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Research Article
Phenotypic rescue of a Drosophila model of mitochondrial ANT1 disease
Suvi Vartiainen, Shanjun Chen, Jack George, Tea Tuomela, Kaisa R. Luoto, Kevin M. C. O’Dell, Howard T. Jacobs
Disease Models & Mechanisms 2014 7: 635-648; doi: 10.1242/dmm.016527
Suvi Vartiainen
1BioMediTech and Tampere University Hospital, FI-33014 University of Tampere, Finland.
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Shanjun Chen
1BioMediTech and Tampere University Hospital, FI-33014 University of Tampere, Finland.
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Jack George
1BioMediTech and Tampere University Hospital, FI-33014 University of Tampere, Finland.
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Tea Tuomela
1BioMediTech and Tampere University Hospital, FI-33014 University of Tampere, Finland.
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Kaisa R. Luoto
1BioMediTech and Tampere University Hospital, FI-33014 University of Tampere, Finland.
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Kevin M. C. O’Dell
2Institute of Molecular, Cell and Systems Biology, University of Glasgow, Glasgow G12 8QQ, Scotland, UK.
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Howard T. Jacobs
1BioMediTech and Tampere University Hospital, FI-33014 University of Tampere, Finland.
3Research Program of Molecular Neurology, FI-00014 University of Helsinki, Finland.
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  • For correspondence: howard.t.jacobs@uta.fi
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Abstract

A point mutation in the Drosophila gene that codes for the major adult isoform of adenine nuclear translocase (ANT) represents a model for human diseases that are associated with ANT insufficiency [stress-sensitive B1 (sesB1)]. We characterized the organismal, bioenergetic and molecular phenotype of sesB1 flies then tested strategies to compensate the mutant phenotype. In addition to developmental delay and mechanical-stress-induced seizures, sesB1 flies have an impaired response to sound, defective male courtship, female sterility and curtailed lifespan. These phenotypes, excluding the latter two, are shared with the mitoribosomal protein S12 mutant, tko25t. Mitochondria from sesB1 adults showed a decreased respiratory control ratio and downregulation of cytochrome oxidase. sesB1 adults exhibited ATP depletion, lactate accumulation and changes in gene expression that were consistent with a metabolic shift towards glycolysis, characterized by activation of lactate dehydrogenase and anaplerotic pathways. Females also showed downregulation of many genes that are required for oogenesis, and their eggs, although fertilized, failed to develop to the larval stages. The sesB1 phenotypes of developmental delay and mechanical-stress-induced seizures were alleviated by an altered mitochondrial DNA background. Female sterility was substantially rescued by somatic expression of alternative oxidase (AOX) from the sea squirt Ciona intestinalis, whereas AOX did not alleviate developmental delay. Our findings illustrate the potential of different therapeutic strategies for ANT-linked diseases, based on alleviating metabolic stress.

Footnotes

  • Competing interests

    The authors declare no competing financial interests.

  • Author contributions

    H.T.J., S.V., S.C. and K.M.C.O’D. conceived and designed the experiments, which were performed by S.C., S.V., T.T., J.G. and K.L. All authors contributed to data analysis. H.T.J. compiled the figures and tables, and drafted the manuscript.

  • Funding

    This work was supported by Academy of Finland (FinMIT Centre of Excellence, Academy Professorship to H.T.J., Academy postdoctoral fellowship to S.V.); Sigrid Juselius Foundation; Tampere University Hospital Medical Research Fund; the European Research Council (Advanced Grant 2326738 to H.T.J.); and the EU Marie Curie Programme (IOF 255472 to S.V.).

  • Supplementary material

    Supplementary material available online at http://dmm.biologists.org/lookup/suppl/doi:10.1242/dmm.016527/-/DC1

  • Received April 10, 2014.
  • Accepted April 28, 2014.
  • © 2014. Published by The Company of Biologists Ltd

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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Keywords

  • Adenine nucleotide translocase
  • Mitochondrial disease
  • Mitochondrial biogenesis
  • Alternative oxidase

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Research Article
Phenotypic rescue of a Drosophila model of mitochondrial ANT1 disease
Suvi Vartiainen, Shanjun Chen, Jack George, Tea Tuomela, Kaisa R. Luoto, Kevin M. C. O’Dell, Howard T. Jacobs
Disease Models & Mechanisms 2014 7: 635-648; doi: 10.1242/dmm.016527
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Research Article
Phenotypic rescue of a Drosophila model of mitochondrial ANT1 disease
Suvi Vartiainen, Shanjun Chen, Jack George, Tea Tuomela, Kaisa R. Luoto, Kevin M. C. O’Dell, Howard T. Jacobs
Disease Models & Mechanisms 2014 7: 635-648; doi: 10.1242/dmm.016527

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