MCUR1 Is a Scaffold Factor for the MCU Complex Function and Promotes Mitochondrial Bioenergetics
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 tha...
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| Format: | Article |
| Language: | English |
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Elsevier
2016-05-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124716304776 |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
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 |
| spellingShingle |
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 MCUR1 Is a Scaffold Factor for the MCU Complex Function and Promotes Mitochondrial Bioenergetics Cell Reports |
| author_facet |
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 |
| author_sort |
Dhanendra Tomar |
| title |
MCUR1 Is a Scaffold Factor for the MCU Complex Function and Promotes Mitochondrial Bioenergetics |
| title_short |
MCUR1 Is a Scaffold Factor for the MCU Complex Function and Promotes Mitochondrial Bioenergetics |
| title_full |
MCUR1 Is a Scaffold Factor for the MCU Complex Function and Promotes Mitochondrial Bioenergetics |
| title_fullStr |
MCUR1 Is a Scaffold Factor for the MCU Complex Function and Promotes Mitochondrial Bioenergetics |
| title_full_unstemmed |
MCUR1 Is a Scaffold Factor for the MCU Complex Function and Promotes Mitochondrial Bioenergetics |
| title_sort |
mcur1 is a scaffold factor for the mcu complex function and promotes mitochondrial bioenergetics |
| publisher |
Elsevier |
| series |
Cell Reports |
| issn |
2211-1247 |
| publishDate |
2016-05-01 |
| description |
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. |
| url |
http://www.sciencedirect.com/science/article/pii/S2211124716304776 |
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doaj-824669f56e69431d8fcf04ba6cd6b4d42020-11-24T21:14:46ZengElsevierCell Reports2211-12472016-05-011581673168510.1016/j.celrep.2016.04.050MCUR1 Is a Scaffold Factor for the MCU Complex Function and Promotes Mitochondrial BioenergeticsDhanendra Tomar0Zhiwei Dong1Santhanam Shanmughapriya2Diana A. Koch3Toby Thomas4Nicholas E. Hoffman5Shrishiv A. Timbalia6Samuel J. Goldman7Sarah L. Breves8Daniel P. Corbally9Neeharika Nemani10Joseph P. Fairweather11Allison R. Cutri12Xueqian Zhang13Jianliang Song14Fabián Jaña15Jianhe Huang16Carlos Barrero17Joseph E. Rabinowitz18Timothy S. Luongo19Sarah M. Schumacher20Michael E. Rockman21Alexander Dietrich22Salim Merali23Jeffrey Caplan24Peter Stathopulos25Rexford S. Ahima26Joseph Y. Cheung27Steven R. Houser28Walter J. Koch29Vickas Patel30Vishal M. Gohil31John W. Elrod32Sudarsan Rajan33Muniswamy Madesh34Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USADepartment of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USADepartment of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USACenter for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USADepartment of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USADepartment of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USADepartment of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USADepartment of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USADepartment of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USADepartment of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USADepartment of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USADepartment of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USADepartment of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USACenter for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USACenter for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USADepartment of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USACardiovascular Research Center and Departments of Medicine and Physiology, Temple University, Philadelphia, PA 19140, USADepartment of Pharmaceutical Sciences, Temple University, Philadelphia, PA 19140, USACenter for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USACenter for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USACenter for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USADepartment of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USAWalther 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, GermanyDepartment of Pharmaceutical Sciences, Temple University, Philadelphia, PA 19140, USADepartment of Biological Sciences, Delaware Biotechnology Institute, University of Delaware, Newark, DE 19711, USADepartment of Physiology and Pharmacology, Western University, London, ON N6A 5C1, CanadaDepartment of Medicine, Division of Endocrinology, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USACenter for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USACardiovascular Research Center and Departments of Medicine and Physiology, Temple University, Philadelphia, PA 19140, USACenter for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USACardiovascular Research Center and Departments of Medicine and Physiology, Temple University, Philadelphia, PA 19140, USADepartment of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USACenter for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USADepartment of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USADepartment of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USAMitochondrial 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.http://www.sciencedirect.com/science/article/pii/S2211124716304776 |