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

GATLIFF J; EAST D; SINGH A; ALVAREZ MS; SAMPSON N; TURKHEIMER F; CAMPANELLA MC

Cell Death & Disease

Nature Publishing Group

Lugar: Roma; Año: 2017

2041-4889

The 18-kDa protein TSPO localizes on the outer mitochondrial membrane (OMM). Overexpressed during neuroinflammation, it has been adopted as a biomarker of cell and tissue pathology in the brain. TSPO inhibits the autophagic removal of mitochondria by limiting PARK2- mediated mitochondrial ubiquitination via accumulation of Reactive Oxygen Species (ROS). Here we describe that TSPO accumulation in response to redox stress deregulates Ca2+ signaling, via phosphorylation of the Voltage Dependent Anion Channel (VDAC1). TSPO recruits Protein Kinase A (PKA) to mitochondria, in complex with the Golgi-derived protein, Acyl-CoA binding domain containing 3 (ACBD3).Inhibition of mitochondrial Ca2+ uptake thus leads to a parallel increase in the cytosolic Ca2+ pool that activates the Ca2+-dependent NADPH oxidase (NOX) thereby increasing ROS. Notably, the neurotransmitter glutamate triggers this TSPO-dependent mechanism of cell signaling.We therefore propose a novel OMM-based pathway to control intracellular Ca2+ dynamics, mediated redox transients and their implications in the definition of neuronal cytoxocity.