Gatliff, J and East, D A and Singh, A and Alvarez, M S and Frison, M and Matic, I and Ferraina, C and Sampson, N and Turkheimer, F and Campanella, M (2017) A role for TSPO in mitochondrial Ca2+ homeostasis and redox stress signaling. CELL DEATH & DISEASE, 8. e2896.
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Abstract
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 Ca2+ signaling leading to a parallel increase in the cytosolic Ca2+ pools that activate the Ca2+-dependent NADPH oxidase (NOX) thereby increasing ROS. The inhibition of mitochondrial Ca2+ 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 Ca2+ dynamics and redox transients in neuronal cytotoxicity.
| Item Type: | Article |
|---|---|
| RVC Publication Type: | Research (full) paper |
| WoS ID: | 000405895200006 |
| DOI: | https://doi.org/10.1038/cddis.2017.186 |
| Departments: | Comparative Biomedical Sciences |
| Research Programmes: | Comparative Physiology & Medicine > Immune Regulation and Cancer |
| Depositing User: | RVC Auto-import |
| Last Modified: | 21 Nov 2020 02:19 |
| URI: | https://researchonline.rvc.ac.uk/id/eprint/10929 |
| Date Deposited: | 22 August 2017 |
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