Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/37404
Title: Genetic analysis of mitochondrial protein misfolding in Drosophila melanogaster
Authors: Pimenta de Castro, I.
Costa, A. C.
Lam, D.
Tufi, R.
Fedele, V.
Moisoi, N.
Dinsdale, D.
Deas, E.
Loh, S. H.
Martins, L. Miguel
First Published: 3-Feb-2012
Publisher: Nature Publishing Group for Congregazione dei Figli dell'Immacolata Concezione (CFIC), Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Dermopatico dell'Immacolata (IDI-IRCCS)
Citation: Cell Death and Differentiation, 2012, 19 (8), pp. 1308-1316
Abstract: Protein misfolding has a key role in several neurological disorders including Parkinson's disease. Although a clear mechanism for such proteinopathic diseases is well established when aggregated proteins accumulate in the cytosol, cell nucleus, endoplasmic reticulum and extracellular space, little is known about the role of protein aggregation in the mitochondria. Here we show that mutations in both human and fly PINK1 result in higher levels of misfolded components of respiratory complexes and increase in markers of the mitochondrial unfolded protein response. Through the development of a genetic model of mitochondrial protein misfolding employing Drosophila melanogaster, we show that the in vivo accumulation of an unfolded protein in mitochondria results in the activation of AMP-activated protein kinase-dependent autophagy and phenocopies of pink1 and parkin mutants. Parkin expression acts to clear mitochondria with enhanced levels of misfolded proteins by promoting their autophagic degradation in vivo, and refractory to Sigma P (ref(2)P), the Drosophila orthologue of mammalian p62, is a critical downstream effector of this quality control pathway. We show that in flies, a pathway involving pink1, parkin and ref(2)P has a role in the maintenance of a viable pool of cellular mitochondria by promoting organellar quality control.
DOI Link: 10.1038/cdd.2012.5
ISSN: 1350-9047
eISSN: 1476-5403
Links: http://www.nature.com/cdd/journal/v19/n8/full/cdd20125a.html
http://hdl.handle.net/2381/37404
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © 2012, the authors. This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 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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