EMRE Is a Matrix Ca(2+) Sensor that Governs Gatekeeping of the Mitochondrial Ca(2+) Uniporter.
EMRE Is a Matrix Ca(2+) Sensor that Governs Gatekeeping of the Mitochondrial Ca(2+) Uniporter.
复制标题
DOI：
10.1016/j.celrep.2015.12.054
复制
发表时间：
2016-01-26
期刊：
影响因子：
8.8
通讯作者：
Foskett JK
中科院分区：
文献类型：
--
作者：
Vais H;Mallilankaraman K;Mak DD;Hoff H;Payne R;Tanis JE;Foskett JK
线粒体单转运体（MCU）是一种离子通道，介导Ca2+摄取到基质中，以调节代谢、细胞死亡和细胞质Ca2+信号传导。基质Ca2+浓度与细胞质相似，尽管有巨大的进入驱动力，但防止线粒体Ca2+过载的机制尚不清楚。在这里，我们通过EMRE表明MCU通道活性受基质Ca2+浓度的控制。其基质定位的酸性羧基端缺失或电荷中和消除了基质Ca2+对MCU Ca2+电流的抑制，导致MCU通道激活，增强线粒体Ca2+摄取，并组成性地提高基质Ca2+浓度。emre依赖性的MCU通道活性调节需要膜间空间定位的MICU1、MICU2和细胞质Ca2+。因此，线粒体通过一种独特的分子复合物保护其免受Ca2+耗尽和Ca2+过载的影响，该分子复合物涉及线粒体内膜两侧的Ca2+传感器，通过EMRE偶联。
The mitochondrial uniporter (MCU) is an ion channel that mediates Ca2+ uptake into the matrix to regulate metabolism, cell death and cytoplasmic Ca2+ signaling. Matrix Ca2+ concentration is similar to that in cytoplasm, despite an enormous driving force for entry, but the mechanisms that prevent mitochondrial Ca2+ overload are unclear. Here, we show that MCU channel activity is governed by matrix Ca2+ concentration through EMRE. Deletion or charge neutralization of its matrix-localized acidic carboxyl terminus abolishes matrix Ca2+ inhibition of MCU Ca2+ currents, resulting in MCU channel activation, enhanced mitochondrial Ca2+ uptake and constitutively elevated matrix Ca2+ concentration. EMRE-dependent regulation of MCU channel activity requires intermembrane space-localized MICU1, MICU2 and cytoplasmic Ca2+. Thus, mitochondria are protected from Ca2+ depletion and Ca2+ overload by a unique molecular complex that involves Ca2+ sensors on both sides of the inner mitochondrial membrane, coupled through EMRE.