TSPO: a conserved mitochondrial conduit linking cellular homeostasis to disease

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.