IMPAIRED MITOCHONDRIAL TRANSLATION IN HUMAN MYOBLASTS HARBORING THE MITOCHONDRIAL-DNA TRANSFER-RNA LYSINE-8344 A-]G (MERRF) MUTATION - RELATIONSHIP TO PROPORTION OF MUTANT MITOCHONDRIAL-DNA

The mitochondrial DNA transfer RNA lysine A8344G mutation is commonly associated with the MERRF (myoclonus epilepsy with ragged red fibre) phenotype. The molecular pathogenesis of disease associated with this mutation is unclear. Theoretically, a mitochondrial tRNA mutation might affect transcription or translation, or both. We therefore studied these processes in cloned primary human myoblast cultures containing different proportions of mutant mtDNA. No abnormality of transcription was observed. However, there was a progressive decrease in mitochondrially encoded protein synthesis as the proportion of mutant mtDNA increased. Furthermore, there was evidence that subunits were differentially affected, based on selective reduction of cytochrome c oxidase subunits with relatively low proportions of mutant mtDNA.