Using small molecule mass spectrometry approaches the Chouchani Lab team show that during exercise, mouse and human muscle selectively release the mitochondrial metabolite succinate into extracellular fluids. This release is unusual since succinate is a dicarboxylate, which should remain trapped in the cell. But during muscle cell acidification that occurs upon exercise, succinate becomes protonated and transformed to a monocarboxylate. This renders succinate a transport substrate for the monocarboxylate transporter MCT1, which facilitates pH-gated release. Once released, succinate co-ordinates paracrine signaling through ligation of its cognate GPCR SUCNR1, which is expressed in a variety of non-myofibrillar cells resident in muscle tissue. This newfound succinate secretion pathway is critical for physiological adaptations to exercise in mice, including remodeling of muscle innervation, muscle ECM, and improvements in muscle strength. Based on these findings the Chouchani Lab team propose a general model whereby intracellular energetic status can be communicated systemically through pH-gated succinate release, which could be broadly relevant in other physiological contexts of cellular acidosis. Read more here!