Cell proliferation depends on mitochondrial Ca 2+ uptake: inhibition by salicylate

Store‐operated Ca 2+ entry (SOCE) is a ubiquitous Ca 2+ influx pathway involved in control of multiple cellular and physiological processes including cell proliferation. Recent evidence has shown that SOCE depends critically on mitochondrial sinking of entering Ca 2+ to avoid Ca 2+ ‐dependent inactivation. Thus, a role of mitochondria in control of cell proliferation could be anticipated. We show here that activation of SOCE induces cytosolic high [Ca 2+ ] domains that are large enough to be sensed and avidly taken up by a pool of nearby mitochondria. Prevention of mitochondrial clearance of the entering Ca 2+ inhibited both SOCE and cell proliferation in several cell types including Jurkat and human colon cancer cells. In addition, we find that therapeutic concentrations of salicylate, the major metabolite of aspirin, depolarize partially mitochondria and inhibit mitochondrial Ca 2+ uptake, as revealed by mitochondrial Ca 2+ measurements with targeted aequorins. This salicylate‐induced inhibition of mitochondrial Ca 2+ sinking prevented SOCE and impaired cell growth of Jurkat and human colon cancer cells. Finally, direct blockade of SOCE by the pyrazole derivative BTP‐2 was sufficient to arrest cell growth. Taken together, our results reveal that cell proliferation depends critically on mitochondrial Ca 2+ uptake and suggest that inhibition of tumour cell proliferation by salicylate may be due to interference with mitochondrial Ca 2+ uptake, which is essential for sustaining SOCE. This novel mechanism may contribute to explaining the reported anti‐proliferative and anti‐tumoral actions of aspirin and dietary salicylates.