title: PRMT1-mediated methylation of MICU1 determines the UCP2/3 dependency of mitochondrial Ca(2+) uptake in immortalized cells.
abstract: Recent studies revealed that mitochondrial Ca(2+) channels, which control energy flow, cell signalling and death, are macromolecular complexes that basically consist of the pore-forming mitochondrial Ca(2+) uniporter (MCU) protein, the essential MCU regulator (EMRE), and the mitochondrial Ca(2+) uptake 1 (MICU1). MICU1 is a regulatory subunit that shields mitochondria from Ca(2+) overload. Before the identification of these core elements, the novel uncoupling proteins 2 and 3 (UCP2/3) have been shown to be fundamental for mitochondrial Ca(2+) uptake. Here we clarify the molecular mechanism that determines the UCP2/3 dependency of mitochondrial Ca(2+) uptake. Our data demonstrate that mitochondrial Ca(2+) uptake is controlled by protein arginine methyl transferase 1 (PRMT1) that asymmetrically methylates MICU1, resulting in decreased Ca(2+) sensitivity. UCP2/3 normalize Ca(2+) sensitivity of methylated MICU1 and, thus, re-establish mitochondrial Ca(2+) uptake activity. These data provide novel insights in the complex regulation of the mitochondrial Ca(2+) uniporter by PRMT1 and UCP2/3.
authors.affiliation: Center for Molecular Medicine, Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21/III, Graz 8010, Austria.
authors.forename: Corina T
authors.initials: CT
authors.lastname: Madreiter-Sokolowski
authors.affiliation: Center for Molecular Medicine, Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21/III, Graz 8010, Austria.
authors.forename: Christiane
authors.initials: C
authors.lastname: Klec
authors.affiliation: Center for Molecular Medicine, Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21/III, Graz 8010, Austria.
authors.forename: Warisara
authors.initials: W
authors.lastname: Parichatikanond
authors.affiliation: Center for Molecular Medicine, Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21/III, Graz 8010, Austria.
authors.forename: Sarah
authors.initials: S
authors.lastname: Stryeck
authors.affiliation: Center for Molecular Medicine, Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21/III, Graz 8010, Austria.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gottschalk
authors.affiliation: Institute of Chemistry, University of Graz, Graz 8010, Austria.
authors.forename: Sergio
authors.initials: S
authors.lastname: Pulido
authors.affiliation: Center for Molecular Medicine, Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21/III, Graz 8010, Austria.
authors.forename: Rene
authors.initials: R
authors.lastname: Rost
authors.affiliation: Center for Molecular Medicine, Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21/III, Graz 8010, Austria.
authors.forename: Emrah
authors.identifier: http://orcid.org/0000-0002-9373-0808
authors.initials: E
authors.lastname: Eroglu
authors.affiliation: Center for Molecular Medicine, Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21/III, Graz 8010, Austria.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Hofmann
authors.affiliation: Center for Molecular Medicine, Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21/III, Graz 8010, Austria.
authors.forename: Alexander I
authors.initials: AI
authors.lastname: Bondarenko
authors.affiliation: Center for Molecular Medicine, Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21/III, Graz 8010, Austria.|Center for Integrated Protein Science, Department Chemistry, Technical University Munich, Garching 85748, Germany.|Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg 85764, Germany.
authors.forename: Tobias
authors.identifier: http://orcid.org/0000-0002-9725-5231
authors.initials: T
authors.lastname: Madl
authors.affiliation: Center for Molecular Medicine, Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21/III, Graz 8010, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Waldeck-Weiermair
authors.affiliation: Center for Molecular Medicine, Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21/III, Graz 8010, Austria.
authors.forename: Roland
authors.initials: R
authors.lastname: Malli
authors.affiliation: Center for Molecular Medicine, Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21/III, Graz 8010, Austria.
authors.forename: Wolfgang F
authors.identifier: http://orcid.org/0000-0003-1871-3298
authors.initials: WF
authors.lastname: Graier
mesh_terms: D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008745:Methylation; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D000071246:Uncoupling Protein 2 / Q000378:metabolism*; D000071247:Uncoupling Protein 3 / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D027682:Cation Transport Proteins; C116241:MICU1 protein, human; D033681:Mitochondrial Membrane Transport Proteins; D012097:Repressor Proteins; C000604389:UCP2 protein, human; C000604392:UCP3 protein, human; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3; C034703:mitochondrial calcium uniporter; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases; D002118:Calcium