Cdk5rap1-mediated 2-methylthio modification of mitochondrial tRNAs governs protein translation and contributes to myopathy in mice and humans

Fan Yan Wei, Bo Zhou, Takeo Suzuki, Keishi Miyata, Yoshihiro Ujihara, Haruki Horiguchi, Nozomu Takahashi, Peiyu Xie, Hiroyuki Michiue, Atsushi Fujimura, Taku Kaitsuka, Hideki Matsui, Yasutoshi Koga, Satoshi Mohri, Tsutomu Suzuki, Yuichi Oike, Kazuhito Tomizawa

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Transfer RNAs (tRNAs) contain a wide variety of posttranscriptional modifications that are important for accurate decoding. Mammalian mitochondrial tRNAs (mt-tRNAs) are modified by nuclear-encoded tRNA-modifying enzymes; however, the physiological roles of these modifications remain largely unknown. In this study, we report that Cdk5 regulatory subunit-associated protein 1 (Cdk5rap1) is responsible for 2-methylthio (ms2) modifications of mammalian mt-tRNAs for Ser(UCN), Phe, Tyr, and Trp codons. Deficiency in ms2 modification markedly impaired mitochondrial protein synthesis, which resulted in respiratory defects in Cdk5rap1 knockout (KO) mice. The KO mice were highly susceptive to stress-induced mitochondrial remodeling and exhibited accelerated myopathy and cardiac dysfunction under stressed conditions. Furthermore, we demonstrate that the ms2 modifications of mt-tRNAs were sensitive to oxidative stress and were reduced in patients with mitochondrial disease. These findings highlight the fundamental role of ms2 modifications of mt-tRNAs in mitochondrial protein synthesis and their pathological consequences in mitochondrial disease.

Original languageEnglish
Pages (from-to)428-442
Number of pages15
JournalCell Metabolism
Volume21
Issue number3
DOIs
Publication statusPublished - 2015 Mar 3
Externally publishedYes

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Wei, F. Y., Zhou, B., Suzuki, T., Miyata, K., Ujihara, Y., Horiguchi, H., Takahashi, N., Xie, P., Michiue, H., Fujimura, A., Kaitsuka, T., Matsui, H., Koga, Y., Mohri, S., Suzuki, T., Oike, Y., & Tomizawa, K. (2015). Cdk5rap1-mediated 2-methylthio modification of mitochondrial tRNAs governs protein translation and contributes to myopathy in mice and humans. Cell Metabolism, 21(3), 428-442. https://doi.org/10.1016/j.cmet.2015.01.019