title: MCUR1 is an essential component of mitochondrial Ca2+ uptake that regulates cellular metabolism.
abstract: Ca(2+) flux across the mitochondrial inner membrane regulates bioenergetics, cytoplasmic Ca(2+) signals and activation of cell death pathways. Mitochondrial Ca(2+) uptake occurs at regions of close apposition with intracellular Ca(2+) release sites, driven by the inner membrane voltage generated by oxidative phosphorylation and mediated by a Ca(2+) selective ion channel (MiCa; ref. ) called the uniporter whose complete molecular identity remains unknown. Mitochondrial calcium uniporter (MCU) was recently identified as the likely ion-conducting pore. In addition, MICU1 was identified as a mitochondrial regulator of uniporter-mediated Ca(2+) uptake in HeLa cells. Here we identified CCDC90A, hereafter referred to as MCUR1 (mitochondrial calcium uniporter regulator 1), an integral membrane protein required for MCU-dependent mitochondrial Ca(2+) uptake. MCUR1 binds to MCU and regulates ruthenium-red-sensitive MCU-dependent Ca(2+) uptake. MCUR1 knockdown does not alter MCU localization, but abrogates Ca(2+) uptake by energized mitochondria in intact and permeabilized cells. Ablation of MCUR1 disrupts oxidative phosphorylation, lowers cellular ATP and activates AMP kinase-dependent pro-survival autophagy. Thus, MCUR1 is a critical component of a mitochondrial uniporter channel complex required for mitochondrial Ca(2+) uptake and maintenance of normal cellular bioenergetics.
authors.affiliation: Department of Biochemistry, Temple University, Philadelphia, Pennsylvania 19140, USA.
authors.forename: Karthik
authors.initials: K
authors.lastname: Mallilankaraman
authors.forename: César
authors.initials: C
authors.lastname: Cárdenas
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Doonan
authors.forename: Harish C
authors.initials: HC
authors.lastname: Chandramoorthy
authors.forename: Krishna M
authors.initials: KM
authors.lastname: Irrinki
authors.forename: Tünde
authors.initials: T
authors.lastname: Golenár
authors.forename: György
authors.initials: G
authors.lastname: Csordás
authors.forename: Priyanka
authors.initials: P
authors.lastname: Madireddi
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Marioly
authors.initials: M
authors.lastname: Müller
authors.forename: Russell
authors.initials: R
authors.lastname: Miller
authors.forename: Jill E
authors.initials: JE
authors.lastname: Kolesar
authors.forename: Jordi
authors.initials: J
authors.lastname: Molgó
authors.forename: Brett
authors.initials: B
authors.lastname: Kaufman
authors.forename: György
authors.initials: G
authors.lastname: Hajnóczky
authors.forename: J Kevin
authors.initials: JK
authors.lastname: Foskett
authors.forename: Muniswamy
authors.initials: M
authors.lastname: Madesh
mesh_terms: D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D027682:Cation Transport Proteins; C000601188:MCUR1 protein, human; C116241:MICU1 protein, human; D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; C034703:mitochondrial calcium uniporter; D002118:Calcium