Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.
Nat Cardiovasc Res. 2024 May;3(5):500-514. doi: 10.1038/s44161-024-00463-7. Epub 2024 May 1.
The mitochondrial calcium (Ca) uniporter channel (mtCU) resides at the inner mitochondrial membrane and is required for Ca to enter the mitochondrial matrix. The mtCU is essential for cellular function, as Ca regulates metabolism, bioenergetics, signaling pathways and cell death. Ca uptake is primarily regulated by the MICU family (MICU1, MICU2, MICU3), EF-hand-containing Ca-sensing proteins, which respond to cytosolic Ca concentrations to modulate mtCU activity. Considering that mitochondrial function and Ca signaling are ubiquitously disrupted in cardiovascular disease, mtCU function has been a hot area of investigation for the last decade. Here we provide an in-depth review of MICU-mediated regulation of mtCU structure and function, as well as potential mtCU-independent functions of these proteins. We detail their role in cardiac physiology and cardiovascular disease by highlighting the phenotypes of different mutant animal models, with an emphasis on therapeutic potential and targets of interest in this pathway.
线粒体钙（Ca）单向转运体通道（mtCU）位于线粒体内膜，是 Ca 进入线粒体基质所必需的。mtCU 对于细胞功能至关重要，因为 Ca 调节代谢、生物能量、信号通路和细胞死亡。Ca 摄取主要受 MICU 家族（MICU1、MICU2、MICU3）、EF 手结构域的 Ca 感应蛋白调节，这些蛋白对细胞质 Ca 浓度做出反应，调节 mtCU 的活性。鉴于心血管疾病中线粒体功能和 Ca 信号的普遍破坏，mtCU 功能在过去十年中一直是研究的热点。本文深入综述了 MICU 介导的 mtCU 结构和功能的调节，以及这些蛋白潜在的 mtCU 非依赖性功能。通过突出不同突变动物模型的表型，详细阐述了它们在心脏生理学和心血管疾病中的作用，重点介绍了该途径的治疗潜力和感兴趣的靶点。
