Store-operated Ca2+ entry depends on mitochondrial Ca2+ uptake

Store-operated Ca2+ channels, which are activated by the emptying of intracellular Ca2+ stores, provide one major route for Ca2+ influx. Under physiological conditions of weak intracellular Ca2+ buffering, the ubiquitous Ca2+ releasing messenger InsP(3) usually fails to activate any store-operated Ca2+ entry unless mitochondria are maintained in an energized state. Mitochondria rapidly take up Ca2+ that has been released by InsP(3), enabling stores to empty sufficiently for store-operated channels to activate. Here, we report a novel role for mitochondria in regulating store-operated channels under physiological conditions. Mitochondrial depolarization suppresses store-operated Ca2+ influx independently of how stores are depleted. This role for mitochondria is unrelated to their actions on promoting InsP(3)-sensitive store depletion, can be distinguished from Ca2+-dependent inactivation of the store-operated channels and does not involve changes in intracellular ATP, oxidants, cytosolic acidification, nitric oxide or the permeability transition pore, but is suppressed when mitochondrial Ca2+ uptake is impaired. Our results suggest that mitochondria may have a more fundamental role in regulating store-operated influx and raise the possibility of bidirectional Ca2+-dependent crosstalk between mitochondria and store-operated Ca2+ channels.