TY - JOUR
T1 - Metabolic and chemical regulation of tRNA modification associated with taurine deficiency and human disease
AU - Asano, Kana
AU - Suzuki, Takeo
AU - Saito, Ayaka
AU - Wei, Fan Yan
AU - Ikeuchi, Yoshiho
AU - Numata, Tomoyuki
AU - Tanaka, Ryou
AU - Yamane, Yoshihisa
AU - Yamamoto, Takeshi
AU - Goto, Takanobu
AU - Kishita, Yoshihito
AU - Murayama, Kei
AU - Ohtake, Akira
AU - Okazaki, Yasushi
AU - Tomizawa, Kazuhito
AU - Sakaguchi, Yuriko
AU - Suzuki, Tsutomu
N1 - Funding Information:
Grant-in-Aid for Scientific Research from Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT); Japan Society for the Promotion of Science (JSPS) (to Ta.S., Ts.S.). Funding for open access charge: JSPS; Grants-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. Conflict of interest statement. None declared.
Publisher Copyright:
© 2017 The Author(s).
PY - 2018/2/28
Y1 - 2018/2/28
N2 - Modified uridine containing taurine, 5-taurinometh yluridine (m5U), is found at the anticodon first position of mitochondrial (mt-)transfer RNAs (tRNAs). Previously, we reported that m5U is absent in mt-tRNAs with pathogenic mutations associated with mitochondrial diseases. However, biogenesis and physiological role of m5U remained elusive. Here, we elucidated m5U biogenesis by confirming that 5,10-methylene-tetrahydrofolate and taurine are metabolic substrates for m5U formation catalyzed by MTO1 and GTPBP3. GTPBP3-knockout cells exhibited respiratory defects and reduced mitochondrial translation. Very little m5U34 was detected in patient's cells with the GTPBP3 mutation, demonstrating that lack of m5U results in pathological consequences. Taurine starvation resulted in downregulation of m5U frequency in cultured cells and animal tissues (cat liver and flatfish). Strikingly, 5-carboxymethylaminomethyluridine (cmnm5U), in which the taurine moiety of m5U is replaced with glycine, was detected in mt-tRNAs from taurinedepleted cells. These results indicate that tRNA modifications are dynamically regulated via sensing of intracellular metabolites under physiological condition.
AB - Modified uridine containing taurine, 5-taurinometh yluridine (m5U), is found at the anticodon first position of mitochondrial (mt-)transfer RNAs (tRNAs). Previously, we reported that m5U is absent in mt-tRNAs with pathogenic mutations associated with mitochondrial diseases. However, biogenesis and physiological role of m5U remained elusive. Here, we elucidated m5U biogenesis by confirming that 5,10-methylene-tetrahydrofolate and taurine are metabolic substrates for m5U formation catalyzed by MTO1 and GTPBP3. GTPBP3-knockout cells exhibited respiratory defects and reduced mitochondrial translation. Very little m5U34 was detected in patient's cells with the GTPBP3 mutation, demonstrating that lack of m5U results in pathological consequences. Taurine starvation resulted in downregulation of m5U frequency in cultured cells and animal tissues (cat liver and flatfish). Strikingly, 5-carboxymethylaminomethyluridine (cmnm5U), in which the taurine moiety of m5U is replaced with glycine, was detected in mt-tRNAs from taurinedepleted cells. These results indicate that tRNA modifications are dynamically regulated via sensing of intracellular metabolites under physiological condition.
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U2 - 10.1093/nar/gky068
DO - 10.1093/nar/gky068
M3 - Article
C2 - 29390138
AN - SCOPUS:85043264679
SN - 0305-1048
VL - 46
SP - 1565
EP - 1583
JO - Nucleic Acids Research
JF - Nucleic Acids Research
IS - 4
ER -
