Respiring mitochondria determine the pattern of activation and inactivation of the store-operated Ca2+ current I-CRAC

In eukaryotic cells, hormones and neurotransmitters that engage the phospho inositide pathway evoke a biphasic increase in intracellular free Ca2+ conc entration: an initial transient release of Ca2+ from intracellular stores i s followed by a sustained phase of Ca2+ influx. This influx is generally st ore dependent. Most attention has focused on the link between the endoplasm ic reticulum and store-operated Ca2+ channels in the plasma membrane. Here, me describe that respiring mitochondria are also essential for the activat ion of macroscopic store-operated Ca2+ currents under physiological conditi ons of weak intracellular Ca2+ buffering. We further show that Ca2+-depende nt slow inactivation of Ca2+ influx, a widespread but poorly understood phe nomenon, is regulated by mitochondrial buffering of cytosolic Ca2+. Thus, b y enabling macroscopic store-operated Ca2+ current to activate, and then by controlling its extent and duration, mitochondria play a crucial role in a ll stages of store-operated Ca2+ influx. Store-operated Ca2+ entry reflects a dynamic interplay between endoplasmic reticulum, mitochondria and plasma membrane.