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Mitochondrial DNA (mtDNA) often exists in a state of heteroplasmy, in which mutant mtDNA co-exists in cells with wild-type mtDNA. High frequencies of pathogenic mtDNA result in maternally inherited diseases; maternally and somatically acquired mutations also accumulate over time and contribute to diseases of ageing. Reducing heteroplasmy is therefore a therapeutic goal and i n vivo  models in post-mitotic tissues are needed to facilitate these studies. Here we describe a transgene-based model of a heteroplasmic lethal mtDNA deletion (mtDNA Δ ) in adult  Drosophila  muscle. Stimulation of autophagy, activation of the  PINK1/parkin  pathway or decreased levels of  mitofusin  result in a selective decrease in mtDNA Δ . Decreased levels of  mitofusin  and increased levels of ATPIF1, an inhibitor of ATP synthase reversal-dependent mitochondrial repolarization, result in a further decrease in mtDNA Δ  levels. These results show that an adult post-mitotic tissue can be cleansed of a deleterious genome, suggesting that therapeutic removal of mutant mtDNA can be achieved.

Selective removal of deletion-bearing mitochondrial DNA in heteroplasmic Drosophila