Deletion of Mtu1 (Trmu) in zebrafish revealed the essential role of tRNA modification in mitochondrial biogenesis and hearing function.
Deletion of Mtu1 (Trmu) in zebrafish revealed the essential role of tRNA modification in mitochondrial biogenesis and hearing function.
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斑马鱼中 Mtu1 (Trmu) 的缺失揭示了 tRNA 修饰在线粒体生物发生和听力功能中的重要作用
DOI：
10.1093/nar/gky758
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发表时间：
2018-11-16
影响因子：
14.9
通讯作者：
Guan MX
中科院分区：
文献类型：
--
作者：
Zhang Q;Zhang L;Chen D;He X;Yao S;Zhang Z;Chen Y;Guan MX
Mtu1（Trmu）是一种高度保守的tRNA修饰酶，在tRNAGln、tRNAGlu和tRNALys的摆动位置负责τm5s2U的生物合成。我们之前的研究表明，MTU1突变调节了耳聋相关线粒体12S rRNA突变的表型表现。然而，MTU1缺乏的病理生理机制仍然知之甚少。利用CRISPR/Cas9系统生成的mtu1敲除斑马鱼，我们证明了mtu1敲除斑马鱼线粒体tRNALys、tRNAGlu和tRNAGln的U34的2-硫脲修饰被取消。这种转录后修饰的消除介导了线粒体tRNA代谢，导致线粒体tRNA水平的整体下降。线粒体tRNA代谢异常导致线粒体翻译障碍、呼吸缺陷和线粒体ATP生成减少。这些线粒体功能障碍导致了听觉器官的缺陷。值得注意的是，mtu1−/ -突变斑马鱼表现出异常的惊吓反应和游泳行为，鳞状耳石的大小和听觉和前庭器官毛细胞的数量显著减少。此外，mtu1−/ -突变斑马鱼的胞囊、囊和lagena的毛束密度显著降低。因此，我们的研究结果可能为耳聋的病理生理提供新的见解，耳聋的病理生理表现为线粒体trna摆动位置的缺陷修饰。
Mtu1(Trmu) is a highly conserved tRNA modifying enzyme responsible for the biosynthesis of τm5s2U at the wobble position of tRNAGln, tRNAGlu and tRNALys. Our previous investigations showed that MTU1 mutation modulated the phenotypic manifestation of deafness-associated mitochondrial 12S rRNA mutation. However, the pathophysiology of MTU1 deficiency remains poorly understood. Using the mtu1 knock-out zebrafish generated by CRISPR/Cas9 system, we demonstrated the abolished 2-thiouridine modification of U34 of mitochondrial tRNALys, tRNAGlu and tRNAGln in the mtu1 knock-out zebrafish. The elimination of this post-transcriptional modification mediated mitochondrial tRNA metabolisms, causing the global decreases in the levels of mitochondrial tRNAs. The aberrant mitochondrial tRNA metabolisms led to the impairment of mitochondrial translation, respiratory deficiencies and reductions of mitochondrial ATP production. These mitochondria dysfunctions caused the defects in hearing organs. Strikingly, mtu1−/– mutant zebrafish displayed the abnormal startle response and swimming behaviors, significant decreases in the sizes of saccular otolith and numbers of hair cells in the auditory and vestibular organs. Furthermore, mtu1−/– mutant zebrafish exhibited the significant reductions in the hair bundle densities in utricle, saccule and lagena. Therefore, our findings may provide new insights into the pathophysiology of deafness, which was manifested by the deficient modifications at wobble position of mitochondrial tRNAs.
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DOI：
10.1016/j.bbagrm.2017.11.007
发表时间：
2018-04
期刊：
Biochimica et biophysica acta. Gene regulatory mechanisms
影响因子：
--
作者：
Chatterjee K;Nostramo RT;Wan Y;Hopper AK
通讯作者：
Hopper AK
DOI：
10.15252/embj.201694885
发表时间：
2016-10-04
期刊：
The EMBO journal
影响因子：
--
作者：
Haag S;Sloan KE;Ranjan N;Warda AS;Kretschmer J;Blessing C;Hübner B;Seikowski J;Dennerlein S;Rehling P;Rodnina MV;Höbartner C;Bohnsack MT
通讯作者：
Bohnsack MT
影响因子：
4.8
作者：
Kurata, Shinya;Weixlbaumer, Albert;Suzuki, Tsutomu
通讯作者：
Suzuki, Tsutomu
影响因子：
5.3
作者：
Johansson, Marcus J. O.;Esberg, Anders;Bystrom, Anders S.
通讯作者：
Bystrom, Anders S.
影响因子：
2.9
作者：
Kambampati, R;Lauhon, CT
通讯作者：
Lauhon, CT