title: MICU1 motifs define mitochondrial calcium uniporter binding and activity.
abstract: Resting mitochondrial matrix Ca(2+) is maintained through a mitochondrial calcium uptake 1 (MICU1)-established threshold inhibition of mitochondrial calcium uniporter (MCU) activity. It is not known how MICU1 interacts with MCU to establish this Ca(2+) threshold for mitochondrial Ca(2+) uptake and MCU activity. Here, we show that MICU1 localizes to the mitochondrial matrix side of the inner mitochondrial membrane and MICU1/MCU binding is determined by a MICU1 N-terminal polybasic domain and two interacting coiled-coil domains of MCU. Further investigation reveals that MICU1 forms homo-oligomers, and this oligomerization is independent of the polybasic region. However, the polybasic region confers MICU1 oligomeric binding to MCU and controls mitochondrial Ca(2+) current (IMCU). Moreover, MICU1 EF hands regulate MCU channel activity, but do not determine MCU binding. Loss of MICU1 promotes MCU activation leading to oxidative burden and a halt to cell migration. These studies establish a molecular mechanism for MICU1 control of MCU-mediated mitochondrial Ca(2+) accumulation, and dysregulation of this mechanism probably enhances vascular dysfunction.
authors: Department of Biochemistry, Temple University, Philadelphia, Pennsylvania 19140, USA.|Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania, 19140, USA.
authors: Nicholas E
authors: NE
authors: Hoffman
authors: Department of Biochemistry, Temple University, Philadelphia, Pennsylvania 19140, USA.|Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania, 19140, USA.|Stem Cell Unit & Department of Clinical Biochemistry, College of Medicine, King Khalid University, Abha P.O. 641, K S A.
authors: Harish C
authors: HC
authors: Chandramoorthy
authors: Department of Biochemistry, Temple University, Philadelphia, Pennsylvania 19140, USA.|Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania, 19140, USA.
authors: Santhanam
authors: S
authors: Shamugapriya
authors: Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania, 19140, USA.
authors: Xueqian
authors: X
authors: Zhang
authors: Department of Biochemistry, Temple University, Philadelphia, Pennsylvania 19140, USA.|Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania, 19140, USA.
authors: Sudarsan
authors: S
authors: Rajan
authors: Department of Biochemistry, Temple University, Philadelphia, Pennsylvania 19140, USA.|Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania, 19140, USA.
authors: Karthik
authors: K
authors: Mallilankaraman
authors: Department of Biochemistry, Temple University, Philadelphia, Pennsylvania 19140, USA.|Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania, 19140, USA.
authors: Rajesh Kumar
authors: RK
authors: Gandhirajan
authors: Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania, 19140, USA.
authors: Ronald J
authors: RJ
authors: Vagnozzi
authors: Department of Surgery, Temple University, Philadelphia, Pennsylvania, 19140, USA.
authors: Lukas M
authors: LM
authors: Ferrer
authors: Department of Biochemistry, Temple University, Philadelphia, Pennsylvania 19140, USA.|Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania, 19140, USA.
authors: Krishnalatha
authors: K
authors: Sreekrishnanilayam
authors: Department of Biochemistry, Temple University, Philadelphia, Pennsylvania 19140, USA.|Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania, 19140, USA.
authors: Kalimuthusamy
authors: K
authors: Natarajaseenivasan
authors: Department of Biochemistry, Temple University, Philadelphia, Pennsylvania 19140, USA.|Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania, 19140, USA.
authors: Sandhya
authors: S
authors: Vallem
authors: Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania, 19140, USA.|Department of Medicine, Temple University, Philadelphia, Pennsylvania, 19140, USA.
authors: Thomas
authors: T
authors: Force
authors: Department of Surgery, Temple University, Philadelphia, Pennsylvania, 19140, USA.|Cardiovascular Research Center, Temple University, Philadelphia, Pennsylvania, 19140, USA.
authors: Eric T
authors: ET
authors: Choi
authors: Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania, 19140, USA.|Department of Medicine, Temple University, Philadelphia, Pennsylvania, 19140, USA.
authors: Joseph Y
authors: JY
authors: Cheung
authors: Department of Biochemistry, Temple University, Philadelphia, Pennsylvania 19140, USA.|Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania, 19140, USA.
authors: Muniswamy
authors: M
authors: Madesh
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization
chemical_list: D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D027682:Cation Transport Proteins; C116241:MICU1 protein, human; D033681:Mitochondrial Membrane Transport Proteins; C585180:SMDT1 protein, human; D002118:Calcium