title: The Ca(2+)-Dependent Release of the Mia40-Induced MICU1-MICU2 Dimer from MCU Regulates Mitochondrial Ca(2+) Uptake.
abstract: The essential oxidoreductase Mia40/CHCHD4 mediates disulfide bond formation and protein folding in the mitochondrial intermembrane space. Here, we investigated the interactome of Mia40 thereby revealing links between thiol-oxidation and apoptosis, energy metabolism, and Ca(2+) signaling. Among the interaction partners of Mia40 is MICU1-the regulator of the mitochondrial Ca(2+) uniporter (MCU), which transfers Ca(2+) across the inner membrane. We examined the biogenesis of MICU1 and find that Mia40 introduces an intermolecular disulfide bond that links MICU1 and its inhibitory paralog MICU2 in a heterodimer. Absence of this disulfide bond results in increased receptor-induced mitochondrial Ca(2+) uptake. In the presence of the disulfide bond, MICU1-MICU2 heterodimer binding to MCU is controlled by Ca(2+) levels: the dimer associates with MCU at low levels of Ca(2+) and dissociates upon high Ca(2+) concentrations. Our findings support a model in which mitochondrial Ca(2+) uptake is regulated by a Ca(2+)-dependent remodeling of the uniporter complex.
authors.affiliation: Cellular Biochemistry, University of Kaiserslautern, Erwin-Schroedinger-Str. 13, 67663 Kaiserslautern, Germany; Institute of Biochemistry, University of Cologne, Zuelpicher Str. 47, 50674 Cologne, Germany.
authors.forename: Carmelina
authors.initials: C
authors.lastname: Petrungaro
authors.affiliation: Department of Biophysics, CIPMM, School of Medicine, University of Saarland, 66421, Homburg, Germany.
authors.forename: Katharina M
authors.initials: KM
authors.lastname: Zimmermann
authors.affiliation: Department of Dermatology, Medical Center, Freiburg Institute for Advanced Studies, BIOSS Centre for Biological Signaling Studies, ZBSA Center for Biological Systems Analysis, University of Freiburg, Habsburgerstr. 49, 79104 Freiburg, Germany.
authors.forename: Victoria
authors.initials: V
authors.lastname: Küttner
authors.affiliation: Cellular Biochemistry, University of Kaiserslautern, Erwin-Schroedinger-Str. 13, 67663 Kaiserslautern, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Fischer
authors.affiliation: Department of Dermatology, Medical Center, Freiburg Institute for Advanced Studies, BIOSS Centre for Biological Signaling Studies, ZBSA Center for Biological Systems Analysis, University of Freiburg, Habsburgerstr. 49, 79104 Freiburg, Germany.
authors.forename: Jörn
authors.initials: J
authors.lastname: Dengjel
authors.affiliation: Department of Biophysics, CIPMM, School of Medicine, University of Saarland, 66421, Homburg, Germany.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bogeski
authors.affiliation: Cellular Biochemistry, University of Kaiserslautern, Erwin-Schroedinger-Str. 13, 67663 Kaiserslautern, Germany; Institute of Biochemistry, University of Cologne, Zuelpicher Str. 47, 50674 Cologne, Germany. Electronic address: jan.riemer@uni-koeln.de.
authors.forename: Jan
authors.initials: J
authors.lastname: Riemer
mesh_terms: D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000737:chemistry / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007477:Ions / Q000737:chemistry / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: C507282:CHCHD4 protein, human; D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D027682:Cation Transport Proteins; D004220:Disulfides; D007477:Ions; C116241:MICU1 protein, human; C582650:MICU2 protein, human; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D034741:RNA, Small Interfering; D002118:Calcium
keywords: CHCHD4; Ca(2+); MCUx; MICU; Mia40; disulfide; mitochondria; redox