title: MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter by exerting opposite effects on MCU activity.
abstract: Mitochondrial calcium accumulation was recently shown to depend on a complex composed of an inner-membrane channel (MCU and MCUb) and regulatory subunits (MICU1, MCUR1, and EMRE). A fundamental property of MCU is low activity at resting cytosolic Ca(2+) concentrations, preventing deleterious Ca(2+) cycling and organelle overload. Here we demonstrate that these properties are ensured by a regulatory heterodimer composed of two proteins with opposite effects, MICU1 and MICU2, which, both in purified lipid bilayers and in intact cells, stimulate and inhibit MCU activity, respectively. Both MICU1 and MICU2 are regulated by calcium through their EF-hand domains, thus accounting for the sigmoidal response of MCU to [Ca(2+)] in situ and allowing tight physiological control. At low [Ca(2+)], the dominant effect of MICU2 largely shuts down MCU activity; at higher [Ca(2+)], the stimulatory effect of MICU1 allows the prompt response of mitochondria to Ca(2+) signals generated in the cytoplasm.
authors.affiliation: Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58, 35131 Padova, Italy; CNR Neuroscience Institute, Via Ugo Bassi 58, 35131 Padova, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Patron
authors.affiliation: Department of Biology, University of Padova, Via Ugo Bassi 58, 35131 Padova, Italy.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Checchetto
authors.affiliation: Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58, 35131 Padova, Italy; CNR Neuroscience Institute, Via Ugo Bassi 58, 35131 Padova, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Raffaello
authors.affiliation: Department of Biology, University of Padova, Via Ugo Bassi 58, 35131 Padova, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Teardo
authors.affiliation: Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58, 35131 Padova, Italy; CNR Neuroscience Institute, Via Ugo Bassi 58, 35131 Padova, Italy.
authors.forename: Denis
authors.initials: D
authors.lastname: Vecellio Reane
authors.affiliation: Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58, 35131 Padova, Italy; CNR Neuroscience Institute, Via Ugo Bassi 58, 35131 Padova, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Mantoan
authors.affiliation: Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58, 35131 Padova, Italy; CNR Neuroscience Institute, Via Ugo Bassi 58, 35131 Padova, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Granatiero
authors.affiliation: Department of Biology, University of Padova, Via Ugo Bassi 58, 35131 Padova, Italy.
authors.forename: Ildikò
authors.initials: I
authors.lastname: Szabò
authors.affiliation: Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58, 35131 Padova, Italy; CNR Neuroscience Institute, Via Ugo Bassi 58, 35131 Padova, Italy. Electronic address: diego.destefani@gmail.com.
authors.forename: Diego
authors.initials: D
authors.lastname: De Stefani
authors.affiliation: Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58, 35131 Padova, Italy; CNR Neuroscience Institute, Via Ugo Bassi 58, 35131 Padova, Italy. Electronic address: rosario.rizzuto@unipd.it.
authors.forename: Rosario
authors.initials: R
authors.lastname: Rizzuto
mesh_terms: D000331:Aequorin / Q000737:chemistry; D002118:Calcium / Q000737:chemistry; D015220:Calcium Channels / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D019281:Dimerization; D004220:Disulfides; D004594:Electrophysiology / Q000379:methods; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D008051:Lipid Bilayers / Q000737:chemistry; D008928:Mitochondria / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D027682:Cation Transport Proteins; D004220:Disulfides; D008051:Lipid Bilayers; C116241:MICU1 protein, human; C582650:MICU2 protein, human; D033681:Mitochondrial Membrane Transport Proteins; D034741:RNA, Small Interfering; D000331:Aequorin; D002118:Calcium