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

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.