Mitochondria control store-operated Ca2+ entry through Na+ and redox signals

Tsipi Ben-Kasus Nissim, Xuexin Zhang, Assaf Elazar, Soumitra Roy, Judith A. Stolwijk, Yandong Zhou, Rajender K. Motiani, Maxime Gueguinou, Nadine Hempel, Michal Hershfinkel, Donald L. Gill, Mohamed Trebak, Israel Sekler

Research output: Contribution to journalArticlepeer-review

72 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)797-815
Number of pages19
JournalEMBO Journal
Issue number6
StatePublished - Mar 15 2017

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)


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