title: Selective removal of deletion-bearing mitochondrial DNA in heteroplasmic Drosophila.
abstract: 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 in 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 (mtDNAΔ) in adult Drosophila muscle. Stimulation of autophagy, activation of the PINK1/parkin pathway or decreased levels of mitofusin result in a selective decrease in mtDNAΔ. Decreased levels of mitofusin and increased levels of ATPIF1, an inhibitor of ATP synthase reversal-dependent mitochondrial repolarization, result in a further decrease in mtDNAΔlevels. 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.
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Mail Code 156-29, 1200 E. California blvd., Pasadena, California 91125, USA.
authors.forename: Nikolay P
authors.initials: NP
authors.lastname: Kandul
authors.affiliation: Department of Neurology, Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA.|Department of Molecular and Medical Pharmacology, Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Mail Code 156-29, 1200 E. California blvd., Pasadena, California 91125, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Hay
authors.affiliation: Department of Neurology, Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA.|Department of Molecular and Medical Pharmacology, Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Guo
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001343:Autophagy / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D063154:Mitochondrial Dynamics / Q000235:genetics*; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000648:ultrastructure; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D000097795:ATPase Inhibitory Protein; D000099202:PTEN-Induced Putative Kinase
chemical_list: D004272:DNA, Mitochondrial; D029721:Drosophila Proteins; D025261:Mitochondrial Proton-Translocating ATPases; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D000097795:ATPase Inhibitory Protein; C534484:PINK1 protein, Drosophila; D000099202:PTEN-Induced Putative Kinase