MCUR1 Is a Scaffold Factor for the MCU Complex Function and Promotes Mitochondrial Bioenergetics

• DOI: 10.1016/j.celrep.2016.04.050
• Publication Date: 2016-05-12T13:47:59Z
• Authors: Dhanendra Tomar; Zhiwei Dong; Santhanam Shanmug...; Diana A. Koch; Toby Thomas; Nicholas E. Hoffman; Shrishiv A. Timbalia; Samuel J. Goldman; Sarah L. Breves; Daniel P. Corbally; Neeharika Nemani; Joseph P. Fairwea...; 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
• Keywords: Mice, Knockout; 0301 basic medicine; QH301-705.5; 610; Endothelial Cells; Neovascularization, Physiologic; Heart; Mitochondria; Mitochondrial Proteins; 03 medical and health sciences; HEK293 Cells; Protein Domains; Cell Movement; Autophagy; Animals; Humans; Calcium; Calcium Channels; Biology (General); Energy Metabolism; Gene Deletion; HeLa Cells; Protein Binding

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.