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.