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Mitochondrial impairment increases FL-PINK1 levels by calcium-dependent gene expression.

Gómez-Sánchez, R; Gegg, ME; Bravo-San Pedro, JM; Niso-Santano, M; Alvarez-Erviti, L; Pizarro-Estrella, E; Gutiérrez-Martín, Y; ... Schapira, AH; + view all (2014) Mitochondrial impairment increases FL-PINK1 levels by calcium-dependent gene expression. Neurobiol Dis , 62 426-440. 10.1016/j.nbd.2013.10.021. Green open access

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Abstract

Mutations of the PTEN-induced kinase 1 (PINK1) gene are a cause of autosomal recessive Parkinson's disease (PD). This gene encodes a mitochondrial serine/threonine kinase, which is partly localized to mitochondria, and has been shown to play a role in protecting neuronal cells from oxidative stress and cell death, perhaps related to its role in mitochondrial dynamics and mitophagy. In this study, we report that increased mitochondrial PINK1 levels observed in human neuroblastoma SH-SY5Y cells after carbonyl cyanide m-chlorophelyhydrazone (CCCP) treatment were due to de novo protein synthesis, and not just increased stabilization of full length PINK1 (FL-PINK1). PINK1 mRNA levels were significantly increased by 4-fold after 24h. FL-PINK1 protein levels at this time point were significantly higher than vehicle-treated, or cells treated with CCCP for 3h, despite mitochondrial content being decreased by 29%. We have also shown that CCCP dissipated the mitochondrial membrane potential (Δψm) and induced entry of extracellular calcium through L/N-type calcium channels. The calcium chelating agent BAPTA-AM impaired the CCCP-induced PINK1 mRNA and protein expression. Furthermore, CCCP treatment activated the transcription factor c-Fos in a calcium-dependent manner. These data indicate that PINK1 expression is significantly increased upon CCCP-induced mitophagy in a calcium-dependent manner. This increase in expression continues after peak Parkin mitochondrial translocation, suggesting a role for PINK1 in mitophagy that is downstream of ubiquitination of mitochondrial substrates. This sensitivity to intracellular calcium levels supports the hypothesis that PINK1 may also play a role in cellular calcium homeostasis and neuroprotection.

Type: Article
Title: Mitochondrial impairment increases FL-PINK1 levels by calcium-dependent gene expression.
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.nbd.2013.10.021
Publisher version: http://dx.doi.org/10.1016/j.nbd.2013.10.021
Additional information: © 2013 The Authors. Published by Elsevier Inc. All rights reserved. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: CCCP, Calcium, Mitophagy, PINK1, Parkinson's disease, SH-SY5Y
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical Neuroscience
URI: http://discovery.ucl.ac.uk/id/eprint/1420481
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