Rose, Michael R.; (1993) Mitochondrial gene translation products in the mitochondrial myopathies. Doctoral thesis (M.D.), UCL (University College London).

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Abstract

The mitochondrial myopathies are associated with an expanding list of mitochondrial DNA (mtDNA) abnormalities including point mutations, single and multiple deletions, tandem duplications, and generalised depletion of the genome. The existence of further mtDNA defects seems likely, but their detection relies either on the fortuitous loss or gain of an endonuclease restriction site, the loss of sufficient base pairs to cause a detectable size shift, or the sequencing of the genome. The correlation between these defects and the biochemical or clinical phenotype is obscure. Investigation of the mitochondrial translation products, either in vitro or in culture, in patients with these diseases, aimed to address both these issues. An in vitro micro-technique for radiolabelling mitochondrially synthesised proteins was established. In 2 out of 5 cases with mtDNA deletions there was evidence for complementation for missing tRNAs. The possibility of complementation in the remaining cases was not excluded. No novel proteins correlating with translation of fusion genes were detected. Two cases with point mutations of tRNAleu(UUR) had mitochondrial protein synthesis rates and polypeptide profiles comparable with that seen in controls, refuting the suggestion that such mutations might alter the ratio of ribosomal to messenger RNA transcription. Of five cases with no detectable mtDNA mutation, one had a abnormality of mtDNA expression correlating with the biochemical defect and consistent with a defect in either a ribosomal or transfer RNA gene. Morphological, biochemical and genetic criteria for characterising the cultures were assessed. Myotubule cultures established from patients with mitochondrial myopathy associated with a heteroplasmic mtDNA deletion were found to loose the mutant mtDNA genomes within a few cell passages. Clonal myotube cultures showed differing proportions of wild type to mutant type mtDNA genomes in the different clones, which was maintained through a large number of cell divisions. The profile of mitochondrial translation products in the uncloned cultures did not differ from that obtained in controls.

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