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

Store-operated Ca super(2+) entry (SOCE) is a ubiquitous Ca super(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 super(2+) to avoid Ca super(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 super(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 super(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 super(2+) uptake, as revealed by mitochondrial Ca super(2+) measurements with targeted aequorins. This salicylate-induced inhibition of mitochondrial Ca super(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 super(2+) uptake and suggest that inhibition of tumour cell proliferation by salicylate may be due to interference with mitochondrial Ca super(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.