Extracellular Succinate: A Physiological Messenger and a Pathological Trigger.

When tissues are under physiological stresses, such as vigorous exercise and cold exposure, skeletal muscle cells secrete succinate into the extracellular space for adaptation and survival. By contrast, environmental toxins and injurious agents induce cellular secretion of succinate to damage tissues, trigger inflammation, and induce tissue fibrosis. Extracellular succinate induces cellular changes and tissue adaptation or damage by ligating cell surface succinate receptor-1 (SUCNR-1) and activating downstream signaling pathways and transcriptional programs. Since SUCNR-1 mediates not only pathological processes but also physiological functions, targeting it for drug development is hampered by incomplete knowledge about the characteristics of its physiological vs. pathological actions. This review summarizes the current status of extracellular succinate in health and disease and discusses the underlying mechanisms and therapeutic implications.