CSIR-Institute of Genomics and Integrative Biology (IGIB), New Delhi 10025, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
Laboratory of Calciomics and Systemic Pathophysiology (LCSP), Regional Centre for Biotechnology (RCB), Faridabad, Delhi-NCR, India.
Mitochondrion. 2021 Mar;57:9-22. doi: 10.1016/j.mito.2020.12.001. Epub 2020 Dec 11.
Mitochondria play vital role in regulating the cellular energetics and metabolism. Further, it is a signaling hub for cell survival and apoptotic pathways. One of the key determinants that calibrate both cellular energetics and survival functions is mitochondrial calcium (Ca) dynamics. Mitochondrial Ca regulates three Ca-sensitive dehydrogenase enzymes involved in tricarboxylic acid cycle (TCA) cycle thereby directly controlling ATP synthesis. On the other hand, excessive Ca concentration within the mitochondrial matrix elevates mitochondrial reactive oxygen species (mROS) levels and causes mitochondrial membrane depolarization. This leads to opening of the mitochondrial permeability transition pore (mPTP) and release of cytochrome c into cytosol eventually triggering apoptosis. Therefore, it is critical for cell to maintain mitochondrial Ca concentration. Since cells can neither synthesize nor metabolize Ca, it is the dynamic interplay of Ca handling proteins involved in mitochondrial Ca influx and efflux that take the center stage. In this review we would discuss the key molecular machinery regulating mitochondrial Ca concentration. We would focus on the channel complex involved in bringing Ca into mitochondrial matrix i.e. Mitochondrial Ca Uniporter (MCU) and its key regulators Mitochondrial Ca Uptake proteins (MICU1, 2 and 3), MCU regulatory subunit b (MCUb), Essential MCU Regulator (EMRE) and Mitochondrial Ca Uniporter Regulator 1 (MCUR1). Further, we would deliberate on major mitochondrial Ca efflux proteins i.e. Mitochondrial Na/Ca/Li exchanger (NCLX) and Leucine zipper EF hand-containing transmembrane1 (Letm1). Moreover, we would highlight the physiological functions of these proteins and discuss their relevance in human pathophysiology. Finally, we would highlight key outstanding questions in the field.
线粒体在调节细胞能量代谢方面起着至关重要的作用。此外，它还是细胞存活和凋亡途径的信号中心。调节细胞能量代谢和存活功能的一个关键决定因素是线粒体钙（Ca）动力学。线粒体 Ca 调节三羧酸（TCA）循环中涉及的三种 Ca 敏感脱氢酶，从而直接控制 ATP 合成。另一方面，线粒体基质中过高的 Ca 浓度会增加线粒体活性氧（mROS）水平并导致线粒体膜去极化。这会导致线粒体通透性转换孔（mPTP）打开，细胞色素 c 释放到细胞质中，最终触发细胞凋亡。因此，细胞维持线粒体 Ca 浓度至关重要。由于细胞既不能合成也不能代谢 Ca，因此参与线粒体 Ca 内流和外流的 Ca 处理蛋白的动态相互作用处于中心地位。在这篇综述中，我们将讨论调节线粒体 Ca 浓度的关键分子机制。我们将重点讨论参与将 Ca 带入线粒体基质的通道复合物，即线粒体 Ca 单向转运体（MCU）及其关键调节剂线粒体 Ca 摄取蛋白（MICU1、2 和 3）、MCU 调节亚基 b（MCUb）、必需 MCU 调节剂（EMRE）和线粒体 Ca 单向转运体调节剂 1（MCUR1）。此外，我们还将讨论主要的线粒体 Ca 外排蛋白，即线粒体 Na/Ca/Li 交换器（NCLX）和亮氨酸拉链 EF 手跨膜 1（Letm1）。此外，我们将强调这些蛋白质的生理功能，并讨论它们在人类病理生理学中的相关性。最后，我们将突出该领域的关键未解决问题。
