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.

Gatliff, J., East, D.a., Singh, A., Alvarez, M.s., Frison, M., Matic, I., et al. (2017). A role for TSPO in mitochondrial Ca2+ homeostasis and redox stress signaling. CELL DEATH & DISEASE, 8(6), e2896 [10.1038/cddis.2017.186].

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

Matic I.
Writing – Original Draft Preparation
;
Campanella M.
2017-06-01

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.
giu-2017
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/11 - BIOLOGIA MOLECOLARE
English
Con Impact Factor ISI
Animals; Calcium; Cyclic AMP-Dependent Protein Kinases; Endoplasmic Reticulum; Glutamic Acid; Humans; Mice; Mitochondria; Mitochondrial Membranes; Models, Biological; NADPH Oxidases; Oxidation-Reduction; Phosphorylation; Reactive Oxygen Species; Receptors, GABA; Voltage-Dependent Anion Channels; Homeostasis; Signal Transduction; Stress, Physiological
Gatliff, J., East, D.a., Singh, A., Alvarez, M.s., Frison, M., Matic, I., et al. (2017). A role for TSPO in mitochondrial Ca2+ homeostasis and redox stress signaling. CELL DEATH & DISEASE, 8(6), e2896 [10.1038/cddis.2017.186].
Gatliff, J; East, Da; Singh, A; Alvarez, Ms; Frison, M; Matic, I; Ferraina, C; Sampson, N; Turkheimer, F; Campanella, M
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/206135
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