Mitochondria exert important control over plasma membrane (PM) Orai1 channels mediating store‐operated Ca2+ entry (SOCE). Although the sensing of endoplasmic reticulum (ER) Ca2+ stores by STIM proteins and coupling to Orai1 channels is well understood, how mitochondria communicate with Orai1 channels to regulate SOCE activation remains elusive. Here, we reveal that SOCE is accompanied by a rise in cytosolic Na+ that is critical in activating the mitochondrial Na+/Ca2+ exchanger (NCLX) causing enhanced mitochondrial Na+ uptake and Ca2+ efflux. Omission of extracellular Na+ prevents the cytosolic Na+ rise, inhibits NCLX activity, and impairs SOCE and Orai1 channel current. We show further that SOCE activates a mitochondrial redox transient which is dependent on NCLX and is required for preventing Orai1 inactivation through oxidation of a critical cysteine (Cys195) in the third transmembrane helix of Orai1. We show that mitochondrial targeting of catalase is sufficient to rescue redox transients, SOCE, and Orai1 currents in NCLX‐deficient cells. Our findings identify a hitherto unknown NCLX‐mediated pathway that coordinates Na+ and Ca2+ signals to effect mitochondrial redox control over SOCE.
Store‐operated calcium entry (SOCE) activates the mitochondrial Na+/Ca2+ exchanger NCLX, causing enhanced mitochondrial Na+ uptake, Ca2+ efflux, and regulating Orai1 redox state and thus function to allow maintenance of SOCE.
NCLX is required for activation of SOCE and calcium release‐activated calcium channels through a mitochondrial proximity‐independent pathway.
The mitochondrial control of SOCE depends on Na+ and Ca2+ signals that propagate from the cytosol to the mitochondria and converge on NCLX.
NCLX in turn controls the redox state of a critical cysteine of Orai1.
The ionic and redox dependent cross talk of mitochondria and Orai1 is required for maintaining the activation of SOCE.
The EMBO Journal (2017) 36: 797–815
- Received July 7, 2015.
- Revision received December 25, 2016.
- Accepted January 5, 2017.
- © 2017 The Authors
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