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Nat Commun. 2016 Nov 14;7:13100. doi: 10.1038/ncomms13100.

Selective removal of deletion-bearing mitochondrial DNA in heteroplasmic Drosophila.

Author information

1
Division of Biology and Biological Engineering, California Institute of Technology, Mail Code 156-29, 1200 E. California blvd., Pasadena, California 91125, USA.
2
Department of Neurology, Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA.
3
Department of Molecular and Medical Pharmacology, Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA.

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 mtDNAΔ 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.

PMID:
27841259
PMCID:
PMC5114534
DOI:
10.1038/ncomms13100
[Indexed for MEDLINE]
Free PMC Article

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