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 Ca2+ concentration: an initial transient phase reflecting Ca2+ release from intracellular stores, followed by a plateau phase due to Ca2+ influx, A major component of this Ca2+ influx is store-dependent and often can be measured directly as the Ca2+ release-activated Ca2+ current (I-CRAC). Under physiological conditions of weak intracellular Ca2+ buffering, respiring mitochondria play a central role in store-operated Ca2+ influx, They determine whether macroscopic ICRAC 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 ICRAC BY increasing the sensitivity of store-operated influx to InsP(3), respiring mitochondria will determine whether modest levels of stimulation are capable of evoking Ca2+ entry or not, Mitochondrial Ca2+ 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 Ca2+ influx.