TSPO: a conserved mitochondrial conduit linking cellular homeostasis to disease

Abstract

Abstract The translocator protein (TSPO) is an evolutionarily conserved 18 kDa protein localised to the outer mitochondrial membrane and increasingly recognised as a multifunctional regulator of cellular homeostasis. Although initially identified as the peripheral benzodiazepine receptor, TSPO has since been implicated in a range of mitochondrial processes. This review integrates current evidence on TSPO function across evolution and in mammalian systems, with a focus on its interactions with mitochondrial gatekeeping proteins. TSPO has been implicated in regulating cholesterol transport, redox homeostasis, calcium (Ca 2+ ) signalling, and mitochondrial quality control. Mechanistically, TSPO has been proposed to modulate Ca 2+ flux and reactive oxygen species (ROS) production through VDAC1-associated pathways, linking mitochondrial dynamics to cellular stress responses. We also evaluate the context-dependent effects of TSPO ligands across disease models. Collectively, these findings position TSPO as a potential integrator of mitochondrial signalling with important implications for understanding disease mechanisms and therapeutic targeting.