Molecular basis for treatment of mitochondrial myopathies

Mitochondrial DNA (mtDNA) is the only autonomously replicating source of DN A outside the nucleus. The mitochondrial genome encodes thirteen essential polypeptides of the mitochondrial respiratory chain. Defects of the mitocho ndrial genome can cause severe neurological and multi-systemic disorders. I n many patients there is a mixture of mutated and wild-type mtDNA in the sa me cell (a situation termed heteroplasmy). In these patients the ratio of m utated to wild-type mtDNA is crucial and a biochemical defect only occurs w ith relatively high levels of mutated mtDNA within an individual cell. This threshold also seems to be critical in the development of mtDNA disease. S ince the genetic defect causes a dysfunction in the terminal stage of oxida tive metabolism, there is little potential for pharmacological intervention . Molecular techniques must be developed to reverse the ratio of mutated an d wild-type mtDNA. In this paper we summarise our approach using both antig enomic peptide nucleic acids and cell necrosis.