The mechanism of MICU-dependent gating of the mitochondrial Ca(2+)uniporter.
The mechanism of MICU-dependent gating of the mitochondrial Ca(2+)uniporter.
复制标题
线粒体Ca（2+）Uniporter的MICU依赖性门控机制。
DOI：
10.7554/elife.69312
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发表时间：
2021-08-31
期刊：
影响因子：
7.7
通讯作者：
Kirichok Y
中科院分区：
文献类型：
--
作者：
Garg V;Suzuki J;Paranjpe I;Unsulangi T;Boyman L;Milescu LS;Lederer WJ;Kirichok Y
钙离子进入线粒体是通过线粒体钙单转运体复合体(MCUcx)，这是一个由五种亚基组成的钙选择性通道。两个MCUcx亚基(MCU和EmRE)横跨线粒体内膜，而三个钙调节亚基(MICU1、MICU2和MICU3)位于膜间隙。在这里，我们通过MCUcx对完整的分离线粒体中的钙和钠离子的流动进行了严格的分析，以了解MICU亚单位的功能。我们还对宏观和单个MCUcx电流进行直接膜片钳记录，以获得进一步的机械洞察。这一综合分析表明，由EmRE和MCU亚基组成的MCUcx孔在线粒体外钙离子缺乏或存在的情况下，不会像广泛报道的那样被MICU堵塞或堵塞。相反，当线粒体外钙离子升高时，MICU会增强MCUcx的活性。MICUS通过修改MCUcx的选通属性来实现这一点，从而允许其在打开状态中花费更多时间。
Ca2+ entry into mitochondria is through the mitochondrial calcium uniporter complex (MCUcx), a Ca2+-selective channel composed of five subunit types. Two MCUcx subunits (MCU and EMRE) span the inner mitochondrial membrane, while three Ca2+-regulatory subunits (MICU1, MICU2, and MICU3) reside in the intermembrane space. Here, we provide rigorous analysis of Ca2+ and Na+ fluxes via MCUcx in intact isolated mitochondria to understand the function of MICU subunits. We also perform direct patch clamp recordings of macroscopic and single MCUcx currents to gain further mechanistic insights. This comprehensive analysis shows that the MCUcx pore, composed of the EMRE and MCU subunits, is not occluded nor plugged by MICUs during the absence or presence of extramitochondrial Ca2+ as has been widely reported. Instead, MICUs potentiate activity of MCUcx as extramitochondrial Ca2+ is elevated. MICUs achieve this by modifying the gating properties of MCUcx allowing it to spend more time in the open state.