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

被引：195

作者：

Tomar, Dhanendra ^{[1
,2
]}

Dong, Zhiwei ^{[1
,2
,12
]}

Shanmughapriya, Santhanam ^{[1
,2
]}

Koch, Diana A. ^{[2
,3
]}

Thomas, Toby ^{[1
,2
]}

Hoffman, Nicholas E. ^{[1
,2
]}

Timbalia, Shrishiv A. ^{[4
]}

Goldman, Samuel J. ^{[1
,2
]}

Breves, Sarah L. ^{[1
,2
]}

Corbally, Daniel P. ^{[1
,2
]}

Nemani, Neeharika ^{[1
,2
]}

Fairweather, Joseph P. ^{[1
,2
]}

Cutri, Allison R. ^{[1
,2
]}

Zhang, Xueqian ^{[2
]}

Song, Jianliang ^{[2
]}

Jana, Fabian ^{[1
,2
]}

Huang, Jianhe ^{[5
,6
,7
]}

Barrero, Carlos ^{[8
]}

Rabinowitz, Joseph E. ^{[2
]}

Luongo, Timothy S. ^{[2
]}

Schumacher, Sarah M. ^{[2
]}

Rockman, Michael E. ^{[1
,2
]}

Dietrich, Alexander ^{[3
]}

Merali, Salim ^{[8
]}

Caplan, Jeffrey ^{[9
]}

Stathopulos, Peter ^{[10
]}

Ahima, Rexford S. ^{[11
]}

Cheung, Joseph Y. ^{[2
]}

Houser, Steven R. ^{[5
,6
,7
]}

Koch, Walter J. ^{[2
]}

Patel, Vickas ^{[5
,6
,7
]}

Gohil, Vishal M. ^{[4
]}

Elrod, John W. ^{[2
]}

Rajan, Sudarsan ^{[1
,2
]}

Madesh, Muniswamy ^{[1
,2
]}

机构：

[1] Temple Univ, Lewis Katz Sch Med, Dept Med Genet & Mol Biochem, Philadelphia, PA 19140 USA

[2] Temple Univ, Lewis Katz Sch Med, Ctr Translat Med, Philadelphia, PA 19140 USA

[3] LM Univ Munich, Sch Med, Walther Straub Inst Pharmacol & Toxicol, Nussbaumstr 26, D-80336 Munich, Germany

[4] Texas A&M Univ, Dept Biochem & Biophys, College Stn, TX 77843 USA

[5] Temple Univ, Cardiovasc Res Ctr, Philadelphia, PA 19140 USA

[6] Temple Univ, Dept Med, Philadelphia, PA 19140 USA

[7] Temple Univ, Dept Physiol, Philadelphia, PA 19140 USA

[8] Temple Univ, Dept Pharmaceut Sci, Philadelphia, PA 19140 USA

[9] Univ Delaware, Delaware Biotechnol Inst, Dept Biol Sci, Newark, DE 19711 USA

[10] Univ Western Ontario, Dept Physiol & Pharmacol, London, ON N6A 5C1, Canada

[11] Univ Penn, Perelman Sch Med, Dept Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA

[12] Third Mil Med Univ, Southwest Hosp, State Key Lab Trauma Burns & Combined Injury, Inst Burn Res, Chongqing 400038, Peoples R China

来源：

CELL REPORTS | 2016年 / 15卷 / 08期

关键词：

CALCIUM UNIPORTER; CA2+ UPTAKE; PERMEABILITY TRANSITION; ESSENTIAL COMPONENT; STRESS RESPONSES; MICU1; METABOLISM; HEART; REGULATOR; CHANNELS;

D O I：

10.1016/j.celrep.2016.04.050

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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 I-MCU 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.

引用

页码：1673 / 1685

页数：13

共 44 条

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