Down-regulation of AMPK signaling pathway rescues nearing loss in TFB1 transgenic mice and delays age-related hearing loss
Down-regulation of AMPK signaling pathway rescues nearing loss in TFB1 transgenic mice and delays age-related hearing loss
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AMPK信号通路的下调可挽救濒临丧失的TFB1转基因小鼠并延缓与年龄相关的听力损失
DOI：
10.18632/aging.102977
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发表时间：
2020-04-15
期刊：
影响因子：
5.2
通讯作者：
Song, Lei
中科院分区：
文献类型：
--
作者：
Zhao, Jingjing;Li, Gen;Song, Lei
AMP活化蛋白激酶（AMPK）是一种集细胞生长和代谢调节于一体的蛋白激酶。AMPK活化响应于由活性氧（ROS）触发的细胞能量下降和线粒体功能障碍而发生。在老年Tg-mtTFB 1小鼠（线粒体耳聋小鼠模型）中，听力损失伴随耳蜗病理学，包括耳蜗内电位（EP）降低和螺旋神经节神经元（SGN）、内毛细胞（IHC）突触和外毛细胞（OHC）丢失。在耳蜗组织中也检测到积累的ROS和增加的凋亡信号，伴随着AMPK的激活。为了进一步探索AMPK信号传导在听觉表型中的作用，我们使用基因敲除AMPK α 1作为对Tg-mtTFB 1小鼠的拯救，并观察到：改善ABR波I、EP和IHC功能，正常SGN、IHC突触形态和OHC存活，耳蜗组织中ROS减少，促凋亡信号传导（Bax）减少和抗凋亡信号传导（Bcl-2）增加，这表明AMPK的减少减弱了耳蜗中通过ROS-AMPK-Bc 12途径的细胞凋亡。总之，AMPK过度激活通过氧化还原失衡和凋亡途径失调导致Tgmt TFB 1小鼠加速老年性耳聋。AMPK下调对促生存功能和减少氧化应激的作用表明AMPK可作为拯救或减轻线粒体听力损失的靶点。
AMP-activated protein kinase (AMPK) integrates the regulation of cell growth and metabolism. AMPK activation occurs in response to cellular energy decline and mitochondrial dysfunction triggered by reactive oxygen species (ROS). In aged Tg-mtTFB1 mice, a mitochondrial deafness mouse model, hearing loss is accompanied with cochlear pathology including reduced endocochlear potential (EP) and loss of spiral ganglion neurons (SGN), inner hair cell (IHC) synapses and outer hair cells (OHC). Accumulated ROS and increased apoptosis signaling were also detected in cochlear tissues, accompanied by activation of AMPK. To further explore the role of AMPK signaling in the auditory phenotype, we used genetically knocked out AMPK alpha 1 as a rescue to Tg-mtTFB1 mice and observed: improved ABR wave I, EP and IHC function, normal SGNs, IHC synapses morphology and OHC survivals, with decreased ROS, reduced pro-apoptotic signaling (Bax) and increased antiapoptotic signaling (Bcl-2) in the cochlear tissues, indicating that reduced AMPK attenuated apoptosis via ROS-AMPK-Bc12 pathway in the cochlea. To conclude, AMPK hyperactivation causes accelerated presbycusis in TgmtTFB1 mice by redox imbalance and dysregulation of the apoptosis pathway. The effects of AMPK downregulation on pro-survival function and reduction of oxidative stress indicate AMPK serves as a target to rescue or relieve mitochondrial hearing loss.