这场争论仍在继续——MCU 和线粒体钙摄取在心脏中的作用是什么？
The debate continues - What is the role of MCU and mitochondrial calcium uptake in the heart?
机构信息
Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
出版信息
J Mol Cell Cardiol. 2020 Jun;143:163-174. doi: 10.1016/j.yjmcc.2020.04.029. Epub 2020 Apr 27.
Abstract
Since the identification of the mitochondrial calcium uniporter (MCU) in 2011, several studies utilizing genetic models have attempted to decipher the role of mitochondrial calcium uptake in cardiac physiology. Confounding results in various mutant mouse models have led to an ongoing debate regarding the function of MCU in the heart. In this review, we evaluate and discuss the totality of evidence for mitochondrial calcium uptake in the cardiac stress response and highlight recent reports that implicate MCU in the control of homeostatic cardiac metabolism and function. This review concludes with a discussion of current gaps in knowledge and remaining experiments to define how MCU contributes to contractile function, cell death, metabolic regulation, and heart failure progression.
摘要
自 2011 年鉴定出线粒体钙单向转运蛋白（MCU）以来，利用遗传模型的多项研究试图阐明线粒体钙摄取在心脏生理学中的作用。在各种突变体小鼠模型中得出的相互矛盾的结果导致了关于 MCU 在心脏中的功能的持续争论。在这篇综述中，我们评估和讨论了线粒体钙摄取在心脏应激反应中的全部证据，并强调了最近的报告表明 MCU 参与了心脏代谢和功能的稳态控制。本综述最后讨论了目前知识上的差距和剩余的实验，以确定 MCU 如何有助于收缩功能、细胞死亡、代谢调节和心力衰竭的进展。
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本文引用的文献
1
EMRE is essential for mitochondrial calcium uniporter activity in a mouse model.
JCI Insight. 2020 Feb 27;5(4):134063. doi: 10.1172/jci.insight.134063.
2
Inorganic polyphosphate is required for sustained free mitochondrial calcium elevation, following calcium uptake.
Cell Calcium. 2020 Mar;86:102127. doi: 10.1016/j.ceca.2019.102127. Epub 2019 Dec 9.
3
Dysregulation of Mitochondrial Ca Uptake and Sarcolemma Repair Underlie Muscle Weakness and Wasting in Patients and Mice Lacking MICU1.
Cell Rep. 2019 Oct 29;29(5):1274-1286.e6. doi: 10.1016/j.celrep.2019.09.063.
4
Mitochondrial Dysfunction Underlies Cardiomyocyte Remodeling in Experimental and Clinical Atrial Fibrillation.
Cells. 2019 Oct 5;8(10):1202. doi: 10.3390/cells8101202.
5
Mitochondrial calcium exchange links metabolism with the epigenome to control cellular differentiation.
Nat Commun. 2019 Oct 4;10(1):4509. doi: 10.1038/s41467-019-12103-x.
6
MCUB Regulates the Molecular Composition of the Mitochondrial Calcium Uniporter Channel to Limit Mitochondrial Calcium Overload During Stress.
Circulation. 2019 Nov 19;140(21):1720-1733. doi: 10.1161/CIRCULATIONAHA.118.037968. Epub 2019 Sep 19.
7
Functional analysis of coiled-coil domains of MCU in mitochondrial calcium uptake.
Biochim Biophys Acta Bioenerg. 2019 Dec 1;1860(12):148061. doi: 10.1016/j.bbabio.2019.148061. Epub 2019 Aug 5.
8
Mitochondrial Ca2+ Transport: Mechanisms, Molecular Structures, and Role in Cells.
Biochemistry (Mosc). 2019 Jun;84(6):593-607. doi: 10.1134/S0006297919060026.
9
Structural Mechanism of EMRE-Dependent Gating of the Human Mitochondrial Calcium Uniporter.
Cell. 2019 May 16;177(5):1252-1261.e13. doi: 10.1016/j.cell.2019.03.050. Epub 2019 May 9.
10
MCUR1 facilitates epithelial-mesenchymal transition and metastasis via the mitochondrial calcium dependent ROS/Nrf2/Notch pathway in hepatocellular carcinoma.
J Exp Clin Cancer Res. 2019 Mar 25;38(1):136. doi: 10.1186/s13046-019-1135-x.
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