Bmi1 regulates auditory hair cell survival by maintaining redox balance.
Bmi1 regulates auditory hair cell survival by maintaining redox balance.
复制标题
Bmi1 通过维持氧化还原平衡来调节听觉毛细胞的存活
DOI：
10.1038/cddis.2014.549
复制
发表时间：
2015-01-22
影响因子：
9
通讯作者：
Li H
中科院分区：
文献类型：
--
作者：
Chen Y;Li L;Ni W;Zhang Y;Sun S;Miao D;Chai R;Li H
活性氧（ROS）的积累参与了噪声和耳毒性药物诱导的毛细胞损失，这是听力损失的主要原因。Bmi 1是Polycomb蛋白家族的成员，据报道可调节胸腺细胞和神经元中的线粒体功能和ROS水平。在这项研究中，我们报告了Bmi 1在小鼠耳蜗的表达，并探讨了Bmi 1在毛细胞存活的作用。bmi 1在小鼠耳蜗毛细胞和支持细胞中表达。Bmi 1 −/−小鼠从出生后第22天开始表现出严重的听力损失和斑片状外毛细胞损失。在体内和体外，与野生型对照组相比，Bmi 1 −/−小鼠中耳毒性药物诱导的毛细胞损失显著增加，表明Bmi 1 −/−毛细胞对耳毒性药物诱导的损伤显著更敏感。切割的caspase-3和TUNEL染色表明，细胞凋亡参与了Bmi 1 −/−小鼠毛细胞损失的增加。氨基苯基荧光素和MitoSOX Red染色显示，由于抗氧化剂-促氧化剂平衡的失衡加剧，Bmi 1 −/−毛细胞中的自由基和线粒体ROS水平增加。此外，抗氧化剂N-乙酰半胱氨酸在体外和体内都从新霉素损伤中拯救了Bmi 1 −/−毛细胞，这表明ROS积累是Bmi 1 −/−毛细胞中氨基糖苷类敏感性增加的主要原因。我们的研究结果表明，Bmi 1通过控制氧化还原平衡和ROS水平在毛细胞存活中起重要作用，因此表明Bmi 1可能作为预防毛细胞死亡的新治疗靶点。
Reactive oxygen species (ROS) accumulation are involved in noise- and ototoxic drug-induced hair cell loss, which is the major cause of hearing loss. Bmi1 is a member of the Polycomb protein family and has been reported to regulate mitochondrial function and ROS level in thymocytes and neurons. In this study, we reported the expression of Bmi1 in mouse cochlea and investigated the role of Bmi1 in hair cell survival. Bmi1 expressed in hair cells and supporting cells in mouse cochlea. Bmi1−/− mice displayed severe hearing loss and patched outer hair cell loss from postnatal day 22. Ototoxic drug-induced hair cells loss dramatically increased in Bmi1−/− mice compared with that in wild-type controls both in vivo and in vitro, indicating Bmi1−/− hair cells were significantly more sensitive to ototoxic drug-induced damage. Cleaved caspase-3 and TUNEL staining demonstrated that apoptosis was involved in the increased hair cell loss of Bmi1−/− mice. Aminophenyl fluorescein and MitoSOX Red staining showed the level of free radicals and mitochondrial ROS increased in Bmi1−/− hair cells due to the aggravated disequilibrium of antioxidant–prooxidant balance. Furthermore, the antioxidant N-acetylcysteine rescued Bmi1−/− hair cells from neomycin injury both in vitro and in vivo, suggesting that ROS accumulation was mainly responsible for the increased aminoglycosides sensitivity in Bmi1−/− hair cells. Our findings demonstrate that Bmi1 has an important role in hair cell survival by controlling redox balance and ROS level, thus suggesting that Bmi1 may work as a new therapeutic target for the prevention of hair cell death.