Mutations in PINK1 and parkin lead to autosomal recessive forms of Parkinson’s disease. We showed that PINK1 and parkin function in a common pathway to regulate mitochondrial integrity and quality. This is accomplished in part through parkin-mediated degradation of Mitofusin, a protein that controls fusion. Overexpression of Mitofusin in Drosophila phenocopies cellular defects due to lack of PINK1 or parkin in Drosophila. Downregulation of mitofusin reverses phenotypes due to lack of PINK1 or parkin. Over the years, we have identified several suppressors of PINK1 and parkin null mutations, including Drp1, MUL1/MULAN/MAPL and VCP/p97. They also play conservative roles in mammalian cells and mice. Mutations in VCP/p97 lead to autosomal dominant disease called inclusion body myopathy, Paget’s disease and frontotemporal dementia (IBMPFD) and sporadic ALS. We have found that VCP disease mutations lead to disease through overactivation of VCP/p97, leading to excessive degradation of Mitofusin. Importantly, treatments of both Drosophila models and human patient fibroblasts with two different VCP/p97 inhibitors revert the pathology in these models. Therefore, VCP/p97 inhibition is an effective therapeutic strategy for IBMPFD. 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; somatically acquired mutations also accumulate over time and contribute to diseases of ageing that include neurodegeneration, metabolic disorders, cancer, heart disease and sarcopenia. Reducing heteroplasmy is therefore a therapeutic goal and in vivo models in post-mitotic tissues are needed to facilitate these studies. We have developed a transgene-based model of a heteroplasmic lethal mtDNA deletion in adult Drosophila post-mitotic tissue muscle. Stimulation of autophagy, activation of the PINK1/parkin pathway among others results in a selective decrease in mtDNA deletion (up to 95%). 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.