title: Mitofusin 2 regulates STIM1 migration from the Ca2+ store to the plasma membrane in cells with depolarized mitochondria.
abstract: Store-operated Ca2+ channels in the plasma membrane (PM) are activated by the depletion of Ca2+ from the endoplasmic reticulum (ER) and constitute a widespread and highly conserved Ca2+ influx pathway. After store emptying, the ER Ca2+ sensor STIM1 forms multimers, which then migrate to ER-PM junctions where they activate the Ca2+ release-activated Ca2+ channel Orai1. Movement of an intracellular protein to such specialized sites where it gates an ion channel is without precedence, but the fundamental question of how STIM1 migrates remains unresolved. Here, we show that trafficking of STIM1 to ER-PM junctions and subsequent Ca2+ release-activated Ca2+ channel activity is impaired following mitochondrial depolarization. We identify the dynamin-related mitochondrial protein mitofusin 2, mutations of which causes the inherited neurodegenerative disease Charcot-Marie-Tooth IIa in humans, as an important component of this mechanism. Our results reveal a molecular mechanism whereby a mitochondrial fusion protein regulates protein trafficking across the endoplasmic reticulum and reveals a homeostatic mechanism whereby mitochondrial depolarization can inhibit store-operated Ca2+ entry, thereby reducing cellular Ca2+ overload.
authors.affiliation: Department of Physiology, Anatomy, and Genetics, University of Oxford, Sherrington Building, Parks Road, Oxford OX1 3PT, United Kingdom.
authors.forename: Karthika
authors.initials: K
authors.lastname: Singaravelu
authors.forename: Charmaine
authors.initials: C
authors.lastname: Nelson
authors.forename: Daniel
authors.initials: D
authors.lastname: Bakowski
authors.forename: Olga Martins
authors.initials: OM
authors.lastname: de Brito
authors.forename: Siaw-Wei
authors.initials: SW
authors.lastname: Ng
authors.forename: Joseph
authors.initials: J
authors.lastname: Di Capite
authors.forename: Trevor
authors.initials: T
authors.lastname: Powell
authors.forename: Luca
authors.initials: L
authors.lastname: Scorrano
authors.forename: Anant B
authors.initials: AB
authors.lastname: Parekh
mesh_terms: D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D020558:GTP Phosphohydrolases; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051381:Rats; D000071737:Stromal Interaction Molecule 1
chemical_list: D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; C103530:STIM1 protein, human; C518857:Stim1 protein, rat; D000071737:Stromal Interaction Molecule 1; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human; C489710:Mfn2 protein, rat; D002118:Calcium