Mitochondrial calcium uniporter Mcu controls excitotoxicity and is transcriptionally repressed by neuroprotective nuclear calcium signals.
Mitochondrial calcium uniporter Mcu controls excitotoxicity and is transcriptionally repressed by neuroprotective nuclear calcium signals.
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DOI：
10.1038/ncomms3034
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发表时间：
2013
影响因子：
16.6
通讯作者：
Hardingham GE
中科院分区：
文献类型：
--
作者：
Qiu J;Tan YW;Hagenston AM;Martel MA;Kneisel N;Skehel PA;Wyllie DJ;Bading H;Hardingham GE
最近对线粒体 Ca2+ 单向转运蛋白基因 (Mcu/Ccdc109a) 的鉴定使我们能够解决其以及线粒体 Ca2+ 摄取在神经元兴奋性毒性中的作用。在这里，我们发现外源表达的 Mcu 位于线粒体，并在 NMDA 受体激活后增加线粒体 Ca2+ 水平，导致线粒体膜去极化增加和兴奋毒性细胞死亡。内源性 Mcu 表达的敲低可减少 NMDA 诱导的线粒体 Ca2+ 增加，从而降低线粒体去极化水平和对兴奋性毒性的抵抗力。 Mcu 受到动态调节，作为活动依赖性适应性机制的一部分，当细胞质 Ca2+ 水平较高时，该机制限制线粒体 Ca2+ 过载。具体来说，突触活性通过涉及核 Ca2+ 和 CaM 激酶介导的 Npas4 诱导的机制，在转录上抑制 Mcu，从而抑制 NMDA 受体诱导的线粒体 Ca2+ 摄取并防止兴奋性毒性死亡。这确立了 Mcu 和调节其表达的途径作为兴奋性毒性的重要决定因素，这可能代表兴奋性毒性疾病的治疗靶点。 线粒体钙单向转运蛋白对钙的吸收与兴奋性毒性有关。这项研究表明，单向转运蛋白基因产物在兴奋性毒性过程中介导线粒体钙摄取和神经元去极化，并受到神经保护性核钙信号的转录抑制。
The recent identification of the mitochondrial Ca2+ uniporter gene (Mcu/Ccdc109a) has enabled us to address its role, and that of mitochondrial Ca2+ uptake, in neuronal excitotoxicity. Here we show that exogenously expressed Mcu is mitochondrially localized and increases mitochondrial Ca2+ levels following NMDA receptor activation, leading to increased mitochondrial membrane depolarization and excitotoxic cell death. Knockdown of endogenous Mcu expression reduces NMDA-induced increases in mitochondrial Ca2+, resulting in lower levels of mitochondrial depolarization and resistance to excitotoxicity. Mcu is subject to dynamic regulation as part of an activity-dependent adaptive mechanism that limits mitochondrial Ca2+ overload when cytoplasmic Ca2+ levels are high. Specifically, synaptic activity transcriptionally represses Mcu, via a mechanism involving the nuclear Ca2+ and CaM kinase-mediated induction of Npas4, resulting in the inhibition of NMDA receptor-induced mitochondrial Ca2+ uptake and preventing excitotoxic death. This establishes Mcu and the pathways regulating its expression as important determinants of excitotoxicity, which may represent therapeutic targets for excitotoxic disorders. Calcium uptake by the mitochondrial calcium uniporter is implicated in excitotoxicity. This study shows that the uniporter gene product mediates mitochondrial calcium uptake and depolarisation in neurons during excitotoxicity, and is transcriptionally repressed by neuroprotective nuclear calcium signals.
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