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A role for TSPO in mitochondrial Ca2+ homeostasis and redox stress signaling

Gatliff, J; East, D A; Singh, A; Alvarez, M S; Frison, M; Matic, I; Ferraina, C; Sampson, N; Turkheimer, F; Campanella, M

Authors

J Gatliff

D A East

A Singh

M S Alvarez

M Frison

I Matic

C Ferraina

N Sampson

F Turkheimer

M Campanella



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.

Citation

Gatliff, J., East, D. A., Singh, A., Alvarez, M. S., Frison, M., Matic, I., …Campanella, M. (2017). A role for TSPO in mitochondrial Ca2+ homeostasis and redox stress signaling. https://doi.org/10.1038/cddis.2017.186

Journal Article Type Article
Acceptance Date Mar 23, 2017
Publication Date Jun 22, 2017
Deposit Date Aug 22, 2017
Publicly Available Date Aug 22, 2017
Journal CELL DEATH & DISEASE
Peer Reviewed Peer Reviewed
Volume 8
Pages e2896
DOI https://doi.org/10.1038/cddis.2017.186
Public URL https://rvc-repository.worktribe.com/output/1391431

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