Wang Xianren, Zhu Yuanping, Long Haishan, Pan Song, Xiong Hao, Fang Qiaojun, Hill Kayla, Lai Ruosha, Yuan Hu, Sha Su-Hua
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, United States.
Department of Otorhinolaryngology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Front Mol Neurosci. 2019 Jan 8;11:469. doi: 10.3389/fnmol.2018.00469. eCollection 2018.
Mitochondria modulate cellular calcium homeostasis by the combined action of the mitochondrial calcium uniporter (MCU), a selective calcium entry channel, and the sodium calcium exchanger (NCLX), which extrudes calcium from mitochondria. In this study, we investigated MCU and NCLX in noise-induced hearing loss (NIHL) using adult CBA/J mice and noise-induced alterations of inner hair cell (IHC) synapses in MCU knockout mice. Following noise exposure, immunoreactivity of MCU increased in cochlear sensory hair cells of the basal turn, while immunoreactivity of NCLX decreased in a time- and exposure-dependent manner. Inhibition of MCU activity MCU siRNA pretreatment or the specific pharmacological inhibitor Ru360 attenuated noise-induced loss of sensory hair cells and synaptic ribbons, wave I amplitudes, and NIHL in CBA/J mice. This protection was afforded, at least in part, through reduced cleavage of caspase 9 (CC9). Furthermore, MCU knockout mice on a hybrid genetic CD1 and C57/B6 background showed resistance to noise-induced seizures compared to wild-type littermates. Owing to the CD1 background, MCU knockouts and littermates suffer genetic high frequency hearing loss, but their IHCs remain intact. Noise-induced loss of IHC synaptic connections and reduction of auditory brainstem response (ABR) wave I amplitude were recovered in MCU knockout mice. These results suggest that cellular calcium influx during noise exposure leads to mitochondrial calcium overload MCU and NCLX. Mitochondrial calcium overload, in turn, initiates cell death pathways and subsequent loss of hair cells and synaptic connections, resulting in NIHL.
线粒体通过线粒体钙单向转运体（MCU，一种选择性钙进入通道）和钠钙交换体（NCLX，将钙从线粒体中排出）的联合作用来调节细胞钙稳态。在本研究中，我们使用成年CBA/J小鼠研究了噪声性听力损失（NIHL）中的MCU和NCLX，以及MCU基因敲除小鼠中噪声诱导的内毛细胞（IHC）突触改变。噪声暴露后，蜗底耳蜗感觉毛细胞中MCU的免疫反应性增加，而NCLX的免疫反应性则呈时间和暴露依赖性降低。抑制MCU活性（MCU siRNA预处理或特异性药理抑制剂Ru360）可减轻CBA/J小鼠中噪声诱导的感觉毛细胞和突触带损失、I波振幅以及NIHL。这种保护至少部分是通过减少半胱天冬酶9（CC9）的切割来实现的。此外，在杂交遗传CD1和C57/B6背景下的MCU基因敲除小鼠与野生型同窝小鼠相比，对噪声诱导的癫痫发作具有抗性。由于CD1背景，MCU基因敲除小鼠和同窝小鼠患有遗传性高频听力损失，但其IHC保持完整。在MCU基因敲除小鼠中，噪声诱导的IHC突触连接损失和听觉脑干反应（ABR）I波振幅降低得到了恢复。这些结果表明，噪声暴露期间细胞钙内流导致线粒体钙超载（通过MCU和NCLX）。反过来，线粒体钙超载会启动细胞死亡途径以及随后毛细胞和突触连接的丧失，从而导致NIHL。
