title: MCUR1 Is a Scaffold Factor for the MCU Complex Function and Promotes Mitochondrial Bioenergetics.
abstract: Mitochondrial Ca(2+) Uniporter (MCU)-dependent mitochondrial Ca(2+) uptake is the primary mechanism for increasing matrix Ca(2+) in most cell types. However, a limited understanding of the MCU complex assembly impedes the comprehension of the precise mechanisms underlying MCU activity. Here, we report that mouse cardiomyocytes and endothelial cells lacking MCU regulator 1 (MCUR1) have severely impaired [Ca(2+)]m uptake and IMCU current. MCUR1 binds to MCU and EMRE and function as a scaffold factor. Our protein binding analyses identified the minimal, highly conserved regions of coiled-coil domain of both MCU and MCUR1 that are necessary for heterooligomeric complex formation. Loss of MCUR1 perturbed MCU heterooligomeric complex and functions as a scaffold factor for the assembly of MCU complex. Vascular endothelial deletion of MCU and MCUR1 impaired mitochondrial bioenergetics, cell proliferation, and migration but elicited autophagy. These studies establish the existence of a MCU complex that assembles at the mitochondrial integral membrane and regulates Ca(2+)-dependent mitochondrial metabolism.
authors.affiliation: Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
authors.forename: Dhanendra
authors.initials: D
authors.lastname: Tomar
authors.affiliation: Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Institute of Burn Research, Southwest Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
authors.forename: Santhanam
authors.initials: S
authors.lastname: Shanmughapriya
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Walther Straub Institute for Pharmacology and Toxicology, Member of the German Center for Lung Research (DZL), School of Medicine, LM University of Munich, Nussbaumstrasse 26, 80336 Munich, Germany.
authors.forename: Diana A
authors.initials: DA
authors.lastname: Koch
authors.affiliation: Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
authors.forename: Toby
authors.initials: T
authors.lastname: Thomas
authors.affiliation: Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Hoffman
authors.affiliation: Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Shrishiv A
authors.initials: SA
authors.lastname: Timbalia
authors.affiliation: Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Goldman
authors.affiliation: Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Breves
authors.affiliation: Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Corbally
authors.affiliation: Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
authors.forename: Neeharika
authors.initials: N
authors.lastname: Nemani
authors.affiliation: Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Fairweather
authors.affiliation: Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
authors.forename: Allison R
authors.initials: AR
authors.lastname: Cutri
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
authors.forename: Xueqian
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
authors.forename: Jianliang
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
authors.forename: Fabián
authors.initials: F
authors.lastname: Jaña
authors.affiliation: Cardiovascular Research Center and Departments of Medicine and Physiology, Temple University, Philadelphia, PA 19140, USA.
authors.forename: Jianhe
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Pharmaceutical Sciences, Temple University, Philadelphia, PA 19140, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Barrero
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Rabinowitz
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Luongo
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Schumacher
authors.affiliation: Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Rockman
authors.affiliation: Walther Straub Institute for Pharmacology and Toxicology, Member of the German Center for Lung Research (DZL), School of Medicine, LM University of Munich, Nussbaumstrasse 26, 80336 Munich, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dietrich
authors.affiliation: Department of Pharmaceutical Sciences, Temple University, Philadelphia, PA 19140, USA.
authors.forename: Salim
authors.initials: S
authors.lastname: Merali
authors.affiliation: Department of Biological Sciences, Delaware Biotechnology Institute, University of Delaware, Newark, DE 19711, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Caplan
authors.affiliation: Department of Physiology and Pharmacology, Western University, London, ON N6A 5C1, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Stathopulos
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Rexford S
authors.initials: RS
authors.lastname: Ahima
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
authors.forename: Joseph Y
authors.initials: JY
authors.lastname: Cheung
authors.affiliation: Cardiovascular Research Center and Departments of Medicine and Physiology, Temple University, Philadelphia, PA 19140, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.affiliation: Cardiovascular Research Center and Departments of Medicine and Physiology, Temple University, Philadelphia, PA 19140, USA.
authors.forename: Vickas
authors.initials: V
authors.lastname: Patel
authors.affiliation: Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Vishal M
authors.initials: VM
authors.lastname: Gohil
authors.affiliation: Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Elrod
authors.affiliation: Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
authors.forename: Sudarsan
authors.initials: S
authors.lastname: Rajan
authors.affiliation: Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA. Electronic address: madeshm@temple.edu.
authors.forename: Muniswamy
authors.initials: M
authors.lastname: Madesh
mesh_terms: D000818:Animals; D001343:Autophagy; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000737:chemistry / Q000378:metabolism*; D002465:Cell Movement; D042783:Endothelial Cells / Q000378:metabolism; D004734:Energy Metabolism; D017353:Gene Deletion; D057809:HEK293 Cells; D006367:HeLa Cells; D006321:Heart / Q000502:physiology; D006801:Humans; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D011485:Protein Binding; D000072417:Protein Domains
chemical_list: D015220:Calcium Channels; C000622748:Emre protein, mouse; C000624617:MCUR1 protein, mouse; D024101:Mitochondrial Proteins; C034703:mitochondrial calcium uniporter; D002118:Calcium