Mitofusin-2 triggers mitochondria Ca2+ influx from the endoplasmic reticulum to induce apoptosis in hepatocellular carcinoma cells
Mitofusin-2 triggers mitochondria Ca2+ influx from the endoplasmic reticulum to induce apoptosis in hepatocellular carcinoma cells
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DOI：
10.1016/j.canlet.2014.12.025
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发表时间：
2015-03-01
期刊：
影响因子：
9.7
通讯作者：
Zheng, Shusen
中科院分区：
文献类型：
--
作者：
Wang, Weilin;Xie, Qingsong;Zheng, Shusen
在之前的研究中，我们证实mitofusin-2（Mfn2）可诱导肝细胞癌（HCC）细胞凋亡。然而，确切的分子机制仍不清楚。与邻近的非癌组织相比，Mfn2 在肿瘤组织中的表达较低。此外，Mfn2免疫染色在HCC组织中非常弱（P<0.05），并且与肿瘤大小和TNM分期显着相关（分别P=0.038和0.040），Mfn2表达较低的HCC患者预后较差。 Mfn2 的过度表达诱导 HepG2 细胞凋亡，降低线粒体膜电位 (Delta Psi m) 和内质网 (ER) 钙离子 (Ca2+) 浓度，并升高细胞内活性氧 (ROS) 和线粒体 Ca2+ 浓度。然而，当用肝素和 RU360 处理过表达 Mfn2 的 HepG2 细胞时，没有诱导细胞凋亡、Delta Psi m 或 ER Ca2+ 下降，或者细胞内 ROS 或线粒体 Ca2+ 增加。我们还发现用Adv-Mfn2转染的细胞中线粒体钙摄取1和2(MICU1和MICU2)的表达下调。因此，我们证实 Mfn2 通过触发 Ca2+ 从 ER 流入线粒体来诱导 HCC 细胞凋亡。 (C) 2014 Elsevier Ireland Ltd. 保留所有权利。
In previous studies, we confirmed that mitofusin-2 (Mfn2) induced apoptosis in hepatocellular carcinoma (HCC) cells. However, the exact molecular mechanism remained unclear. Mfn2 expressed lower in tumour tissues, compared with adjacent non-cancer tissues. Furthermore, Mfn2 immunostaining was very weak in HCC tissue (P < 0.05) and was significantly associated with tumour size and TNM stage (P = 0.038 and 0.040, respectively), and patients with HCC with lower Mfn2 expression had a poorer prognosis. Overexpression of Mfn2 induced HepG2 cells apoptosis, reduced the mitochondrial membrane potential (Delta Psi m) and endoplasmic reticulum (ER) calcium ion (Ca2+) concentrations, and elevated intracellular reactive oxygen species (ROS) and mitochondrial Ca2+ concentrations. However, when HepG2 cells overexpressing Mfn2 were treated with both heparin and RU360, there was no induction of apoptosis, decline in Delta Psi m or ER Ca2+, or increase in intracellular ROS or mitochondrial Ca2+. We also found downregulation in the expression of mitochondrial calcium uptakel and 2 (MICUl and MICU2) in cells transfected with Adv-Mfn2. Thus, we confirmed that Mfn2 induced apoptosis in HCC cells by triggering influx of Ca2+ into the mitochondria from the ER. (C) 2014 Elsevier Ireland Ltd. All rights reserved.