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A role for TSPO in mitochondrial Ca(2+) homeostasis and redox stress signaling
The 18 kDa translocator protein TSPO localizes on the outer mitochondrial membrane (OMM). Systematically overexpressed at sites of neuroinflammation it is adopted as a biomarker of brain conditions. TSPO inhibits the autophagic removal of mitochondria by limiting PARK2-mediated mitochondrial ubiquit...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520880/ https://www.ncbi.nlm.nih.gov/pubmed/28640253 http://dx.doi.org/10.1038/cddis.2017.186 |
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author | Gatliff, Jemma East, Daniel A Singh, Aarti Alvarez, Maria Soledad Frison, Michele Matic, Ivana Ferraina, Caterina Sampson, Natalie Turkheimer, Federico Campanella, Michelangelo |
author_facet | Gatliff, Jemma East, Daniel A Singh, Aarti Alvarez, Maria Soledad Frison, Michele Matic, Ivana Ferraina, Caterina Sampson, Natalie Turkheimer, Federico Campanella, Michelangelo |
author_sort | Gatliff, Jemma |
collection | PubMed |
description | The 18 kDa translocator protein TSPO localizes on the outer mitochondrial membrane (OMM). Systematically overexpressed at sites of neuroinflammation it is adopted as a biomarker of brain conditions. TSPO inhibits the autophagic removal of mitochondria by limiting PARK2-mediated mitochondrial ubiquitination via a peri-organelle accumulation of reactive oxygen species (ROS). Here we describe that TSPO deregulates mitochondrial Ca(2+) signaling leading to a parallel increase in the cytosolic Ca(2+) pools that activate the Ca(2+)-dependent NADPH oxidase (NOX) thereby increasing ROS. The inhibition of mitochondrial Ca(2+) uptake by TSPO is a consequence of the phosphorylation of the voltage-dependent anion channel (VDAC1) by the protein kinase A (PKA), which is recruited to the mitochondria, in complex with the Acyl-CoA binding domain containing 3 (ACBD3). Notably, the neurotransmitter glutamate, which contributes neuronal toxicity in age-dependent conditions, triggers this TSPO-dependent mechanism of cell signaling leading to cellular demise. TSPO is therefore proposed as a novel OMM-based pathway to control intracellular Ca(2+) dynamics and redox transients in neuronal cytotoxicity. |
format | Online Article Text |
id | pubmed-5520880 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-55208802017-07-27 A role for TSPO in mitochondrial Ca(2+) homeostasis and redox stress signaling Gatliff, Jemma East, Daniel A Singh, Aarti Alvarez, Maria Soledad Frison, Michele Matic, Ivana Ferraina, Caterina Sampson, Natalie Turkheimer, Federico Campanella, Michelangelo Cell Death Dis Original Article The 18 kDa translocator protein TSPO localizes on the outer mitochondrial membrane (OMM). Systematically overexpressed at sites of neuroinflammation it is adopted as a biomarker of brain conditions. TSPO inhibits the autophagic removal of mitochondria by limiting PARK2-mediated mitochondrial ubiquitination via a peri-organelle accumulation of reactive oxygen species (ROS). Here we describe that TSPO deregulates mitochondrial Ca(2+) signaling leading to a parallel increase in the cytosolic Ca(2+) pools that activate the Ca(2+)-dependent NADPH oxidase (NOX) thereby increasing ROS. The inhibition of mitochondrial Ca(2+) uptake by TSPO is a consequence of the phosphorylation of the voltage-dependent anion channel (VDAC1) by the protein kinase A (PKA), which is recruited to the mitochondria, in complex with the Acyl-CoA binding domain containing 3 (ACBD3). Notably, the neurotransmitter glutamate, which contributes neuronal toxicity in age-dependent conditions, triggers this TSPO-dependent mechanism of cell signaling leading to cellular demise. TSPO is therefore proposed as a novel OMM-based pathway to control intracellular Ca(2+) dynamics and redox transients in neuronal cytotoxicity. Nature Publishing Group 2017-06 2017-06-22 /pmc/articles/PMC5520880/ /pubmed/28640253 http://dx.doi.org/10.1038/cddis.2017.186 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Original Article Gatliff, Jemma East, Daniel A Singh, Aarti Alvarez, Maria Soledad Frison, Michele Matic, Ivana Ferraina, Caterina Sampson, Natalie Turkheimer, Federico Campanella, Michelangelo A role for TSPO in mitochondrial Ca(2+) homeostasis and redox stress signaling |
title | A role for TSPO in mitochondrial Ca(2+) homeostasis and redox stress signaling |
title_full | A role for TSPO in mitochondrial Ca(2+) homeostasis and redox stress signaling |
title_fullStr | A role for TSPO in mitochondrial Ca(2+) homeostasis and redox stress signaling |
title_full_unstemmed | A role for TSPO in mitochondrial Ca(2+) homeostasis and redox stress signaling |
title_short | A role for TSPO in mitochondrial Ca(2+) homeostasis and redox stress signaling |
title_sort | role for tspo in mitochondrial ca(2+) homeostasis and redox stress signaling |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520880/ https://www.ncbi.nlm.nih.gov/pubmed/28640253 http://dx.doi.org/10.1038/cddis.2017.186 |
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