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

Abstract

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