Mitochondria control store‐operated Ca ²⁺ entry through Na ⁺ and redox signals

Abstract

Mitochondria exert important control over plasma membrane (PM) Orai1 channels mediating store-operated Ca 2+ entry (SOCE).

Crosstalk between calcium and reactive oxygen species signaling in cancer

“…CRAC currents are mediated by the Orai protein family (ORAI1, 2 & 3), and their activation is regulated by STIM1 and STIM2 proteins, which are ER-localized Ca 2+ sensors [174-177]. In addition to the ER, mitochondria are involved in the regulation of SOCE, either due to their Ca 2+ buffering capability [178, 179] or through mitochondria-derived redox-signaling [180]. The plasma membrane, mitochondria and ER are associated with ROS production, and hence it is not surprising that redox regulation of ORAI channels and STIM proteins could be of importance in a variety of cell types.…”

“…Indeed, it was demonstrated that forced expression of NCLX could increase mitochondrial oxidation of the redox sensitive RoGFP probe and abrogate histamine-induced increases in mitochondrial Ca 2+ and NAD(P)H, presumably through its role in decreasing mitochondrial Ca 2+ levels and hence inhibiting matrix dehydrogenase activity [263]. Recently, the consequences of this mitochondrial ROS-NCLX interplay were further explored using a model of NCLX knock-down [180]. In this study, it was demonstrated that knockdown of NCLX increases mitochondrial ROS production by enhancing mitochondrial Ca 2+ levels and that this mediates inhibition of the CRAC channel ORAI1.…”

“…In this study, it was demonstrated that knockdown of NCLX increases mitochondrial ROS production by enhancing mitochondrial Ca 2+ levels and that this mediates inhibition of the CRAC channel ORAI1. Interestingly, ER Ca 2+ store depletion resulted in both SOCE activation and cytosolic Na + accumulation, suggesting an important interplay between SOCE and NCLX regulation [180]. While knock-down of NCLX had no effect on ORAI1-STIM1 interaction, it blunted CRAC channel activity, which was demonstrated to be dependent on an increase in mitochondrial ROS generation.…”

“…Scavenging of mitochondrial H 2 O 2 with a mitochondrial targeted catalase construct could rescue SOCE. It was shown that in response to NCLX knockdown, increased mitochondrial H 2 O 2 inactivates ORAI1 through oxidation of C195, as the ORAI1 C195S was insensitive to NCLX expression loss [180]. The above two studies demonstrate that regulation of Ca 2+ transients by NCLX is important in modulating mitochondrial ROS production, and that both NCLX-dependent decreases or increases in mitochondrial Ca 2+ can result in enhanced mitochondrial ROS production.…”

“…Studies have shown that activation of NCLX may increase mitochondrial ROS production, by decreasing Ca 2+ levels in mitochondria [306] [263]. However, NCLX knock down can also result in ROS generation, presumably due to its important role in fine tuning Na + /Ca 2+ balance [180]. The consequences of NCLX –mediated mitochondrial ROS production on cellular signaling are still unclear, but could have influence redox regulation of the CRAC channel ORAI [180].…”