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Mitochondrial translation requires folate-dependent tRNA methylation

机译：线粒体翻译需要依赖叶酸的tRNA甲基化

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摘要

Folates enable the activation and transfer of one-carbon units for the biosynthesis of purines, thymidine and methionine(1-3). Antifolates are important immunosuppressive4 and anticancer agents(5). In proliferating lymphocytes(6) and human cancers(7,8), mitochondrial folate enzymes are particularly strongly upregulated. This in part reflects the need for mitochondria to generate one-carbon units and export them to the cytosol for anabolic metabolism(2,9). The full range of uses of folate-bound one-carbon units in the mitochondrial compartment itself, however, has not been thoroughly explored. Here we show that loss of the catalytic activity of the mitochondrial folate enzyme serine hydroxymethyltransferase 2 (SHMT2), but not of other folate enzymes, leads to defective oxidative phosphorylation in human cells due to impaired mitochondrial translation. We find that SHMT2, presumably by generating mitochondrial 5,10-methylenetetrahydrofolate, provides methyl donors to produce the taurinomethyluridine base at the wobble position of select mitochondrial tRNAs. Mitochondrial ribosome profiling in SHMT2-knockout human cells reveals that the lack of this modified base causes defective translation, with preferential mitochondrial ribosome stalling at certain lysine (AAG) and leucine (UUG) codons. This results in the impaired expression of respiratory chain enzymes. Stalling at these specific codons also occurs in certain inborn errors of mitochondrial metabolism. Disruption of whole-cell folate metabolism, by either folate deficiency or antifolate treatment, also impairs the respiratory chain. In summary, mammalian mitochondria use folate-bound one-carbon units to methylate tRNA, and this modification is required for mitochondrial translation and thus oxidative phosphorylation.
机译：叶酸能够激活和转移一碳单元，用于嘌呤，胸苷和蛋氨酸的生物合成（1-3）。抗叶酸是重要的免疫抑制剂4和抗癌药（5）。在增殖性淋巴细胞（6）和人类癌症（7,8）中，线粒体叶酸酶特别强烈上调。这部分反映了线粒体需要生成一碳单元并将其输出到细胞质中以进行同化代谢（2,9）。然而，尚未充分探索线粒体区室中叶酸结合的一碳单元的全部用途。在这里，我们显示线粒体叶酸酶丝氨酸羟甲基转移酶2（SHMT2）而不是其他叶酸酶的催化​​活性丧失，由于线粒体翻译受损，导致人类细胞中的氧化磷酸化缺陷。我们发现SHMT2，大概是通过产生线粒体5,10-亚甲基四氢叶酸，提供了甲基供体，以在选定的线粒体tRNA的摆动位置上产生牛磺酸甲基尿苷碱基。 SHMT2基因敲除的人类细胞中的线粒体核糖体分析显示，缺少这种修饰的碱基会导致翻译缺陷，优先的线粒体核糖体停滞在某些赖氨酸（AAG）和亮氨酸（UUG）密码子上。这导致呼吸链酶的表达受损。在某些先天性线粒体代谢错误中也会发生这些特定密码子的失速。通过叶酸缺乏或抗叶酸治疗破坏全细胞叶酸代谢，也会损害呼吸链。总之，哺乳动物的线粒体使用叶酸结合的一碳单元使tRNA甲基化，而这种修饰是线粒体翻译和氧化磷酸化所必需的。

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