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  3. Metabolic and chemical regulation of tRNA modification associated with taurine deficiency and human disease

Metabolic and chemical regulation of tRNA modification associated with taurine deficiency and human disease

  • Nucleic Acids Res. 2018 Feb 28;46(4):1565-1583. doi: 10.1093/nar/gky068.
Kana Asano 1,  Takeo Suzuki 1,  Ayaka Saito 1,  Fan-Yan Wei 2,  Yoshiho Ikeuchi 3,  Tomoyuki Numata 4,  Ryou Tanaka 5,  Yoshihisa Yamane 5,  Takeshi Yamamoto 6,  Takanobu Goto 7,  Yoshihito Kishita 8,  Kei Murayama 9,  Akira Ohtake 10,  Yasushi Okazaki 8 11,  Kazuhito Tomizawa 2,  Yuriko Sakaguchi 1,  Tsutomu Suzuki 1
Affiliations

Affiliations

  • 1 Department of Chemistry and Biotechnology, Graduate School of Engineering, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
  • 2 Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
  • 3 Institute of Industrial Science, University of Tokyo, Meguro-ku, Tokyo 153-8505, Japan.
  • 4 Biological Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8566, Japan.
  • 5 Department of Veterinary Surgery, Tokyo University of Agriculture and Technology, Animal Medical Center, Fuchu, Tokyo 183-8509, Japan.
  • 6 Tamaki Laboratory, National Research Institute of Aquaculture, Japan Fisheries Research and Education Agency, Tamaki, Mie 519-0423, Japan.
  • 7 Department of Chemistry & Biochemistry, National Institute of Technology, Numazu College, Numazu, Shizuoka 410-8501, Japan.
  • 8 Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama 350-1240, Japan.
  • 9 Department of Metabolism, Chiba Children's Hospital, Midori-ku, Chiba 266-0007, Japan.
  • 10 Department of Pediatrics, Saitama Medical University, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan.
  • 11 Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama 350-1240, Japan.
PMID: 29390138 DOI: 10.1093/nar/gky068
Abstract

Modified uridine containing taurine, 5-taurinomethyluridine (τm5U), is found at the anticodon first position of mitochondrial (mt-)transfer RNAs (tRNAs). Previously, we reported that τm5U is absent in mt-tRNAs with pathogenic mutations associated with mitochondrial diseases. However, biogenesis and physiological role of τm5U remained elusive. Here, we elucidated τm5U biogenesis by confirming that 5,10-methylene-tetrahydrofolate and taurine are metabolic substrates for τm5U formation catalyzed by MTO1 and GTPBP3. GTPBP3-knockout cells exhibited respiratory defects and reduced mitochondrial translation. Very little τm5U34 was detected in patient's cells with the GTPBP3 mutation, demonstrating that lack of τm5U results in pathological consequences. Taurine starvation resulted in downregulation of τm5U frequency in cultured cells and animal tissues (cat liver and flatfish). Strikingly, 5-carboxymethylaminomethyluridine (cmnm5U), in which the taurine moiety of τm5U is replaced with glycine, was detected in mt-tRNAs from taurine-depleted cells. These results indicate that tRNA modifications are dynamically regulated via sensing of intracellular metabolites under physiological condition.

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