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. LuongoSarah 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

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74 Scopus citations

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

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Tomar, D., Dong, Z., Shanmughapriya, S., Koch, D. A., Thomas, T., Hoffman, N. E., Timbalia, S. A., Goldman, S. J., Breves, S. L., Corbally, D. P., Nemani, N., Fairweather, J. P., Cutri, A. R., Zhang, X., Song, J., Jaña, F., Huang, J., Barrero, C., Rabinowitz, J. E., ... Madesh, M. (2016). MCUR1 Is a Scaffold Factor for the MCU Complex Function and Promotes Mitochondrial Bioenergetics. Cell Reports, 15(8), 1673-1685. https://doi.org/10.1016/j.celrep.2016.04.050