Mitochondrial DNA (mtDNA) often exists in a state of heteroplasmy, in which deleterious mutant mtDNA co-exists in cells along with wildtype mtDNA. Heteroplasmy for pathogenic mutations is common, and high frequencies of mutant mtDNA result in severe maternally inherited syndromes. Inherited and somatically acquired mutations also accumulate over time and contribute to a number of diseases of aging. Reducing heteroplasmy is therefore an important therapeutic goal. Intergenerational selection against mtDNA mutations occurs in germ cells, but whether it also acts in somatic non-diving cells is unclear. To address this question, and provide a system in which genes and drugs that increase mtDNA quality control can be identified, we created a transgene-based model of a lethal heteroplasmic mtDNA deletion (mtDNA∆) in a non-dividing somatic tissue, the Drosophila indirect flight muscle (IFM). A pulse of transcription driven by the Flightin promoter drives the expression of two transgenes, which together create mtDNA∆ directly in IFMs. Quantitative PCR (qPCR) and in situ target primed rolling circle amplification show that up to 75% of the total mtDNA in the IFM carries the deletion. High amounts of mtDNA∆ activate autophagy in the IFM. To determine if mtDNA quality control can be manipulated we overexpressed and knocked down genes in the mtDNA∆ background, and monitored changes in numbers of mtDNA∆ molecules. We found that increasing expression of genes involved in autophagy and PINK1/parkin pathway, and knocking down Mitofusin (Mfn) result in a decrease in mtDNA∆, but not wildtype mtDNA. Conversely, suppressing the autophagy pathway causes a further increase of mtDNA∆. The selective removal of mtDNA∆ by parkin overexpression is prevented in an autophagy mutant background. In summary, we have developed a system in which the fate of an mtDNA deletion can be monitored in vivo, in a tissue important for aging. We also provide evidence that levels of mutant mtDNA can be decreased through manipulation of autophagy/mitophagy, suggesting pharmacological approaches to inhibiting a major cause of age-related decline in cell function.