Enigmatic Translocator protein (TSPO) and cellular stress regulation

•TSPOs are not classical transporter proteins.•TSPOs’ endogenous ligands are essential in understanding their functions.•TSPOs regulate stress-dependent signaling.•TSPOs’ physiological role involves redox homeostasis.

Translocator proteins (TSPOs) are conserved, ubiquitous membrane proteins identified initially as benzodiazepine-binding proteins in mammalian cells. Recent genetic and biochemical studies have challenged the accepted model that TSPOs are essential and required for steroidogenesis in animal cells. Instead, evidence from different kingdoms of life suggests that TSPOs are encoded by nonessential genes that are temporally upregulated in cells encountering conditions of oxidative stress, including inflammation and tissue injury. Here we discuss how TSPOs may be involved in complex homeostasis signaling mechanisms. We suggest that the main physiological role of TSPOs may be to modulate oxidative stress, irrespective of the cell type or subcellular localization, in part through the subtle regulation of tetrapyrrole metabolism.