越来越多的证据表明，在不同的生物过程中，各种表观转录的RNA修饰扮演着至关重要的角色。甲基转移酶METTL8在体外安装了线粒体tRNA的3-甲基脲嘧啶（m3C）修饰，然而它在完整的生物系统中的作用尚不清楚。本文的研究表明，Mettl8定位在线粒体，特异性地在小鼠胚胎皮质神经干细胞中将m3C安装在线粒体tRNAThr/Ser（UCN）上。在分子和细胞水平上，Mettl8在皮质神经干细胞中的缺失会导致线粒体蛋白翻译减少和呼吸活性减弱。在功能水平上，条件性的Mettl8除去会导致小鼠中的胚胎皮质神经干细胞维持受损，在体内可以通过药理学增强线粒体功能来得到挽救。类似地，METTL8促进人类前脑皮质器官的线粒体蛋白表达和神经干细胞维持。我们的研究揭示了Mettl8和线粒体tRNA m3C修饰在小鼠和人类胚胎皮质神经干细胞中维持的表观转录机制。版权所有© 2023 Elsevier Inc.。保留所有权利。

Increasing evidence implicates the critical roles of various epitranscriptomic RNA modifications in different biological processes. Methyltransferase METTL8 installs 3-methylcytosine (m3C) modification of mitochondrial tRNAs in vitro; however, its role in intact biological systems is unknown. Here, we show that Mettl8 is localized in mitochondria and installs m3C specifically on mitochondrial tRNAThr/Ser(UCN) in mouse embryonic cortical neural stem cells. At molecular and cellular levels, Mettl8 deletion in cortical neural stem cells leads to reduced mitochondrial protein translation and attenuated respiration activity. At the functional level, conditional Mettl8 deletion in mice results in impaired embryonic cortical neural stem cell maintenance in vivo, which can be rescued by pharmacologically enhancing mitochondrial functions. Similarly, METTL8 promotes mitochondrial protein expression and neural stem cell maintenance in human forebrain cortical organoids. Together, our study reveals a conserved epitranscriptomic mechanism of Mettl8 and mitochondrial tRNA m3C modification in maintaining embryonic cortical neural stem cells in mice and humans.Copyright © 2023 Elsevier Inc. All rights reserved.