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

Abstract

Modified uridine containing taurine, 5-taurinomethyluridine (τm5U), is found at the anticodon first position of mitochondrial (mt-)transfer RNAs (tRNAs). Previously, we reported that τm5U is absent in mt-tRNAs with pathogenic mutations associated with mitochondrial diseases. However, biogenesis and physiological role of τm5U remained elusive. Here, we elucidated τm5U biogenesis by confirming that 5,10-methylene-tetrahydrofolate and taurine are metabolic substrates for τm5U formation catalyzed by MTO1 and GTPBP3. GTPBP3-knockout cells exhibited respiratory defects and reduced mitochondrial translation. Very little τm5U34 was detected in patient’s cells with the GTPBP3 mutation, demonstrating that lack of τm5U results in pathological consequences. Taurine starvation resulted in downregulation of τm5U frequency in cultured cells and animal tissues (cat liver and flatfish). Strikingly, 5-carboxymethylaminomethyluridine (cmnm5U), in which the taurine moiety of τm5U 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.

Bacillus subtilis exhibits MnmC-like tRNA modification activities

“…Therefore, the fact that a particular tRNA, such as Bs-tRNA Lys UUU , can be effectively modified by the ammonium pathway seems to depend on the biological context ( E. coli or B. subtilis ), which could include factors like the affinity of a particular MnmEG-tRNA complex to ammonium and the sensitivity of tRNAs containing nm 5 s 2 U (instead of cmnm 5 s 2 U or mnm 5 s 2 U) to endogenous nucleases. Interestingly, the complex formed by the human MnmE and MnmG homologs (named GTPBP3 and MTO1, respectively), which usually incorporates taurine instead of glycine into mitochondrial tRNAs, can use glycine when HeLa cells are grown under taurine-depleted conditions [22]. Moreover, the E. coli MnmEG complex catalyzes the in vitro incorporation of taurine into in vitro synthesized E. coli tRNA Gly UCC , albeit inefficiently [22].…”

“…Interestingly, the complex formed by the human MnmE and MnmG homologs (named GTPBP3 and MTO1, respectively), which usually incorporates taurine instead of glycine into mitochondrial tRNAs, can use glycine when HeLa cells are grown under taurine-depleted conditions [22]. Moreover, the E. coli MnmEG complex catalyzes the in vitro incorporation of taurine into in vitro synthesized E. coli tRNA Gly UCC , albeit inefficiently [22]. Altogether these data uphold the view that the affinity of MnmEG and its homologs to ammonium, glycine and taurine in the presence of different substrate tRNAs may be a key factor for regulating the modification reaction.…”

The mitochondrial transfer RNAAsp A7551G mutation may contribute to the clinical expression of deafness associated with the A1555G mutation in a pedigree with hearing impairment

“…The nucleotide at position 37 in tRNA Asp is highly conserved among different vertebrates (21). In fact, A37 in tRNAs is often chemically modified (by thiolation or methylation) (22), therefore, the A7551G mutation may contribute to maintenance of the level of tRNA Asp (23). Notably, the well-known A4435G mutation occurring at the same position in the tRNA Met gene was previously found to be a risk factor for hypertension (24) and Leber's hereditary optic neuropathy (LHON) (25).…”

The mitochondrial tRNAAla 5587T>C and tRNALeu(CUN) 12280A>G mutations may be associated with hypertension in a Chinese family

“…The molecular mechanisms may be as follows: The mutations altered the secondary structure of tRNA Ala and tRNA Leu (CUN) , subsequently, the structural alternations led to a decrease in the steady-state levels of tRNA Ala and tRNA Leu(CUN) , and caused the impairments of mt-tRNAs metabolism. As a result, mitochondrial protein synthesis, the respiration chain and ATP levels declined significantly; additionally, decreased tRNA steady-state levels may also affect tRNA aminoacylation, mtDNA copy number and ROS generation (35,36). Therefore, the mitochondrial dysfunction, caused by 5587T>C and 12280A>G mutations, may contribute to the progression of hypertension in this family.…”