title: Mitochondria control store-operated Ca2+entry through Na+and redox signals.
abstract: 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.
authors.affiliation: The Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Tsipi
authors.initials: T
authors.lastname: Ben-Kasus Nissim
authors.affiliation: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
authors.forename: Xuexin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: The Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Assaf
authors.initials: A
authors.lastname: Elazar
authors.affiliation: The Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Soumitra
authors.initials: S
authors.lastname: Roy
authors.affiliation: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Stolwijk
authors.affiliation: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
authors.forename: Yandong
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
authors.forename: Rajender K
authors.initials: RK
authors.lastname: Motiani
authors.affiliation: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
authors.forename: Maxime
authors.initials: M
authors.lastname: Gueguinou
authors.affiliation: Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
authors.forename: Nadine
authors.initials: N
authors.lastname: Hempel
authors.affiliation: The Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Hershfinkel
authors.affiliation: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
authors.forename: Donald L
authors.initials: DL
authors.lastname: Gill
authors.affiliation: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, USA mtrebak@psu.edu sekler@bgu.ac.il.
authors.forename: Mohamed
authors.identifier: 0000-0001-6759-864X
authors.initials: M
authors.lastname: Trebak
authors.affiliation: The Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel mtrebak@psu.edu sekler@bgu.ac.il.
authors.forename: Israel
authors.identifier: 0000-0002-7550-1550
authors.initials: I
authors.lastname: Sekler
mesh_terms: D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins; D000071740:ORAI1 Protein / Q000378:metabolism*; D010084:Oxidation-Reduction; D012964:Sodium / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*
chemical_list: D024101:Mitochondrial Proteins; D000071740:ORAI1 Protein; C483046:SLC8B1 protein, human; D019831:Sodium-Calcium Exchanger; D012964:Sodium; D002118:Calcium
keywords: 
  NCLX
  ; 
  SOCE
  ; CRAC channel; mitochondrial redox; sodium signaling