Cell Reports (May 2016)
MCUR1 Is a Scaffold Factor for the MCU Complex Function and Promotes Mitochondrial Bioenergetics
- Dhanendra Tomar,
- Zhiwei Dong,
- Santhanam Shanmughapriya,
- Diana A. Koch,
- Toby Thomas,
- Nicholas E. Hoffman,
- Shrishiv A. Timbalia,
- Samuel J. Goldman,
- Sarah L. Breves,
- Daniel P. Corbally,
- Neeharika Nemani,
- Joseph P. Fairweather,
- Allison R. Cutri,
- Xueqian Zhang,
- Jianliang Song,
- Fabián Jaña,
- Jianhe Huang,
- Carlos Barrero,
- Joseph E. Rabinowitz,
- Timothy S. Luongo,
- Sarah M. Schumacher,
- Michael E. Rockman,
- Alexander Dietrich,
- Salim Merali,
- Jeffrey Caplan,
- Peter Stathopulos,
- Rexford S. Ahima,
- Joseph Y. Cheung,
- Steven R. Houser,
- Walter J. Koch,
- Vickas Patel,
- Vishal M. Gohil,
- John W. Elrod,
- Sudarsan Rajan,
- Muniswamy Madesh
Affiliations
- Dhanendra Tomar
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Zhiwei Dong
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Santhanam Shanmughapriya
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Diana A. Koch
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Toby Thomas
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Nicholas E. Hoffman
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Shrishiv A. Timbalia
- Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA
- Samuel J. Goldman
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Sarah L. Breves
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Daniel P. Corbally
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Neeharika Nemani
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Joseph P. Fairweather
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Allison R. Cutri
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Xueqian Zhang
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Jianliang Song
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Fabián Jaña
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Jianhe Huang
- Cardiovascular Research Center and Departments of Medicine and Physiology, Temple University, Philadelphia, PA 19140, USA
- Carlos Barrero
- Department of Pharmaceutical Sciences, Temple University, Philadelphia, PA 19140, USA
- Joseph E. Rabinowitz
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Timothy S. Luongo
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Sarah M. Schumacher
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Michael E. Rockman
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Alexander Dietrich
- 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
- Salim Merali
- Department of Pharmaceutical Sciences, Temple University, Philadelphia, PA 19140, USA
- Jeffrey Caplan
- Department of Biological Sciences, Delaware Biotechnology Institute, University of Delaware, Newark, DE 19711, USA
- Peter Stathopulos
- Department of Physiology and Pharmacology, Western University, London, ON N6A 5C1, Canada
- Rexford S. Ahima
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Joseph Y. Cheung
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Steven R. Houser
- Cardiovascular Research Center and Departments of Medicine and Physiology, Temple University, Philadelphia, PA 19140, USA
- Walter J. Koch
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Vickas Patel
- Cardiovascular Research Center and Departments of Medicine and Physiology, Temple University, Philadelphia, PA 19140, USA
- Vishal M. Gohil
- Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA
- John W. Elrod
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Sudarsan Rajan
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Muniswamy Madesh
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- DOI
- https://doi.org/10.1016/j.celrep.2016.04.050
- Journal volume & issue
-
Vol. 15,
no. 8
pp. 1673 – 1685
Abstract
Mitochondrial Ca2+ Uniporter (MCU)-dependent mitochondrial Ca2+ uptake is the primary mechanism for increasing matrix Ca2+ 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 [Ca2+]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 Ca2+-dependent mitochondrial metabolism.
