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。
相似文献
1
The debate continues - What is the role of MCU and mitochondrial calcium uptake in the heart?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？
J Mol Cell Cardiol. 2020 Jun;143:163-174. doi: 10.1016/j.yjmcc.2020.04.029. Epub 2020 Apr 27.
2
Is MCU dispensable for normal heart function?MCU 对于心脏正常功能可有可无？
J Mol Cell Cardiol. 2020 Jun;143:175-183. doi: 10.1016/j.yjmcc.2020.04.028. Epub 2020 May 7.
3
MCUB Regulates the Molecular Composition of the Mitochondrial Calcium Uniporter Channel to Limit Mitochondrial Calcium Overload During Stress.MCUB 调节线粒体钙单向转运体通道的分子组成，以限制应激时线粒体钙过载。
Circulation. 2019 Nov 19;140(21):1720-1733. doi: 10.1161/CIRCULATIONAHA.118.037968. Epub 2019 Sep 19.
4
Inhibition of MCU forces extramitochondrial adaptations governing physiological and pathological stress responses in heart.抑制线粒体钙单向转运体可促使线粒体外适应性变化，从而调控心脏的生理和病理应激反应。
Proc Natl Acad Sci U S A. 2015 Jul 21;112(29):9129-34. doi: 10.1073/pnas.1504705112. Epub 2015 Jul 7.
5
MICU1 and MICU2 control mitochondrial calcium signaling in the mammalian heart.MICU1 和 MICU2 控制哺乳动物心脏中线粒体钙信号。
Proc Natl Acad Sci U S A. 2024 Aug 27;121(35):e2402491121. doi: 10.1073/pnas.2402491121. Epub 2024 Aug 20.
6
Assessment of cardiac function in mice lacking the mitochondrial calcium uniporter.对缺乏线粒体钙单向转运体的小鼠心脏功能的评估。
J Mol Cell Cardiol. 2015 Aug;85:178-82. doi: 10.1016/j.yjmcc.2015.05.022. Epub 2015 Jun 6.
7
Sleep/wake calcium dynamics, respiratory function, and ROS production in cardiac mitochondria.心脏线粒体的睡眠/觉醒钙动力学、呼吸功能和 ROS 产生。
J Adv Res. 2021 Jan 12;31:35-47. doi: 10.1016/j.jare.2021.01.006. eCollection 2021 Jul.
8
The Mitochondrial Calcium Uniporter Selectively Matches Metabolic Output to Acute Contractile Stress in the Heart.线粒体钙单向转运体使心脏代谢输出与急性收缩应激选择性匹配。
Cell Rep. 2015 Jul 7;12(1):15-22. doi: 10.1016/j.celrep.2015.06.002. Epub 2015 Jun 25.
9
Tissue-Specific Mitochondrial Decoding of Cytoplasmic Ca Signals Is Controlled by the Stoichiometry of MICU1/2 and MCU.细胞质钙信号的组织特异性线粒体解码由MICU1/2和MCU的化学计量控制。
Cell Rep. 2017 Mar 7;18(10):2291-2300. doi: 10.1016/j.celrep.2017.02.032.
10
Deletion of mitochondrial calcium uniporter incompletely inhibits calcium uptake and induction of the permeability transition pore in brain mitochondria.线粒体钙单向转运体的缺失不完全抑制脑线粒体的钙摄取和通透性转换孔的诱导。
J Biol Chem. 2018 Oct 5;293(40):15652-15663. doi: 10.1074/jbc.RA118.002926. Epub 2018 Aug 28.
引用本文的文献
1
Sarcoplasmic reticulum-mitochondria microdomains: hugging and kissing in the heart.肌浆网-线粒体微区：心脏中的“相拥”与“亲吻”
Am J Physiol Cell Physiol. 2025 Aug 1;329(2):C599-C610. doi: 10.1152/ajpcell.00435.2025. Epub 2025 Jul 11.
2
The mitochondria as a potential therapeutic target in cerebral I/R injury.线粒体作为脑缺血/再灌注损伤的潜在治疗靶点。
Front Neurosci. 2025 Jan 7;18:1500647. doi: 10.3389/fnins.2024.1500647. eCollection 2024.
3
Mitochondrial calcium uniporter complex: An emerging therapeutic target for cardiovascular diseases (Review).线粒体钙单向转运体复合物：心血管疾病中一个新出现的治疗靶点（综述）
Int J Mol Med. 2025 Mar;55(3). doi: 10.3892/ijmm.2024.5481. Epub 2025 Jan 3.
4
Mitochondrial Structure and Function in Human Heart Failure.线粒体结构和功能在人类心力衰竭中的作用。
Circ Res. 2024 Jul 5;135(2):372-396. doi: 10.1161/CIRCRESAHA.124.323800. Epub 2024 Jul 4.
5
Mitochondrial Calcium Regulation of Cardiac Metabolism in Health and Disease.线粒体钙调节在心脏代谢中的作用：健康与疾病。
Physiology (Bethesda). 2024 Sep 1;39(5):0. doi: 10.1152/physiol.00014.2024. Epub 2024 May 7.
6
Mitochondrial Ca Uniporter-Dependent Energetic Dysfunction Drives Hypertrophy in Heart Failure.线粒体钙单向转运体依赖性能量功能障碍驱动心力衰竭中的心肌肥大。
JACC Basic Transl Sci. 2024 Apr 22;9(4):496-518. doi: 10.1016/j.jacbts.2024.01.007. eCollection 2024 Apr.
7
The mitochondrial Ca channel MCU is critical for tumor growth by supporting cell cycle progression and proliferation.线粒体钙通道MCU通过支持细胞周期进程和增殖对肿瘤生长至关重要。
Front Cell Dev Biol. 2023 Jun 8;11:1082213. doi: 10.3389/fcell.2023.1082213. eCollection 2023.
8
Modeling Duchenne Muscular Dystrophy Cardiomyopathy with Patients' Induced Pluripotent Stem-Cell-Derived Cardiomyocytes.利用患者诱导多能干细胞衍生的心肌细胞建立杜氏肌营养不良症心肌病模型。
Int J Mol Sci. 2023 May 12;24(10):8657. doi: 10.3390/ijms24108657.
9
Deficiency of mitochondrial calcium uniporter abrogates iron overload-induced cardiac dysfunction by reducing ferroptosis.线粒体钙单向转运蛋白缺失通过减少铁死亡来消除铁过载诱导的心脏功能障碍。
Basic Res Cardiol. 2023 May 25;118(1):21. doi: 10.1007/s00395-023-00990-7.
10
The mitochondrial Ca channel MCU is critical for tumor growth by supporting cell cycle progression and proliferation.线粒体钙通道MCU通过支持细胞周期进程和增殖对肿瘤生长至关重要。
bioRxiv. 2023 Apr 28:2023.04.26.538295. doi: 10.1101/2023.04.26.538295.
本文引用的文献
1
EMRE is essential for mitochondrial calcium uniporter activity in a mouse model.在小鼠模型中，EMRE对于线粒体钙单向转运体活性至关重要。
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.无机多聚磷酸盐是钙摄取后持续升高游离线粒体钙所必需的。
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.线粒体钙摄取和肌膜修复失调是缺乏 MICU1 的患者和小鼠肌肉无力和萎缩的基础。
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.线粒体功能障碍是实验性和临床心房颤动中心肌细胞重构的基础。
Cells. 2019 Oct 5;8(10):1202. doi: 10.3390/cells8101202.
5
Mitochondrial calcium exchange links metabolism with the epigenome to control cellular differentiation.线粒体钙交换将代谢与表观基因组联系起来，以控制细胞分化。
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.MCUB 调节线粒体钙单向转运体通道的分子组成，以限制应激时线粒体钙过载。
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.MCU 卷曲螺旋结构域在线粒体钙摄取中的功能分析。
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.线粒体钙转运：机制、分子结构及其在细胞中的作用
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.EMRE 依赖性调控的人线粒体钙单向转运体的结构机制。
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.MCUR1 通过线粒体钙依赖性 ROS/Nrf2/Notch 通路促进肝癌中的上皮-间充质转化和转移。
J Exp Clin Cancer Res. 2019 Mar 25;38(1):136. doi: 10.1186/s13046-019-1135-x.
Zotero 插件