Disruption of Hars2 in Cochlear Hair Cells Causes Progressive Mitochondrial Dysfunction and Hearing Loss in Mice.
Disruption of Hars2 in Cochlear Hair Cells Causes Progressive Mitochondrial Dysfunction and Hearing Loss in Mice.
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耳蜗毛细胞 Hars2 的破坏导致小鼠进行性线粒体功能障碍和听力损失
DOI：
10.3389/fncel.2021.804345
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发表时间：
2021
影响因子：
5.3
通讯作者：
Yang T
中科院分区：
文献类型：
--
作者：
Xu P;Wang L;Peng H;Liu H;Liu H;Yuan Q;Lin Y;Xu J;Pang X;Wu H;Yang T
线粒体氨基酰-tRNA合成酶基因突变可导致人类非综合征性和/或综合征性感音神经性听力损失，而其在耳蜗内的细胞和生理病理很少被活体研究。在这项研究中，我们发现组氨酰-tRNA合成酶HARS2在出生后的小鼠耳蜗组织中大量表达，包括外毛细胞和内毛细胞，其缺陷与Perrault综合征2(PRLTS2)相关。在小鼠毛细胞中靶向敲除Hars2导致延迟起病(P30)，快速进行性听力损失，类似于PRLTS2听力表型。随着ROS水平的升高和线粒体凋亡途径的激活，从P45开始观察到显著的毛细胞丢失。尽管有正常的带状突触形成，内毛细胞的全细胞膜片钳在P30毛细胞丢失之前显示出钙内流减少和持续突触吐出减少，这与听性脑干反应的阈值上I波幅度降低一致。从P14开始，透射电子显微镜观察到线粒体形态异常的比例增加，表现为肿胀、变形、脊丢失和出现与线粒体功能障碍有关的大的内在空泡。虽然线粒体异常在内毛细胞中更为突出，但外毛细胞遭受的细胞丢失更严重。综上所述，我们的结果表明，在小鼠耳蜗毛细胞中，Hars2的条件性敲除导致线粒体功能障碍和ROS应激的积累，触发以毛细胞突触和细胞凋亡为重点的进行性听力损失，并被内毛细胞和外毛细胞区别对待。
Mutations in a number of genes encoding mitochondrial aminoacyl-tRNA synthetases lead to non-syndromic and/or syndromic sensorineural hearing loss in humans, while their cellular and physiological pathology in cochlea has rarely been investigated in vivo. In this study, we showed that histidyl-tRNA synthetase HARS2, whose deficiency is associated with Perrault syndrome 2 (PRLTS2), is robustly expressed in postnatal mouse cochlea including the outer and inner hair cells. Targeted knockout of Hars2 in mouse hair cells resulted in delayed onset (P30), rapidly progressive hearing loss similar to the PRLTS2 hearing phenotype. Significant hair cell loss was observed starting from P45 following elevated reactive oxygen species (ROS) level and activated mitochondrial apoptotic pathway. Despite of normal ribbon synapse formation, whole-cell patch clamp of the inner hair cells revealed reduced calcium influx and compromised sustained synaptic exocytosis prior to the hair cell loss at P30, consistent with the decreased supra-threshold wave I amplitudes of the auditory brainstem response. Starting from P14, increasing proportion of morphologically abnormal mitochondria was observed by transmission electron microscope, exhibiting swelling, deformation, loss of cristae and emergence of large intrinsic vacuoles that are associated with mitochondrial dysfunction. Though the mitochondrial abnormalities are more prominent in inner hair cells, it is the outer hair cells suffering more severe cell loss. Taken together, our results suggest that conditional knockout of Hars2 in mouse cochlear hair cells leads to accumulating mitochondrial dysfunction and ROS stress, triggers progressive hearing loss highlighted by hair cell synaptopathy and apoptosis, and is differentially perceived by inner and outer hair cells.
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影响因子：
5.3
作者：
Fu X;Wan P;Li P;Wang J;Guo S;Zhang Y;An Y;Ye C;Liu Z;Gao J;Yang J;Fan J;Chai R
通讯作者：
Chai R
DOI：
10.1523/jneurosci.1866-11.2011
发表时间：
2011-11-16
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Graydon CW;Cho S;Li GL;Kachar B;von Gersdorff H
通讯作者：
von Gersdorff H
影响因子：
5.3
作者：
Guo L;Cao W;Niu Y;He S;Chai R;Yang J
通讯作者：
Yang J
影响因子：
5.3
作者：
Castellano-Muñoz M;Ricci AJ
通讯作者：
Ricci AJ
长期高脂肪饮食会增加 d-半乳糖诱导的衰老大鼠内耳的氧化应激、线粒体损伤和细胞凋亡
影响因子：
2.8
作者：
Du, Zhengde;Yang, Yang;Kong, Weijia
通讯作者：
Kong, Weijia