Logic and mechanisms of metabolite signalling

Metabolites have emerged as central regulators of biological function, but understanding mechanisms of metabolite regulation has proven challenging. In 2021 we have seen discoveries in the field of metabolite signalling motivated by a combination of scientific intuition and the elegant deployment of new technologies. Key advances In mammalian cells, lactate production as a consequence of aerobic glycolysis drives NAD + regeneration, which might influence a wide range of biological processes that are directly regulated by the cytosolic NAD + /NADH couple 1 . In mice, dietary fructose increased the surface area of intestinal villi via the interaction of fructose 1-phosphate and pyruvate kinase M2 isoform, which drove enhanced nutrient absorption, thereby demonstrating the potential of exogenous nutrients to regulate organismal adaptation 3 . Work in the model amoeba Dictyostelium discoideum showed that cysteine sequestration into the glutathione pool facilitated the differentiated multicellular switch, providing a framework for how cellular fate might be regulated by cellular thiols and redox biochemistry 5 . In human cells, glutathione availability and redox status regulates mitochondrial import of glutathione via SLC25A39, providing a mechanistic basis for the regulation of glutathione partitioning through cellular redox status 6 . A pre-print paper reports a promising new approach using mass spectrometry and the principle of equilibrium dialysis (MIDAS), which will enable the systematic discovery of metabolite–protein interactions 8 .