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

Natalie Sampson,Michelangelo Campanella,Michele Frison,Aarti Singh,Maria Soledad Alvarez,Daniel A East,Federico Turkheimer,Caterina Ferraina,Ivana Matic,Jemma Gatliff

doi:10.1038/cddis.2017.186

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.

Highlights

The 18 kDa translocator protein TSPO localizes on the outer mitochondrial membrane (OMM)
We previously ascribed the inhibition of cellular mitophagy by TSPO to reactive oxygen species (ROS) microdomains that prevent the in situ ubiquitination for autophagic removal.[17]
The increased ROS levels were reduced by KN93 (10 μM), an inhibitor of the Ca2+/Calmodulin-dependent protein kinase (CaMK) II21 which is pivotal for the activation of the NADPH

Summary

Introduction

The 18 kDa translocator protein TSPO localizes on the outer mitochondrial membrane (OMM). 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). TSPO initially characterized as the peripheral binding site for the benzodiazepines[1,2] complexes with the voltagedependent anion channel (VDAC).[3] Even though questioned, the role of TSPO in transporting cholesterol into mitochondria for steroidogenesis[4,5,6] remains the best-characterized one.[7]. TSPO interacts with the Acyl-CoA binding domain containing 3 protein (ACBD3)[18] that complexes with the cAMP-dependent protein kinase (PKA)[19] which, via phosphorylation,[20] regulates VDAC activity

Methods

Results

Conclusion