Regulation of Mitochondrial Signaling and Quality Control by the 18KDA Translocator Protein (TSPO)

The 18-kDa translocator protein (TSPO) is localized to the outer mitochondrial membrane (OMM) where it is found in complex with the voltage dependent anion channel (VDAC). TSPO expression is elevated in cancer and inflammatory conditions and it is well known for its ligand binding properties and application in PET imaging as a marker of neuroinflammation. TSPO is implicated in multiple mitochondrial functions including steroidogenesis, apoptosis and ATP production although precise molecular mechanisms remain to be elucidated. We recently demonstrated that increased TSPO expression limits mitochondrial ubiquitination and mitophagy through a reactive oxygen species (ROS) -dependent process, which leads to changes in mitochondrial morphology and biomass.Here we have corroborated this pathway by establishing an interplay with the protein kinase A (PKA) signaling complex, which is recruited to mitochondria by TSPO via acyl-CoA binding domain containing 3 (ACBD3). Using targeted luminescent protein chimeras, we show that the combined accumulation of TSPO and PKA alters subcellular Ca2+ dynamics and metabolism, which we propose arises from increased VDAC phosphorylation and subsequent changes in channel activity. Of note, this pathway is activated under glutamate-induced cell stress in the neuronal cell line, SH-SY5Y.This work highlights an important role for the OMM in fine-tuning mitochondrial signaling and mitophagy. As an inducible factor, TSPO represents a critical physiological element that facilitates mitochondrial adaptation to altered cellular metabolic requirements under stress conditions.