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

NEUROBIOLOGY OF DISEASE

卷:62

Article

Gomez-Sanchez, Ruben¹  Gegg, Matthew E.²  Bravo-San Pedro, Jose M.^1,3  Niso-Santano, Mireia^1,3  Alvarez-Erviti, Lydia²  Pizarro-Estrella, Elisa¹  Gutierrez-Martin, Yolanda⁴  Alvarez-Barrientos, Alberto⁴  Fuentes, Jose M.¹  Ana Gonzalez-Polo, Rosa¹  Schapira, Anthony H. V.² 

[1] Univ Extremadura, Dept Bioquim & Biol Mol & Genet, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Caceres 10003, Spain

[2] UCL, Inst Neurol, Dept Clin Neurosci, London NW3 2PF, England

[3] Univ Paris 11, Inst Gustave Roussy, INSERM, U848, F-94805 Villejuif, France

[4] Univ Extremadura, Serv Tecn Aplicadas Biociencias, E-06071 Badajoz, Spain

关键词: SH-SY5Y;    CCCP;    Parkinson's disease;    PINK1;    Calcium;    Mitophagy;   

DOI  :  10.1016/j.nbd.2013.10.021

来源: Elsevier

【 摘 要 】

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 Idnase, 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 24 h. FL-PINK1 protein levels at this time point were significantly higher than vehide-treated, or cells treated with CCCP for 3 h, despite mitochondrial content being decreased by 29%. We have also shown that CCCP dissipated the mitochondrial membrane potential (Delta psi m) 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. (C) 2013 The Authors. Published by Elsevier Int. All rights reserved.

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