Regulation of store-operated calcium channels by the intermediary metabolite pyruvic acid

A rise in cytosolic Ca2+ concentration is used as a key activation signal in virtually all animal cells, where it triggers a range of responses, including neurotransmitter release, muscle contraction, and cell growth and proliferation [1,2]. A major route for Ca2+ influx is through store-operated Ca2+ channels. One important intracellular target for Ca2+ entry through store-operated channels is the mitochondrion, which increases aerobic metabolism and ATP production after Ca2+ uptake. Here, we reveal a novel feedback pathway whereby pyruvic acid, a critical rate-limiting substrate for mitochondrial respiration, increases store-operated entry by reducing inactivation of the channels. Importantly, the effects of pyruvic acid are manifest at physiologically relevant concentrations and membrane potentials. The reduction in the inactivation of calcium release-activated calcium (CRAC) channels by pyruvate is highly specific in that it is not mimicked by other intermediary metabolic acids, does not require its metabolism, is independent of its Ca2+ buffering action, and does not involve mitochondrial Ca2+ uptake or ATP production. These results reveal a new and direct link between intermediary metabolism and ion-channel gating and identify pyruvate as a potential signaling messenger linking energy demand to calcium-channel function.