Energized mitochondria increase the dynamic range over which inositol 145-trisphosphate activates store-operated calcium influx

摘要

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 (ICRAC). 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 (InsP3) that is required to activate ICRAC. By increasing the sensitivity of store-operated influx to InsP3, 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 InsP3 is able to function as the physiological messenger that triggers the activation of store-operated Ca²⁺ influx.