Glucose-regulated protein 75 determines ER-mitochondrial coupling and sensitivity to oxidative stress in neuronal cells.
Glucose-regulated protein 75 determines ER-mitochondrial coupling and sensitivity to oxidative stress in neuronal cells.
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DOI：
10.1038/cddiscovery.2017.76
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发表时间：
2017
影响因子：
7
通讯作者：
Dolga AM
中科院分区：
文献类型：
--
作者：
Honrath B;Metz I;Bendridi N;Rieusset J;Culmsee C;Dolga AM
不同细胞器之间的串扰允许蛋白质、脂类和离子的交换。内质网(ER)和线粒体通过线粒体相关膜(MAM)物理连接并发出信号，调节钙离子从内质网到线粒体基质的转移，从而影响线粒体功能和细胞内钙稳态。伴侣葡萄糖调节蛋白75(GRP75)是MAM界面表达的一种关键蛋白，调节内质网-线粒体钙离子转运。先前的研究表明，GRP75表达的调节在很大程度上影响线粒体的完整性和对细胞死亡的易感性。在本研究中，我们表明，在谷氨酸诱导的氧化应激模型中，通过削弱内质网-线粒体连接，GRP75的遗传消融提供了对线粒体功能障碍和细胞死亡的保护。有趣的是，GRP75沉默减轻了氧化应激条件下胞浆和线粒体的钙超载，阻止了活性氧的形成，并保护了线粒体的呼吸。这些数据揭示了GRP75在调节线粒体功能、钙离子和氧化还原动态平衡方面的主要作用。GRP75的过表达增强了谷氨酸诱导的细胞氧化死亡。总体而言，我们的发现表明，通过抑制GRP75来削弱内质网-线粒体的连接，是神经细胞氧化应激范例中的一种新的保护方法。
The crosstalk between different organelles allows for the exchange of proteins, lipids and ions. Endoplasmic reticulum (ER) and mitochondria are physically linked and signal through the mitochondria-associated membrane (MAM) to regulate the transfer of Ca2+ from ER stores into the mitochondrial matrix, thereby affecting mitochondrial function and intracellular Ca2+ homeostasis. The chaperone glucose-regulated protein 75 (GRP75) is a key protein expressed at the MAM interface which regulates ER–mitochondrial Ca2+ transfer. Previous studies revealed that modulation of GRP75 expression largely affected mitochondrial integrity and vulnerability to cell death. In the present study, we show that genetic ablation of GRP75, by weakening ER–mitochondrial junctions, provided protection against mitochondrial dysfunction and cell death in a model of glutamate-induced oxidative stress. Interestingly, GRP75 silencing attenuated both cytosolic and mitochondrial Ca2+ overload in conditions of oxidative stress, blocked the formation of reactive oxygen species and preserved mitochondrial respiration. These data revealed a major role for GRP75 in regulating mitochondrial function, Ca2+ and redox homeostasis. In line, GRP75 overexpression enhanced oxidative cell death induced by glutamate. Overall, our findings suggest weakening ER–mitochondrial connectivity by GRP75 inhibition as a novel protective approach in paradigms of oxidative stress in neuronal cells.
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DOI：
10.1016/j.biocel.2009.04.010
发表时间：
2009-10
影响因子：
4
作者：
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影响因子：
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影响因子：
4.6
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影响因子：
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作者：
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影响因子：
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