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Selective removal of deletion-bearing mitochondrial DNA in heteroplasmic Drosophila

Kandul, Nikolay P. and Zhang, Ting and Hay, Bruce A. and Guo, Ming (2016) Selective removal of deletion-bearing mitochondrial DNA in heteroplasmic Drosophila. Nature Communications, 7 . Art. No. 13100. ISSN 2041-1723. PMCID PMC5114534. http://resolver.caltech.edu/CaltechAUTHORS:20161118-192406651

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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 (mtDNA^Δ) in adult Drosophila muscle. Stimulation of autophagy, activation of the PINK1/parkin pathway or decreased levels of mitofusin result in a selective decrease in mtDNA^Δ. Decreased levels of mitofusin and increased levels of ATPIF1, an inhibitor of ATP synthase reversal-dependent mitochondrial repolarization, result in a further decrease in mtDNA^Δ 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.


Item Type:Article
Related URLs:
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http://dx.doi.org/10.1038/ncomms13100DOIArticle
http://www.nature.com/articles/ncomms13100PublisherArticle
http://www.ncbi.nlm.nih.gov/nuccore/?term=http://www.ncbi.nlm.nih.gov/nuccore/?term=KX696451Organizationsequence of plasmid used to generate mitoAflIII flies
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5114534/PubMed CentralArticle
Additional Information:© 2016 Macmillan Publishers Limited. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ Received: 21 June 2016. Accepted: 01 September 2016. Published online: 14 November 2016. This work was supported by an Alcott Postdoctoral Fellowship (N.P.K.), the Ellison Medical Foundation Senior Scholar Award (M.G. and B.A.H.) and awards to M.G. from the National Institute of Health (NIA R01 and NINDS EUREKA award), the Kenneth Glenn Family Foundation, and the Natalie R. and Eugene S. Jones Fund in Aging and Neurodegenerative Disease Research. We are grateful to Thomas Neufeld for providing fly strains used in this study, and to David J. Anderson and the Milliard and Muriel Jacobs Genetics and Genomics laboratory at Caltech for technical assistance. Author Contributions: B.A.H., N.P.K. and M.G. conceived of the project. N.P.K. carried out all experiments except for characterization of muscle histology and EM ultrastructure, which was carried out by T.Z. All authors contributed to the writing of the manuscript. The authors declare no competing financial interests.
Funders:
Funding AgencyGrant Number
Alcott Postdoctoral fellowshipUNSPECIFIED
Ellison Medical FoundationUNSPECIFIED
NIHUNSPECIFIED
Kenneth Glenn Family FoundationUNSPECIFIED
Natalie R. and Eugene S. Jones Fund in Aging and Neurodegenerative Disease ResearchUNSPECIFIED
PubMed Central ID:PMC5114534
Record Number:CaltechAUTHORS:20161118-192406651
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20161118-192406651
Official Citation:Kandul, N. P. et al. Selective removal of deletion-bearing mitochondrial DNA in heteroplasmic Drosophila. Nat. Commun. 7, 13100 doi: 10.1038/ncomms13100 (2016).
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:72178
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:19 Nov 2016 03:33
Last Modified:18 Jul 2017 21:00

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