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 & 15 others 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, Madesh Muniswamy

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1673-1685
Number of pages13
JournalCell Reports
Volume15
Issue number8
DOIs
StatePublished - May 24 2016
Externally publishedYes

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Autophagy
Mitochondrial Membranes
Cardiac Myocytes
Protein Binding
Scaffolds
Energy Metabolism
Cell Movement
Blood Vessels
Endothelial Cells
Cell Proliferation
Endothelial cells
Cell proliferation
Metabolism
Membranes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

MCUR1 Is a Scaffold Factor for the MCU Complex Function and Promotes Mitochondrial Bioenergetics. / Tomar, Dhanendra; Dong, Zhiwei; Shanmughapriya, Santhanam; Koch, Diana A.; Thomas, Toby; Hoffman, Nicholas E.; Timbalia, Shrishiv A.; Goldman, Samuel J.; Breves, Sarah L.; Corbally, Daniel P.; Nemani, Neeharika; Fairweather, Joseph P.; Cutri, Allison R.; Zhang, Xueqian; Song, Jianliang; Jaña, Fabián; Huang, Jianhe; Barrero, Carlos; Rabinowitz, Joseph E.; Luongo, Timothy S.; Schumacher, Sarah M.; Rockman, Michael E.; Dietrich, Alexander; Merali, Salim; Caplan, Jeffrey; Stathopulos, Peter; Ahima, Rexford S.; Cheung, Joseph Y.; Houser, Steven R.; Koch, Walter J.; Patel, Vickas; Gohil, Vishal M.; Elrod, John W.; Rajan, Sudarsan; Muniswamy, Madesh.

In: Cell Reports, Vol. 15, No. 8, 24.05.2016, p. 1673-1685.

Research output: Contribution to journalArticle

Tomar, D, Dong, Z, Shanmughapriya, S, Koch, DA, Thomas, T, Hoffman, NE, Timbalia, SA, Goldman, SJ, Breves, SL, Corbally, DP, Nemani, N, Fairweather, JP, Cutri, AR, Zhang, X, Song, J, Jaña, F, Huang, J, Barrero, C, Rabinowitz, JE, Luongo, TS, Schumacher, SM, Rockman, ME, Dietrich, A, Merali, S, Caplan, J, Stathopulos, P, Ahima, RS, Cheung, JY, Houser, SR, Koch, WJ, Patel, V, Gohil, VM, Elrod, JW, Rajan, S & Muniswamy, M 2016, 'MCUR1 Is a Scaffold Factor for the MCU Complex Function and Promotes Mitochondrial Bioenergetics', Cell Reports, vol. 15, no. 8, pp. 1673-1685. https://doi.org/10.1016/j.celrep.2016.04.050
Tomar D, Dong Z, Shanmughapriya S, Koch DA, Thomas T, Hoffman NE et al. MCUR1 Is a Scaffold Factor for the MCU Complex Function and Promotes Mitochondrial Bioenergetics. Cell Reports. 2016 May 24;15(8):1673-1685. https://doi.org/10.1016/j.celrep.2016.04.050
Tomar, Dhanendra ; Dong, Zhiwei ; Shanmughapriya, Santhanam ; Koch, Diana A. ; Thomas, Toby ; Hoffman, Nicholas E. ; Timbalia, Shrishiv A. ; Goldman, Samuel J. ; Breves, Sarah L. ; Corbally, Daniel P. ; Nemani, Neeharika ; Fairweather, Joseph P. ; Cutri, Allison R. ; Zhang, Xueqian ; Song, Jianliang ; Jaña, Fabián ; Huang, Jianhe ; Barrero, Carlos ; Rabinowitz, Joseph E. ; Luongo, Timothy S. ; Schumacher, Sarah M. ; Rockman, Michael E. ; Dietrich, Alexander ; Merali, Salim ; Caplan, Jeffrey ; Stathopulos, Peter ; Ahima, Rexford S. ; Cheung, Joseph Y. ; Houser, Steven R. ; Koch, Walter J. ; Patel, Vickas ; Gohil, Vishal M. ; Elrod, John W. ; Rajan, Sudarsan ; Muniswamy, Madesh. / MCUR1 Is a Scaffold Factor for the MCU Complex Function and Promotes Mitochondrial Bioenergetics. In: Cell Reports. 2016 ; Vol. 15, No. 8. pp. 1673-1685.
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AU - Thomas, Toby

AU - Hoffman, Nicholas E.

AU - Timbalia, Shrishiv A.

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AU - Breves, Sarah L.

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AU - Stathopulos, Peter

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AU - Houser, Steven R.

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AU - Patel, Vickas

AU - Gohil, Vishal M.

AU - Elrod, John W.

AU - Rajan, Sudarsan

AU - Muniswamy, Madesh

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