Translocator protein 18 kDa (TSPO) was previously known as the peripheral benzodiazepine receptor (PBR) in eukaryotes, where it is mainly localized to the mitochondrial outer membrane. Considerable evidence indicates that it plays regulatory roles in steroidogenesis and apoptosis and is involved in various human diseases, such as metastatic cancer, Alzheimer’s and Parkinson’s disease, inflammation, and anxiety disorders. Ligands of TSPO are widely used as diagnostic tools and treatment options, despite there being no clear understanding of the function of TSPO. An ortholog in the photosynthetic bacterium Rhodobacter was independently discovered as the tryptophan-rich sensory protein (TspO) and found to play a role in the response to changes in oxygen and light conditions that regulate photosynthesis and respiration. As part of this highly conserved protein family found in all three kingdoms, the rat TSPO is able to rescue the knockout phenotype in Rhodobacter, indicating functional as well as structural conservation. Recently, a major breakthrough in the field was achieved: the determination of atomic-resolution structures of TSPO from different species by several independent groups. This now allows us to reexamine the function of TSPO with a molecular perspective. In this review, we focus on recently determined structures of TSPO and their implications for potential functions of this ubiquitous multifaceted protein. We suggest that TSPO is an ancient bacterial receptor/stress sensor that has developed additional interactions, partners, and roles in its mitochondrial outer membrane environment in eukaryotes.

The way that males and females react to environmental exposures and negative impacts on their neurological systems is often different. Although previous research has examined the cognitively impairing effects of solitary metal exposures, the relationship between metal mixtures and cognitive function, particularly when considering an individual’s sex, remains elusive. This study aimed to investigate the sex differences in the association between multiple metal combinations and cognitive function in older Americans. This research employed the 2011–2014 NHANES survey of elderly Americans. The association between five mixed metals and four cognitive tests (the animal fluency test (AFT), the digit symbol substitution test (DSST), the instant recall test (IRT), and the delayed recall test (DRT)) were investigated with generalized linear regression model (GLM), Bayesian kernel machine regression model (BKMR), weighted quantile sum regression model (WQS), and quantile g-computation regression model (Qgcomp). A total of 1833 people, including 883 males and 950 females, enrolled in this cross-sectional study. We discovered that blood lead and blood cadmium were negatively associated with cognitive performance, while blood selenium demonstrated a positive association with cognitive function in older people. The negative relationship of heavy metal combinations on cognitive function might be somewhat reduced or even reversed via selenium. The IRT, AFT, and DSST are three of the four cognitive tests where men had more dramatic positive or negative results. There was a sex-specific connection between blood metal ratios and cognitive function among older Americans, as evidenced by the more significant relationship between mixed metals and cognitive performance in men (either positively or negatively). These results emphasize the impacts of ambient heavy metal exposure on cognitive function by employing sex-specific methods.