2. Academic Validation
  3. MCUR1 Is a Scaffold Factor for the MCU Complex Function and Promotes Mitochondrial Bioenergetics

MCUR1 Is a Scaffold Factor for the MCU Complex Function and Promotes Mitochondrial Bioenergetics

  • Cell Rep. 2016 May 24;15(8):1673-85. doi: 10.1016/j.celrep.2016.04.050.
Dhanendra Tomar 1,  Zhiwei Dong 2,  Santhanam Shanmughapriya 1,  Diana A Koch 3,  Toby Thomas 1,  Nicholas E Hoffman 1,  Shrishiv A Timbalia 4,  Samuel J Goldman 1,  Sarah L Breves 1,  Daniel P Corbally 1,  Neeharika Nemani 1,  Joseph P Fairweather 1,  Allison R Cutri 1,  Xueqian Zhang 5,  Jianliang Song 5,  Fabián Jaña 1,  Jianhe Huang 6,  Carlos Barrero 7,  Joseph E Rabinowitz 5,  Timothy S Luongo 5,  Sarah M Schumacher 5,  Michael E Rockman 1,  Alexander Dietrich 8,  Salim Merali 7,  Jeffrey Caplan 9,  Peter Stathopulos 10,  Rexford S Ahima 11,  Joseph Y Cheung 5,  Steven R Houser 6,  Walter J Koch 5,  Vickas Patel 6,  Vishal M Gohil 4,  John W Elrod 5,  Sudarsan Rajan 1,  Muniswamy Madesh 12
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 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.
  • 4 Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
  • 5 Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
  • 6 Cardiovascular Research Center and Departments of Medicine and Physiology, Temple University, Philadelphia, PA 19140, USA.
  • 7 Department of Pharmaceutical Sciences, Temple University, Philadelphia, PA 19140, USA.
  • 8 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.
  • 9 Department of Biological Sciences, Delaware Biotechnology Institute, University of Delaware, Newark, DE 19711, USA.
  • 10 Department of Physiology and Pharmacology, Western University, London, ON N6A 5C1, Canada.
  • 11 Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 12 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: [email protected].
PMID: 27184846 DOI: 10.1016/j.celrep.2016.04.050
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.

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