Decreased aminoacylation of mutant tRNAs in MELAS but not in MERRF patients

Mutations in human mitochondrial tRNA genes are associated with a number of multisystemic disorders. Using an assay that combines tRNA oxidation and c ircularization we have determined the relative amounts and states of aminoa cylation of mutant and wild-type tRNAs in tissue samples from patients with MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, s troke-like episodes) and MERRF syndrome (myoclonus epilepsy with ragged red fibers), respectively. In most, but not all, biopsies from MELAS patients carrying the A3243G substitution in the mitochondrial tRNA(Leu(UUR)) gene, the mutant tRNA is under-represented among processed and/or aminoacylated t RNAs, In contrast, in biopsies from MERRF patients harboring the A8344G sub stitution in the tRNA(Lys) gene neither the relative abundance nor the amin oacylation of the mutated tRNA is affected. Thus, whereas the A3243G mutati on may contribute to the pathogenesis of MELAS by reducing the amount of am inoacylated tRNA(Leu), the A8344G mutation does not affect tRNA(Lys) functi on in the same way.