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.

中文翻译：

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ALA保护柠檬酸合酶表达低的耳蜗细胞模型中的ERS介导的细胞凋亡。

A / J小鼠是与年龄有关的听力损失（AHL）的模型。小鼠的柠檬酸合酶（Cs）基因突变在听力损失和耳蜗细胞变性中起重要作用。为了研究由Cs突变引起的A / J小鼠耳蜗细胞损伤的发病机制，我们通过shRNA下调了小鼠耳蜗细胞系HEI-OC1中CS的表达水平。结果表明，低CS表达导致低的细胞增殖能力。进一步的研究揭示了活性氧（ROS）水平的提高，ATF6介导的内质网应激（ERS）的激活以及细胞中caspase12和Bax的高表达水平。此外，ATF6抑制剂AEBSF可以通过抑制细胞中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表达低的细胞模型中的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与A / J小鼠耳蜗的细胞变性有关。