title: Ero1α regulates Ca(2+) fluxes at the endoplasmic reticulum-mitochondria interface (MAM).
abstract: OBJECTIVE
  The endoplasmic reticulum (ER) is involved in many functions, including protein folding, redox homeostasis, and Ca(2+) storage and signaling. To perform these multiple tasks, the ER is composed of distinct, specialized subregions, amongst which mitochondrial-associated ER membranes (MAM) emerge as key signaling hubs. How these multiple functions are integrated with one another in living cells remains unclear.
  
  
  RESULTS
  Here we show that Ero1α, a key controller of oxidative folding and ER redox homeostasis, is enriched in MAM and regulates Ca(2+) fluxes. Downregulation of Ero1α by RNA interference inhibits mitochondrial Ca(2+) fluxes and modifies the activity of mitochondrial Ca(2+) uniporters. The overexpression of redox active Ero1α increases passive Ca(2+) efflux from the ER, lowering [Ca(2+)](ER) and mitochondrial Ca(2+) fluxes in response to IP3 agonists.
  
  
  METHODS
  The unexpected observation that Ca(2+) fluxes are affected by either increasing or decreasing the levels of Ero1α reveals a pivotal role for this oxidase in the early secretory compartment and implies a strict control of its amounts.
  
  
  CONCLUSIONS
  Taken together, our results indicate that the levels, subcellular localization, and activity of Ero1α coordinately regulate Ca(2+) and redox homeostasis and signaling in the early secretory compartment.
authors.affiliation: Università Vita-Salute San Raffaele, Milano, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Anelli
authors.forename: Leda
authors.initials: L
authors.lastname: Bergamelli
authors.forename: Eva
authors.initials: E
authors.lastname: Margittai
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rimessi
authors.forename: Claudio
authors.initials: C
authors.lastname: Fagioli
authors.forename: Antonio
authors.initials: A
authors.lastname: Malgaroli
authors.forename: Paolo
authors.initials: P
authors.lastname: Pinton
authors.forename: Maddalena
authors.initials: M
authors.lastname: Ripamonti
authors.forename: Rosario
authors.initials: R
authors.lastname: Rizzuto
authors.forename: Roberto
authors.initials: R
authors.lastname: Sitia
mesh_terms: D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction
chemical_list: C451899:ERP44 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; C405327:ERO1A protein, human; D010088:Oxidoreductases; D002118:Calcium