Mitochondrial Ca(2+) Uniporter Is a Mitochondrial Luminal Redox Sensor that Augments MCU Channel Activity.
Mitochondrial Ca(2+) Uniporter Is a Mitochondrial Luminal Redox Sensor that Augments MCU Channel Activity.
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DOI：
10.1016/j.molcel.2017.01.032
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发表时间：
2017-03-16
期刊：
影响因子：
16
通讯作者：
Madesh M
中科院分区：
文献类型：
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作者：
Dong Z;Shanmughapriya S;Tomar D;Siddiqui N;Lynch S;Nemani N;Breves SL;Zhang X;Tripathi A;Palaniappan P;Riitano MF;Worth AM;Seelam A;Carvalho E;Subbiah R;Jaña F;Soboloff J;Peng Y;Cheung JY;Joseph SK;Caplan J;Rajan S;Stathopulos PB;Madesh M
Ca 2+动力学和氧化信号是线粒体生物能量学和细胞功能的基本机制。MCU复合物是这些信号在线粒体中整合的主要途径。这些相互作用的元素是否以及如何与MCU相互作用尚未确定。作为理解氧化环境对MCU通道的调节的方法，我们采用了炎症和缺氧模型。我们确定了保守的半胱氨酸97是人类MCU中经历S-谷胱甘肽化的唯一反应性硫醇。此外，生化，结构和超分辨率成像分析表明，MCU氧化促进MCU高阶低聚物的形成。MCU Cys-97的氧化和突变均表现出持续的MCU通道活性，具有更高的[Ca 2 +]m摄取速率，升高的mROS和增强的[Ca 2 +]m过载诱导的细胞死亡。相比之下，这些影响在很大程度上是独立的MCU与其监管机构的相互作用。这些发现揭示了Cys-97在ROS传感和MCU活性调节中的独特功能作用。
Ca2+ dynamics and oxidative signaling are fundamental mechanisms for mitochondrial bioenergetics and cell function. The MCU complex is the major pathway by which these signals are integrated in mitochondria. Whether and how these coactive elements interact with MCU has not been established. As an approach towards understanding the regulation of MCU channel by oxidative milieu, we adapted inflammatory and hypoxia models. We identified the conserved cysteine 97 to be the only reactive thiol in human MCU that undergoes S-glutathionylation. Furthermore, biochemical, structural and superresolution imaging analysis revealed that MCU oxidation promotes MCU higher-order oligomer formation. Both oxidation and mutation of MCU Cys-97 exhibited persistent MCU channel activity with higher [Ca2+]m uptake rate, elevated mROS and enhanced [Ca2+]m overload-induced cell death. In contrast, these effects were largely independent of MCU interaction with its regulators. These findings reveal a distinct functional role for Cys-97 in ROS sensing and regulation of MCU activity.