Proteolytic control of the mitochondrial calcium uniporter complex
Proteolytic control of the mitochondrial calcium uniporter complex
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DOI：
10.1073/pnas.1702938114
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发表时间：
2017-04-25
影响因子：
11.1
通讯作者：
Tsai, Ming-Feng
中科院分区：
文献类型：
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作者：
Tsai, Chen-Wei;Wu, Yujiao;Tsai, Ming-Feng
线粒体钙单转运体是一种钙激活的钙通道复合体，介导线粒体钙摄取，这一过程对钙信号、生物能量学和细胞死亡至关重要。单转运蛋白由成孔的MCU蛋白、把关MICU1和MICU2的亚基以及连接MCU和MICU1的单通膜蛋白EmRE组成。作为通道功能所需的桥联亚基，EmRE在过量表达的情况下可以反常地抑制单转运蛋白复合体的形成。在这里，我们证明了线粒体MAAA蛋白酶AFG3L2和SPG7利用ATP水解的能量快速降解未组装的EmRE。一旦Emre被并入该建筑群，其营业额将被抑制15倍。具有蛋白酶抗性的EmRE突变体产生单一转运体亚复合体，导致结构性钙离子泄漏到线粒体，这种情况与人类衰弱的神经肌肉疾病有关。这些结果突出了单转运体亚单位组装的动态性质，必须严格调控，以确保线粒体对细胞内钙信号做出适当的反应。
The mitochondrial calcium uniporter is a Ca2+-activated Ca2+ channel complex mediating mitochondrial Ca2+ uptake, a process crucial for Ca2+ signaling, bioenergetics, and cell death. The uniporter is composed of the pore-forming MCU protein, the gatekeeping MICU1 and MICU2 subunits, and EMRE, a single-passmembrane protein that links MCU and MICU1 together. As a bridging subunit required for channel function, EMRE could paradoxically inhibit uniporter complex formation if expressed in excess. Here, we show that mitochondrial mAAA proteases AFG3L2 and SPG7 rapidly degrade unassembled EMRE using the energy of ATP hydrolysis. Once EMRE is incorporated into the complex, its turnover is inhibited >15-fold. Protease-resistant EMRE mutants produce uniporter subcomplexes that induce constitutive Ca2+ leakage into mitochondria, a condition linked to debilitating neuromuscular disorders in humans. The results highlight the dynamic nature of uniporter subunit assembly, which must be tightly regulated to ensure proper mitochondrial responses to intracellular Ca2+ signals.