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

Abstract

Modified uridine containing taurine, 5-taurinomethyluridine (τm(5)U), is found at the anticodon first position of mitochondrial (mt-)transfer RNAs (tRNAs). Previously, we reported that τm(5)U is absent in mt-tRNAs with pathogenic mutations associated with mitochondrial diseases. However, biogenesis and physiological role of τm(5)U remained elusive. Here, we elucidated τm(5)U biogenesis by confirming that 5,10-methylene-tetrahydrofolate and taurine are metabolic substrates for τm(5)U formation catalyzed by MTO1 and GTPBP3. GTPBP3-knockout cells exhibited respiratory defects and reduced mitochondrial translation. Very little τm(5)U34 was detected in patient’s cells with the GTPBP3 mutation, demonstrating that lack of τm(5)U results in pathological consequences. Taurine starvation resulted in downregulation of τm(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 τm(5)U 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.