ALA protects against ERS-mediated apoptosis in a cochlear cell model with low citrate synthase expression
ALA protects against ERS-mediated apoptosis in a cochlear cell model with low citrate synthase expression
复制标题
ALA 可防止柠檬酸合酶表达低的耳蜗细胞模型中 ERS 介导的细胞凋亡
DOI：
10.1016/j.abb.2020.108402
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发表时间：
2020-07-30
影响因子：
3.9
通讯作者：
Han, Fengchan
中科院分区：
文献类型：
--
作者：
Xu, Ang;Shang, Wenjing;Han, Fengchan
A/J小鼠是年龄相关性听力损失（AHL）的一种模型。小鼠柠檬酸合酶（Cs）基因的突变在听力损失和耳蜗细胞退变中起重要作用。为了研究A/J小鼠中因Cs突变导致的耳蜗细胞损伤的发病机制，我们通过短发夹RNA（shRNA）下调了小鼠耳蜗细胞系HEI - OC1中CS的表达水平。结果表明，CS低表达导致细胞增殖能力降低。进一步研究显示，细胞内活性氧（ROS）水平升高，激活了由活化转录因子6（ATF6）介导的内质网应激（ERS），半胱天冬酶12（caspase12）和Bax表达水平升高。此外，ATF6抑制剂AEBSF可通过抑制细胞内ATF6的水解来降低caspase - 12和Bax的表达水平。最后，抗氧化剂α - 硫辛酸（ALA）降低了CS低表达细胞模型中的ROS水平和凋亡信号。因此，我们得出结论：由ROS触发的ERS介导的细胞凋亡可能参与了A/J小鼠耳蜗的细胞退变。
A/J mouse is a model of age-related hearing loss (AHL). Mutation in the citrate synthase (Cs) gene of the mouse plays an important role in the hearing loss and degeneration of cochlear cells. To investigate the pathogenesis of cochlear cell damage in A/J mice resulted from Cs mutation, we downregulated the expression level of CS in HEI-OC1, a cell line of mouse cochlea, by shRNA. The results showed that low CS expression led to low ability of cell proliferation. Further study revealed an increase level of reactive oxygen species (ROS), activation of ATF6 mediated endoplasmic reticulum stress (ERS) and high expression levels of caspase12 and Bax in the cells. Moreover, the AEBSF, an ATF6 inhibitor, could reduce the expression levels of caspase-12 and Bax by inhibiting the hydrolysis of ATF6 in the cells. Finally, antioxidant alpha-lipoic acid (ALA) reduced the ROS levels and the apoptotic signals in the cell model with low CS expression. We therefore conclude that the ERS mediated apoptosis, which is triggered by ROS, may be involved in the cell degeneration in the cochleae of A/J mice.