Key Laboratory for Genetic Hearing Disorders in Shandong, Binzhou Medical University, 346 Guanhai Road, Yantai, 264003, Shandong, PR China; Department of Otolaryngology, Yantai Affiliated Hospital of Binzhou Medical University, 717 Jinbu Road of Muping District, Yantai, 264100, Shandong, PR China.
Key Laboratory for Genetic Hearing Disorders in Shandong, Binzhou Medical University, 346 Guanhai Road, Yantai, 264003, Shandong, PR China; Department of Biochemistry and Molecular Biology, Binzhou Medical University, 346 Guanhai Road, Yantai, 264003, Shandong, PR China.
Arch Biochem Biophys. 2020 Jul 30;688:108402. doi: 10.1016/j.abb.2020.108402. Epub 2020 May 11.
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.
A/J 小鼠是一种与年龄相关的听力损失（AHL）模型。小鼠柠檬酸合酶（Cs）基因的突变在耳蜗细胞的听力损失和退化中起着重要作用。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 表达导致细胞增殖能力降低。进一步的研究表明，细胞内活性氧（ROS）水平升高，ATF6 介导的内质网应激（ERS）激活，caspase12 和 Bax 的表达水平升高。此外，ATF6 抑制剂 AEBSF 通过抑制 ATF6 的水解，降低了细胞中 caspase-12 和 Bax 的表达水平。最后，抗氧化剂α-硫辛酸（ALA）降低了低 CS 表达细胞模型中的 ROS 水平和凋亡信号。因此，我们得出结论，ROS 触发的 ERS 介导的细胞凋亡可能参与了 A/J 小鼠耳蜗的细胞退化。
