Mutations in human mitochondrial tRNA genes are responsible for a variety of human inherited diseases. Investigations of the molecular mechanisms of these diseases are of great interest for nowadays scientists. According to the study of post-transcriptional modification patterns of human mitochondrial tRNAs, novel taurine-containing modifications were identified at the anticodon wobble nucleotides of mitochondrial tRNA^Leu(UUR) and tRNA^Lys. Recently, it was reported that mitochondrial tRNAs harboring one of those encephalomyopathies related mutations, such as A8344G, A3243G, T3271C etc., lacked the normal taurine-containing modification at their anticodon wobble positions. Wobble modification deficiencies of mutant mitochondrial tRNAs were found from cybrid cells, as well as from patient tissues. Molecular surgery experiments showed that the wobble modification is essential for the interaction between the anticodon in tRNA and the codon in mRNA. Furthermore, the enzyme that is responsible for the formation of the modification was identified and characterized. These studies strongly suggested a key molecular factor responsible for the inherited mitochondrial encephalomyopathies and could potentially lead to the development of a gene therapy for these diseases.