Balancing of mitochondrial translation through METTL8-mediated m3C modification of mitochondrial tRNAs
Balancing of mitochondrial translation through METTL8-mediated m3C modification of mitochondrial tRNAs
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DOI：
10.1016/j.molcel.2021.10.018
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发表时间：
2021-12-02
期刊：
影响因子：
16
通讯作者：
Meister, Gunter
中科院分区：
文献类型：
--
作者：
Scholler, Eva;Marks, James;Meister, Gunter
线粒体含有一种特定的翻译机制，用于合成呼吸链编码的呼吸链成分。线粒体tRNA（mt-tRNA）也从线粒体DNA产生，并且与它们的细胞质对应物类似，是转录后修饰的。在这里，我们发现RNA甲基转移酶胃L 8是一种线粒体蛋白质，它促进mt-tRNA（ser（UCN））和mt-tRNA（Thr）的C-32位的3-甲基-胞苷（m（3）C）甲基化。胃L 8敲除细胞显示呼吸链活性降低，而过表达增加活性。在胰腺癌中，胃L 8水平很高，这与较低的患者生存率和增强的呼吸链活性相关。线粒体核糖体分析发现线粒体核糖体停滞在mt-tRNA（ser（UCN））和mt-tRNA（Thr）依赖的密码子上。使用质谱法对呼吸链复合物的进一步分析揭示了减少的经编码的蛋白质ND 6和ND 1掺入复合物I中。因此，通过胃L 8介导的m（3）C（32）甲基化，mt-tRNA（ser（UCN））和mt-tRNA（Thr）依赖性密码子的良好平衡翻译可能促进线粒体的最佳组成和功能！呼吸链
Mitochondria contain a specific translation machinery for the synthesis of mitochondria-encoded respiratory chain components. Mitochondrial tRNAs (mt-tRNAs) are also generated from the mitochondrial DNA and, similar to their cytoplasmic counterparts, are post-transcriptionally modified. Here, we find that the RNA methyltransferase METTL8 is a mitochondrial protein that facilitates 3-methyl-cytidine (m(3)C) methylation at position C-32 of the mt-tRNA(ser(UCN)) and mt-tRNA(Thr). METTL8 knockout cells show a reduction in respiratory chain activity, whereas overexpression increases activity. In pancreatic cancer, METTL8 levels are high, which correlates with lower patient survival and an enhanced respiratory chain activity. Mitochondrial ribosome profiling uncovered mitoribosome stalling on mt-tRNA(ser(UCN)) - and mt-tRNA(Thr) -dependent codons. Further analysis of the respiratory chain complexes using mass spectrometry revealed reduced incorporation of the mitochondrially encoded proteins ND6 and ND1 into complex I. The well-balanced translation of mt-tRNA(ser(UCN)) - and mt-tRNA(Thr) -dependent codons through METTL8-mediated m(3)C(32) methylation might, therefore, facilitate the optimal composition and function of the mitochondria! respiratory chain.