MELAS Syndrome: Mediated by Impaired Taurinomethyluridine Synthesis

Abstract

Taurine (2-aminoethanesulfonate) is a ubiquitous β-amino acid found in a very high concentration in excitable tissue. One of its most important functions is its conjugation with uridine located in the wobble position of tRNALeu(UUR). Because the wobble modification stabilizes the UG base pairing, it facilitates the decoding of UUG codons. Consequently, taurine deficiency, which reduces the wobble modification, decreases the synthesis of proteins whose mRNA has a high UUG codon content. The synthesis of one such protein, ND6, plunges 60% after a 50% decline in taurine content. Because ND6 is a subunit of respiratory chain complex I, taurine depletion also leads to a decline in the activity of the electron transport chain. A similar sequence of events occurs in the mitochondrial disease, MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). The initial event in most MELAS patients is the appearance of one mutation in tRNALeu(UUR), which in turn blocks the taurinomethyl modification of the wobble nucleotide. As a result, the synthesis of ND6 and other UUG-dependent proteins falls. As respiratory function declines, the generation of ATP is compromised and in some cases the mitochondria begin to produce oxidants. Because mutations in tRNALeu(UUR) trigger multiple events, the identification of which event causes mitochondrial dysfunction has been challenging. The taurine-deficient model has aided in the identification of at least one pathological pathway that contributes to the development of the MELAS disorder.