Mechanisms and significance of tissue-specific MICU regulation of the mitochondrial calcium uniporter complex.
Mechanisms and significance of tissue-specific MICU regulation of the mitochondrial calcium uniporter complex.
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组织特异性MICU调控线粒体钙单转运复合物的机制和意义。
DOI：
10.1016/j.molcel.2022.09.006
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发表时间：
2022-10-06
期刊：
影响因子：
16
通讯作者：
Tsai, Ming-Feng
中科院分区：
文献类型：
--
作者：
Tsai, Chen-Wei;Rodriguez, Madison X.;Van Keuren, Anna M.;Phillips, Charles B.;Shushunov, Hannah M.;Lee, Jessica E.;Garcia, Anastacia M.;Ambardekar, Amrut, V;Cleveland, Joseph C.;Reisz, Julie A.;Proenza, Catherine;Chatfield, Kathryn C.;Tsai, Ming-Feng
线粒体钙摄取由线粒体钙单一转运体介导，调节氧化磷酸化、细胞凋亡和细胞内钙信号转导。先前的研究表明，非神经元单一转运蛋白仅受MICU1-MICU2异源二聚体的调控。在这里，我们显示骨骼肌和肾脏单转运蛋白也与MICU1-MICU1同源二聚体复合，而人/鼠心脏单转运蛋白基本上缺乏MICU。细胞使用蛋白质输入机制来微调MICU1同源和异源二聚体的相对丰度，并利用保守的MICU亚基间二硫键来保护正确组装的二聚体免受YME1L1的蛋白质降解。使用MICU1同源二聚体或去除MICU1可以使线粒体更容易地吸收钙离子，从而使细胞能够产生更多的ATP，以响应细胞内的钙瞬变。然而，权衡的是ROS升高，基础代谢受损，死亡的易感性更高。这些结果为组织如何操纵线粒体的钙摄取特性以支持其独特的生理功能提供了机械性的见解。线粒体钙摄取调节氧化磷酸化、细胞死亡和胞浆钙信号。Tsai et al.演示组织如何通过调节线粒体钙单一转运体复合体中MICU亚单位的组成和表达来定制其线粒体钙摄取特性，并探索这种组织特异性的生理意义。
Mitochondrial Ca2+ uptake, mediated by the mitochondrial Ca2+ uniporter, regulates oxidative phosphorylation, apoptosis, and intracellular Ca2+ signaling. Previous studies suggest that non-neuronal uniporters are exclusively regulated by a MICU1-MICU2 heterodimer. Here, we show that skeletal-muscle and kidney uniporters also complex with a MICU1-MICU1 homodimer, and that human/mouse cardiac uniporters are largely devoid of MICUs. Cells employ protein-importation machineries to fine-tune the relative abundance of MICU1 homo- and heterodimers, and utilize a conserved MICU intersubunit disulfide to protect properly assembled dimers from proteolysis by YME1L1. Using the MICU1 homodimer or removing MICU1 allows mitochondria to more readily take up Ca2+ so that cells can produce more ATP in response to intracellular Ca2+ transients. However, the trade-off is elevated ROS, impaired basal metabolism, and higher susceptibility to death. These results provide mechanistic insights into how tissues can manipulate mitochondrial Ca2+ uptake properties to support their unique physiological functions. Mitochondrial Ca2+ uptake regulates oxidative phosphorylation, cell death, and cytoplasmic Ca2+ signaling. Tsai et al. demonstrate how tissues can customize their mitochondrial Ca2+ uptake properties by modulating the composition and expression of the MICU subunits in their mitochondrial Ca2+ uniporter complexes, and also explore the physiological significance of such tissue-specificity.
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作者：
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影响因子：
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作者：
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DOI：
10.1038/nrcardio.2016.203
发表时间：
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期刊：
Nature reviews. Cardiology
影响因子：
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作者：
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