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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 , Jana 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 , Madesh M
MCUR1 Is a Scaffold Factor for the MCU Complex Function and Promotes Mitochondrial Bioenergetics
Cell Rep. 2016 May 24;15(8) :1673-85
PMID: 27184846    PMCID: PMC4880542   
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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.
Notes
2211-1247 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 Jana, Fabian 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 Madesh, Muniswamy R01 GM111672/GM/NIGMS NIH HHS/United States R01 HL119306/HL/NHLBI NIH HHS/United States P01 DA037830/DA/NIDA NIH HHS/United States R01 GM109882/GM/NIGMS NIH HHS/United States P20 GM103446/GM/NIGMS NIH HHS/United States S10 RR027327/RR/NCRR NIH HHS/United States P01 HL091799/HL/NHLBI NIH HHS/United States P30 DK019525/DK/NIDDK NIH HHS/United States R01 HL086699/HL/NHLBI NIH HHS/United States Journal Article United States Cell Rep. 2016 May 24;15(8):1673-85. doi: 10.1016/j.celrep.2016.04.050. Epub 2016 May 12.