The Translocator Protein (TSPO) in Mitochondrial Bioenergetics and Immune Processes

Abstract

The translocator protein (TSPO) is an outer mitochondrial membrane protein that is widely used as a biomarker of neuroinflammation, being markedly upregulated in activated microglia in a range of brain pathologies. Despite its extensive use as a target in molecular imaging studies, the exact cellular functions of this protein remain in question. The long-held view that TSPO plays a fundamental role in the translocation of cholesterol through the mitochondrial membranes, and thus, steroidogenesis, has been disputed by several groups with the advent of TSPO knockout mouse models. Instead, much evidence is emerging that TSPO plays a fundamental role in cellular bioenergetics and associated mitochondrial functions, also part of a greater role in the innate immune processes of microglia. In this review, we examine the more direct experimental literature surrounding the immunomodulatory effects of TSPO. We also review studies which highlight a more central role for TSPO in mitochondrial processes, from energy metabolism, to the propagation of inflammatory responses through reactive oxygen species (ROS) modulation. In this way, we highlight a paradigm shift in approaches to TSPO functioning.

Keywords: microglia; mitochondria; neuroinflammation; reactive oxygen species; translocator protein.

Figure 1

Overview of the translocator protein (TSPO) in the inflammatory responses of microglia and its interaction with mitochondrial processes. Under stress conditions, TSPO is upregulated in activated, pro-inflammatory (M1) microglia. Located on the outer mitochondrial membrane, TSPO interacts with reactive oxygen species (ROS), a key part of the microglial inflammatory response. TSPO also interacts with inflammatory transcriptional pathways including MAPK and the NLRP3 inflammasome, resulting in the release of cytokines. These processes can be modulated by TSPO ligands, and by genetic deletion of TSPO, indicating a key role for TSPO in these processes.