Molecular histology of mitochondrial and nuclear transcripts in the muscle of patients harbouring a single mitochondrial DNA deletion.

ABSTRACT

The distribution of transcripts of mitochondrial and nuclear genes involved in oxidative phosphorylation and of the mitochondrial creatine kinase nuclear gene was examined, using in situ hybridisation, in the skeletal muscle of 11 patients harbouring a heteroplasmic mitochondrial DNA (mtDNA) single deletion. Levels of mRNAs transcribed from genes located within the deletions were not decreased, suggesting that the remaining wild-type mtDNA was still transcribed. Those muscle fibres with characteristic abnormal mitochondrial proliferation always showed overexpression of mRNAs and rRNAs transcribed from mitochondrial genes located outside the deletions. Interestingly, they also showed overexpression of the nuclear-encoded ATP synthase beta subunit mRNA, but not of mitochondrial creatine kinase mRNA. These observations lead to three proposals (1) overexpression of mitochondrial transcripts within fibres harbouring mitochondrial proliferation, together with the apparently normal expression of the remaining wild-type mtDNA, is not related to decreased mitochondrial translation; (2) it is more probably related to an up-regulation mechanism which co-ordinates both mitochondrial and nuclear expression; and (3) this mechanism is restricted to transcripts directly involved in oxidative phosphorylation and to fibres with mitochondrial accumulation.