MELAS, a first-ever tRNA modification disorder is alleviated by taurine supplementation therapy

Francis Crick postulated certain chemical modifications at the first anticodon nucleotide in each tRNA, because the first anticodon nucleotide interacts with the corresponding third codon nucleotide in mRNA through non-canonical Watson-Crick geometry. So far, several post-transcriptional chemical modifications have been discovered in the first anticodon nucleotides in tRNAs. We found a modification of taurine at the first anticodon nucleotide in the normal mitochondrial (mt) tRNALeu(UUR). Surprisingly, the taurine modification is completely deficient in the mt tRNALeu(UUR) derived from tissues from MELAS patients harboring the A3243G transition. Because the taurine modification defect in the mutant mt tRNALeu(UUR) causes a deficiency in deciphering codons, we regard MELAS as a first-ever tRNA-modification disorder. Indeed, high-dose taurine supplementation ameliorates impaired mt dysfunction in patient-derived cells and prevents stroke-like episodes in two MELAS patients for more than nine years. Here we performed a multi-center, open, phase 3 trial to approve the clinical efficiencies of oral taurine supplementation on preventing stroke-like episodes in patients with MELAS for 2 years. We enrolled 10 patients suffering from repeated stroke-like episodes in the trial. Initial two-year oral administration of taurine completely prevents stroke-like episodes in 6 patients and significantly decreased its annual relapsing rates in the other patients. During the trial, taurine modification ratio in the mt tRNALeu(UUR) in peripheral white blood cells were significantly increased in 5 out of 9 patients. Taurine could prevent stroke-like episodes in MELAS by reversing impaired the taurine modification in mt tRNALeu(UUR).