Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel.
Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel.
Semin Cell Dev Biol. 2019 Oct;94:59-65. doi: 10.1016/j.semcdb.2019.01.009. Epub 2019 Jan 30.
Mitochondrial Ca transient is the earliest discovered organellar Ca signaling pathway. It consist of a Ca influx, mediated by mitochondrial Ca uniporter (MCU), and mitochondrial Ca efflux mediated by a Na/Ca exchanger (NCLX). Mitochondrial Ca signaling machinery plays a fundamental role in linking metabolic activity to cellular Ca signaling, and in controlling local Ca concertation in distinct cellular compartments. Impaired balance between mitochondrial Ca influx and efflux leads to mitochondrial Ca overload, an early and key event in ischemic or neurodegenerative syndromes. Molecular identification of NCLX and MCU happened only recently. Surprisingly, MCU knockout yielded a relatively mild phenotype while conditional knockout of NCLX led to a rapid fatal heart failure. Here we will focus on recent functional and molecular studies on NCLX structure and its mode of regulation. We will describe the unique crosstalk of this exchanger with Na and Ca signaling pathways in the cell membrane and the endoplasmic reticulum, and with protein kinases that posttranslationally modulate NCLX activity. We will critically compare selectivity of pharmacological blockers versus molecular control of NCLX expression and activity. Finally we will discuss why this exchanger is essential for survival and can serve as an attractive therapeutic target.
线粒体钙瞬变是最早发现的细胞器钙信号通路。它由钙内流组成，由线粒体钙单向转运蛋白 (MCU) 介导，由钠/钙交换器 (NCLX) 介导的线粒体钙外排。线粒体钙信号机制在将代谢活性与细胞钙信号联系起来，以及控制不同细胞区室中的局部钙浓度方面发挥着基本作用。线粒体钙内流和外排之间的平衡失调会导致线粒体钙超载，这是缺血或神经退行性综合征的早期和关键事件。NCLX 和 MCU 的分子鉴定最近才发生。令人惊讶的是，MCU 敲除产生了相对温和的表型，而 NCLX 的条件敲除导致快速致命的心力衰竭。在这里，我们将重点介绍 NCLX 结构及其调节方式的最新功能和分子研究。我们将描述该交换器与细胞膜和内质网中的钠和钙信号通路以及翻译后调节 NCLX 活性的蛋白激酶之间的独特串扰。我们将批判性地比较药理学阻滞剂的选择性与 NCLX 表达和活性的分子控制。最后，我们将讨论为什么这个交换器对生存至关重要，并且可以作为一个有吸引力的治疗靶点。
