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

Abstract

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 re¯ecting Ca 2+ release from intracellular stores, followed by a plateau phase due to Ca 2+ in¯ux. A major component of this Ca 2+ in¯ux 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+ in¯ux. 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 in¯ux 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+ in¯ux.

Benzoquinone ansamycin 17AAG binds to mitochondrial voltage-dependent anion channel and inhibits cell invasion

“…5 and Figs. S5 and S6), the mechanism is unlikely to be working through a HSP90 client protein affect; rather, we postulate that the mitochondrial VDAC serves as a target for 17AAG, GA, and Ub0, resulting in depolarization of the mitochondrial membrane potential, a rise in [Ca 2+ ] i , and a corresponding decrease in membrane cationic current (i.e., I CRAC ) (35,36 (37). GA derivatives all have a quinone moiety and are metabolized by the NQO1 enzyme (6), indicating that they interact with mitochondria.…”

The Role of Mitochondria for Ca2+ Refilling of the Endoplasmic Reticulum

“…Refs. [7][8][9][10][11] and its/their molecular nature are still under debate (12)(13)(14), recent investigations point to a fundamental role of mitochondria in the maintenance (15)(16)(17)(18)(19) and modulation (20) of the CCE in many cell types. Notably, the intriguing aptitude of mitochondria to effectively impound subplasmalemmal Ca 2ϩ (i.e.…”

Sustained Ca2+ Transfer across Mitochondria Is Essential for Mitochondrial Ca2+ Buffering, Store-operated Ca2+ Entry, and Ca2+ Store Refilling

“…Paradoxically, despite this close contact to Ca 2ϩ sources, the mitochondrial free Ca 2ϩ concentration ([Ca 2ϩ ] mito ) increases only transiently during cell stimulation and returns rapidly to base line, regardless of the long lasting elevations in free cytosolic Ca 2ϩ concentration ([Ca 2ϩ ] cyto ) (9 -11). The transient nature of mitochondrial Ca 2ϩ signals is surprising, as the subplasmalemmal microdomains of low Ca 2ϩ generated around Ca 2ϩ influx pathways can be maintained for extended periods (6,(12)(13)(14)(15)(16). Such long lasting microdomains have been postulated to underlie mitochondrial modulation of capacitative Ca 2ϩ entry (CCE), which is activated by emptying of the ER either by inositol 1,4,5-triphosphate (IP 3 ) or by SERCA inhibition (17,18).…”

“…Such long lasting microdomains have been postulated to underlie mitochondrial modulation of capacitative Ca 2ϩ entry (CCE), which is activated by emptying of the ER either by inositol 1,4,5-triphosphate (IP 3 ) or by SERCA inhibition (17,18). Although the channel(s) responsible for CCE are still under investigation, CCE has been clearly demonstrated to be prevented by enhanced [Ca 2ϩ ] cyto at the inner gate of the channel (6,(12)(13)(14)(15)(16). Inhibition of mitochondrial Ca 2ϩ uptake, either by mitochondrial depolarization or by inhibition of mitochondrial Ca 2ϩ uniporter, prevents the maintenance of CCE (12)(13)(14)19), suggesting that mitochondria maintain a low subplasmalemmal Ca 2ϩ at the mouth of this Ca 2ϩ -inhibitable, Ca 2ϩ -entry pathway (20).…”

“…Although the channel(s) responsible for CCE are still under investigation, CCE has been clearly demonstrated to be prevented by enhanced [Ca 2ϩ ] cyto at the inner gate of the channel (6,(12)(13)(14)(15)(16). Inhibition of mitochondrial Ca 2ϩ uptake, either by mitochondrial depolarization or by inhibition of mitochondrial Ca 2ϩ uniporter, prevents the maintenance of CCE (12)(13)(14)19), suggesting that mitochondria maintain a low subplasmalemmal Ca 2ϩ at the mouth of this Ca 2ϩ -inhibitable, Ca 2ϩ -entry pathway (20). However, to account for the long lasting activation of CCE, the microdomain of low Ca 2ϩ generated by mitochondria must be maintained for several minutes.…”