Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/37344
Title: Drosophila ref(2)P is required for the parkin-mediated suppression of mitochondrial dysfunction in pink1 mutants
Authors: de Castro, I. P.
Costa, A. C.
Celardo, I.
Tufi, R.
Dinsdale, D.
Loh, S. H.
Martins, L. Miguel
First Published: 24-Oct-2013
Publisher: Nature Publishing Group for Associazione Differenziamento e Morte Cellulare
Citation: Cell Death and Disease, 2013, 4, e873
Abstract: Autophagy is a critical regulator of organellar homeostasis, particularly of mitochondria. Upon the loss of membrane potential, dysfunctional mitochondria are selectively removed by autophagy through recruitment of the E3 ligase Parkin by the PTEN-induced kinase 1 (PINK1) and subsequent ubiquitination of mitochondrial membrane proteins. Mammalian sequestrome-1 (p62/SQSTM1) is an autophagy adaptor, which has been proposed to shuttle ubiquitinated cargo for autophagic degradation downstream of Parkin. Here, we show that loss of ref(2)P, the Drosophila orthologue of mammalian P62, results in abnormalities, including mitochondrial defects and an accumulation of mitochondrial DNA with heteroplasmic mutations, correlated with locomotor defects. Furthermore, we show that expression of Ref(2)P is able to ameliorate the defects caused by loss of Pink1 and that this depends on the presence of functional Parkin. Finally, we show that both the PB1 and UBA domains of Ref(2)P are crucial for mitochondrial clustering. We conclude that Ref(2)P is a crucial downstream effector of a pathway involving Pink1 and Parkin and is responsible for the maintenance of a viable pool of cellular mitochondria by promoting their aggregation and autophagic clearance.
DOI Link: 10.1038/cddis.2013.394
eISSN: 2041-4889
Links: http://www.nature.com/cddis/journal/v4/n10/full/cddis2013394a.html
http://hdl.handle.net/2381/37344
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © 2013, the authors. This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.
Appears in Collections:Published Articles, MRC Toxicology Unit

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