Selective removal of deletion-bearing mitochondrial DNA in heteroplasmic Drosophila

Nikolay P. Kandul, Ting Zhang, Bruce A. Hay () and Ming Guo ()
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Nikolay P. Kandul: California Institute of Technology
Ting Zhang: Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles
Bruce A. Hay: California Institute of Technology
Ming Guo: Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13100

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