Metabolic and chemical regulation of tRNA modification associated with taurine deficiency and human disease
| Autor: | Kazuhito Tomizawa, Yoshihito Kishita, Ryou Tanaka, Tomoyuki Numata, Takanobu Goto, Takeshi Yamamoto, Kei Murayama, Akira Ohtake, Kana Asano, Takeo Suzuki, Ayaka Saito, Yasushi Okazaki, Yoshiho Ikeuchi, Tsutomu Suzuki, Yuriko Sakaguchi, Yoshihisa Yamane, Fan Yan Wei |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Taurine TRNA modification Mitochondrial Diseases Mitochondrial translation NAR Breakthrough Article Biology Mitochondrion 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine RNA Transfer GTP-Binding Proteins Genetics Animals Humans Uridine RNA-Binding Proteins RNA Mitochondria HEK293 Cells 030104 developmental biology Biochemistry chemistry Child Preschool Transfer RNA Cats Female Carrier Proteins GTPBP3 030217 neurology & neurosurgery Biogenesis HeLa Cells |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| DOI: | 10.1093/nar/gky068 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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