The uptake of calcium into and extrusion of calcium from the mitochondrial matrix is a fundamental biological process that has critical effects on cellular metabolism, signaling, and survival. Disruption of mitochondrial calcium (_mCa²⁺) cycling is implicated in numerous acquired diseases such as heart failure, stroke, neurodegeneration, diabetes, and cancer, and is genetically linked to several inherited neuromuscular disorders. Understanding the mechanisms responsible for _mCa²⁺ exchange therefore holds great promise for the treatment of these diseases. The past decade has seen the genetic identification of many of the key proteins that mediate mitochondrial calcium uptake and efflux. Here, we present an overview of the phenomenon of _mCa²⁺ transport, and a comprehensive examination of the molecular machinery that mediates calcium flux across the inner mitochondrial membrane: the mitochondrial uniporter complex (consisting of MCU, EMRE, MICU1, MICU2, MICU3, MCUB, and MCUR1), NCLX, LETM1, the mitochondrial ryanodine receptor, and the mitochondrial permeability transition pore. We then consider the physiological implications of _mCa²⁺ flux and evaluate how alterations in _mCa²⁺ homeostasis contribute to human disease. This review concludes by highlighting opportunities and challenges for therapeutic intervention in pathologies characterized by aberrant _mCa²⁺ handling and by summarizing critical unanswered questions regarding the biology of _mCa²⁺ flux.

中文翻译：

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生理学和疾病中的线粒体钙交换


线粒体基质吸收钙和从线粒体基质挤出钙是一个基本的生物过程，对细胞代谢、信号传导和生存具有至关重要的影响。线粒体钙 ( _m Ca ²⁺ ) 循环的破坏与许多后天性疾病有关，例如心力衰竭、中风、神经退行性变、糖尿病和癌症，并且与多种遗传性神经肌肉疾病存在遗传关联。因此，了解负责_m Ca ²⁺交换的机制为治疗这些疾病带来了巨大希望。在过去的十年里，许多介导线粒体钙吸收和流出的关键蛋白质得到了遗传鉴定。在这里，我们概述了_m Ca ²⁺转运现象，并对介导钙流穿过线粒体内膜的分子机制进行了全面检查：线粒体单向转运蛋白复合体（由 MCU、EMRE、MICU1、MICU2、MICU3 组成） 、MCUB 和 MCUR1)、NCLX、LETM1、线粒体兰尼碱受体和线粒体通透性转换孔。然后我们考虑_m Ca ²⁺通量的生理学意义，并评估_m Ca ²⁺稳态的改变如何导致人类疾病。本综述最后强调了以异常_m Ca ²⁺处理为特征的病理学治疗干预的机遇和挑战，并总结了有关_m Ca ²⁺通量生物学的关键未解答问题。