Ehud Ohana

Metabolic communication is the exchange of information by metabolites between different cells and tissues to control bioenergetics and other physiological processes. This is mediated by receptor signaling and the transport of metabolites across membranes by various transporters. The SLC13 family of transporters, for instance, plays a vital role in mediating the transport of succinate and citrate, which are important metabolic communication signals and intermediates of the TCA cycle. This transport is essential for bioenergetic processes and metabolic signaling. The appended abstract highlights how extracellular TCA cycle metabolites, referred to as exometabolites, influence critical physiological functions including transepithelial absorption and bioenergetics, and proposes that transmembrane exometabolite fluxes act as independent metabolic pathways controlling bioenergetics. Specifically, hepatic citrate/succinate transporter (NaCT) is described as interacting with glucose and anion transporters to coordinate nutrient homeostasis and drive bioenergetics. In the context of immune metabolism, succinate is emerging as a pro-inflammatory metabolite, and its uptake into macrophages, mediated by Na+-dependent succinate transporters like those in the SLC13 family, is elevated to enhance and perpetuate inflammation, particularly in inflammatory bowel diseases (IBD). This suggests a link between gut microbiota-generated succinate and chronic inflammation through impaired transporter function. Furthermore, the homeostasis of succinate and citrate, regulated by transporters and signaling pathways, is shown to be important for kidney physiology and blood pressure control, potentially linking kidney stone formation and hypertension through impaired metabolite transport. The SLC26A6 transporter is also implicated in regulating succinate transport and interacting with SLC13 transporters . These findings collectively underscore the critical role of transporters in facilitating metabolic communication and impacting various aspects of physiology and immune metabolism.