MOLECULAR HISTOLOGY OF MITOCHONDRIAL AND NUCLEAR TRANSCRIPTS IN THE MUSCLE OF PATIENTS HARBORING A SINGLE MITOCHONDRIAL-DNA DELETION

The distribution of transcripts of mitochondrial and nuclear genes inv olved in oxidative phosphorylation and of the mitochondrial creatine k inase nuclear gene was examined, using in situ hybridisation, in the s keletal muscle of ii patients harbouring a heteroplasmic mitochondrial DNA (mtDNA) single deletion. Levels of mRNAs transcribed from genes l ocated within the deletions were not decreased, suggesting that the re maining wild-type mtDNA was still transcribed. Those muscle fibres wit h characteristic abnormal mitochondrial proliferation always showed ov erexpression of mRNAs and rRNAs transcribed from mitochondrial genes l ocated outside the deletions. Interestingly, they also showed overexpr ession of the nuclear-encoded ATP synthase beta subunit mRNA, but not of mitochondrial creatine kinase mRNA, These observations lead to thre e proposals: (1) overexpression of mitochondrial transcripts within fi bres harbouring mitochondrial proliferation, together with the apparen tly normal expression of the remaining wild-type mtDNA, is not related to decreased mitochondrial translation; (2) it is more probably relat ed to an up-regulation mechanism which co-ordinates both mitochondrial and nuclear expression; and (3) this mechanism is restricted to trans cripts directly involved in oxidative phosphorylation and to fibres wi th mitochondrial accumulation.