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

Modified uridine containing taurine, 5-taurinometh yluridine (tau m(5)U), is found at the anticodon first position of mitochondrial (mt-)transfer RNAs (tRNAs). Previously, we reported that tau m(5)U is absent in mt-tRNAs with pathogenic mutations associated with mitochondrial diseases. However, biogenesis and physiological role of tau m(5)U remained elusive. Here, we elucidated tau m(5)U biogenesis by confirming that 5,10-methylene-tetrahydrofolate and taurine are metabolic substrates for tau m(5)U formation catalyzed by MTO1 and GTPBP3. GTPBP3-knockout cells exhibited respiratory defects and reduced mitochondrial translation. Very little tau m(5) U34 was detected in patient's cells with the GTPBP3 mutation, demonstrating that lack of tau m(5)U results in patho-logical consequences. Taurine starvation resulted in downregulation of tau m(5)U frequency in cultured cells and animal tissues (cat liver and flatfish). Strikingly, 5-carboxymethylaminomethyluridine (cmnm(5)U), in which the taurine moiety of tau m(5)U 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.