title: IP3-mediated STIM1 oligomerization requires intact mitochondrial Ca2+ uptake.
abstract: Mitochondria contribute to cell signaling by controlling store-operated Ca(2+) entry (SOCE). SOCE is activated by Ca(2+) release from the endoplasmic reticulum (ER), whereupon stromal interacting molecule 1 (STIM1) forms oligomers, redistributes to ER-plasma-membrane junctions and opens plasma membrane Ca(2+) channels. The mechanisms by which mitochondria interfere with the complex process of SOCE are insufficiently clarified. In this study, we used an shRNA approach to investigate the direct involvement of mitochondrial Ca(2+) buffering in SOCE. We demonstrate that knockdown of either of two proteins that are essential for mitochondrial Ca(2+) uptake, the mitochondrial calcium uniporter (MCU) or uncoupling protein 2 (UCP2), results in decelerated STIM1 oligomerization and impaired SOCE following cell stimulation with an inositol-1,4,5-trisphosphate (IP3)-generating agonist. Upon artificially augmented cytosolic Ca(2+) buffering or ER Ca(2+) depletion by sarcoplasmic or endoplasmic reticulum Ca(2+)-ATPase (SERCA) inhibitors, STIM1 oligomerization did not rely on intact mitochondrial Ca(2+) uptake. However, MCU-dependent mitochondrial sequestration of Ca(2+) entering through the SOCE pathway was essential to prevent slow deactivation of SOCE. Our findings show a stimulus-specific contribution of mitochondrial Ca(2+) uptake to the SOCE machinery, likely through a role in shaping cytosolic Ca(2+) micro-domains.
authors.affiliation: The Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, 8010-Graz, Austria.
authors.forename: Andras T
authors.initials: AT
authors.lastname: Deak
authors.affiliation: The Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, 8010-Graz, Austria.
authors.forename: Sandra
authors.initials: S
authors.lastname: Blass
authors.affiliation: The Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, 8010-Graz, Austria.
authors.forename: Muhammad J
authors.initials: MJ
authors.lastname: Khan
authors.affiliation: The Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, 8010-Graz, Austria.
authors.forename: Lukas N
authors.initials: LN
authors.lastname: Groschner
authors.affiliation: The Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, 8010-Graz, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Waldeck-Weiermair
authors.affiliation: The Institute of Physiological Chemistry, Center of Physiological Medicine, Medical University of Graz, 8010-Graz, Austria.
authors.forename: Seth
authors.initials: S
authors.lastname: Hallström
authors.affiliation: The Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, 8010-Graz, Austria.
authors.forename: Wolfgang F
authors.initials: WF
authors.lastname: Graier
authors.affiliation: The Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, 8010-Graz, Austria roland.malli@medunigraz.at.
authors.forename: Roland
authors.initials: R
authors.lastname: Malli
mesh_terms: D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling; D006367:HeLa Cells; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D000071737:Stromal Interaction Molecule 1
chemical_list: D015220:Calcium Channels; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; C034703:mitochondrial calcium uniporter; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium
keywords: MCU; Mitochondrial Ca2+ uptake; SOCE; STIM1 oligomerization; UCP2