysfunction in model organisms. Parkin is selectively recruited from the cytosol to damaged mitochondria to trigger their autophagy. How Parkin recognizes damaged mitochondria, however, is unknown. Here, we...

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Autores principales:	Derek P Narendra, Seok Min Jin, Atsushi Tanaka, Der-Fen Suen, Clement A Gautier, Jie Shen, Mark R Cookson, Richard J Youle
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/8e127fc52b86486593b7ee294d8b508c
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spelling	oai:doaj.org-article:8e127fc52b86486593b7ee294d8b508c2021-11-25T05:34:24ZPINK1 is selectively stabilized on impaired mitochondria to activate Parkin.1544-91731545-788510.1371/journal.pbio.1000298https://doaj.org/article/8e127fc52b86486593b7ee294d8b508c2010-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20126261/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Loss-of-function mutations in PINK1 and Parkin cause parkinsonism in humans and mitochondrial dysfunction in model organisms. Parkin is selectively recruited from the cytosol to damaged mitochondria to trigger their autophagy. How Parkin recognizes damaged mitochondria, however, is unknown. Here, we show that expression of PINK1 on individual mitochondria is regulated by voltage-dependent proteolysis to maintain low levels of PINK1 on healthy, polarized mitochondria, while facilitating the rapid accumulation of PINK1 on mitochondria that sustain damage. PINK1 accumulation on mitochondria is both necessary and sufficient for Parkin recruitment to mitochondria, and disease-causing mutations in PINK1 and Parkin disrupt Parkin recruitment and Parkin-induced mitophagy at distinct steps. These findings provide a biochemical explanation for the genetic epistasis between PINK1 and Parkin in Drosophila melanogaster. In addition, they support a novel model for the negative selection of damaged mitochondria, in which PINK1 signals mitochondrial dysfunction to Parkin, and Parkin promotes their elimination.Derek P NarendraSeok Min JinAtsushi TanakaDer-Fen SuenClement A GautierJie ShenMark R CooksonRichard J YoulePublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 8, Iss 1, p e1000298 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Derek P Narendra Seok Min Jin Atsushi Tanaka Der-Fen Suen Clement A Gautier Jie Shen Mark R Cookson Richard J Youle PINK1 is selectively stabilized on impaired mitochondria to activate Parkin.
description	Loss-of-function mutations in PINK1 and Parkin cause parkinsonism in humans and mitochondrial dysfunction in model organisms. Parkin is selectively recruited from the cytosol to damaged mitochondria to trigger their autophagy. How Parkin recognizes damaged mitochondria, however, is unknown. Here, we show that expression of PINK1 on individual mitochondria is regulated by voltage-dependent proteolysis to maintain low levels of PINK1 on healthy, polarized mitochondria, while facilitating the rapid accumulation of PINK1 on mitochondria that sustain damage. PINK1 accumulation on mitochondria is both necessary and sufficient for Parkin recruitment to mitochondria, and disease-causing mutations in PINK1 and Parkin disrupt Parkin recruitment and Parkin-induced mitophagy at distinct steps. These findings provide a biochemical explanation for the genetic epistasis between PINK1 and Parkin in Drosophila melanogaster. In addition, they support a novel model for the negative selection of damaged mitochondria, in which PINK1 signals mitochondrial dysfunction to Parkin, and Parkin promotes their elimination.
format	article
author	Derek P Narendra Seok Min Jin Atsushi Tanaka Der-Fen Suen Clement A Gautier Jie Shen Mark R Cookson Richard J Youle
author_facet	Derek P Narendra Seok Min Jin Atsushi Tanaka Der-Fen Suen Clement A Gautier Jie Shen Mark R Cookson Richard J Youle
author_sort	Derek P Narendra
title	PINK1 is selectively stabilized on impaired mitochondria to activate Parkin.
title_short	PINK1 is selectively stabilized on impaired mitochondria to activate Parkin.
title_full	PINK1 is selectively stabilized on impaired mitochondria to activate Parkin.
title_fullStr	PINK1 is selectively stabilized on impaired mitochondria to activate Parkin.
title_full_unstemmed	PINK1 is selectively stabilized on impaired mitochondria to activate Parkin.
title_sort	pink1 is selectively stabilized on impaired mitochondria to activate parkin.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/8e127fc52b86486593b7ee294d8b508c
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_version_	1718414589588144128

PINK1 is selectively stabilized on impaired mitochondria to activate Parkin.

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