Energized mitochondria increase the dynamic range over which inositol 1,4,5-trisphosphate activates store-operated calcium influx

In eukaryotic cells, activation of cell surface receptors that couple to the phosphoinositide pathway evokes a biphasic increase in intracellular free Ca(2+) concentration: an initial transient phase reflecting Ca(2+) release from intracellular stores, followed by a plateau phase due to Ca(2+) influx. A major component of this Ca(2+) influx is store-dependent and often can be measured directly as the Ca(2+) release-activated Ca(2+) current (I(CRAC)). Under physiological conditions of weak intracellular Ca(2+) buffering, respiring mitochondria play a central role in store-operated Ca(2+) influx. They determine whether macroscopic I(CRAC) activates or not, to what extent and for how long. Here we describe an additional role for energized mitochondria: they reduce the amount of inositol 1,4,5-trisphosphate (InsP(3)) that is required to activate I(CRAC). By increasing the sensitivity of store-operated influx to InsP(3), respiring mitochondria will determine whether modest levels of stimulation are capable of evoking Ca(2+) entry or not. Mitochondrial Ca(2+) buffering therefore increases the dynamic range of concentrations over which the InsP(3) is able to function as the physiological messenger that triggers the activation of store-operated Ca(2+) influx.