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RESEARCH ARTICLE
A Drosophila model for mito-nuclear diseases generated by an incompatible interaction between tRNA and tRNA synthetase
Marissa A. Holmbeck, Julia R. Donner, Eugenia Villa-Cuesta, David M. Rand
Disease Models & Mechanisms 2015 8: 843-854; doi: 10.1242/dmm.019323
Marissa A. Holmbeck
1Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912, USA
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Julia R. Donner
2Department of Ecology and Evolutionary Biology, Brown University, Providence, RI 02912, USA
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Eugenia Villa-Cuesta
3Department of Biology, Adelphi University, Garden City, NY 11530, USA
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David M. Rand
2Department of Ecology and Evolutionary Biology, Brown University, Providence, RI 02912, USA
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  • For correspondence: David_Rand@Brown.edu
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ABSTRACT

Communication between the mitochondrial and nuclear genomes is vital for cellular function. The assembly of mitochondrial enzyme complexes, which produce the majority of cellular energy, requires the coordinated expression and translation of both mitochondrially and nuclear-encoded proteins. The joint genetic architecture of this system complicates the basis of mitochondrial diseases, and mutations both in mitochondrial DNA (mtDNA)- and nuclear-encoded genes have been implicated in mitochondrial dysfunction. Previously, in a set of mitochondrial-nuclear introgression strains, we characterized a dual genome epistasis in which a naturally occurring mutation in the Drosophila simulans simw501 mtDNA-encoded transfer RNA (tRNA) for tyrosine (tRNATyr) interacts with a mutation in the nuclear-encoded mitochondrially localized tyrosyl-tRNA synthetase from Drosophila melanogaster. Here, we show that the incompatible mitochondrial-nuclear combination results in locomotor defects, reduced mitochondrial respiratory capacity, decreased oxidative phosphorylation (OXPHOS) enzyme activity and severe alterations in mitochondrial morphology. Transgenic rescue strains containing nuclear variants of the tyrosyl-tRNA synthetase are sufficient to rescue many of the deleterious phenotypes identified when paired with the simw501 mtDNA. However, the severity of this defective mito-nuclear interaction varies across traits and genetic backgrounds, suggesting that the impact of mitochondrial dysfunction might be tissue specific. Because mutations in mitochondrial tRNATyr are associated with exercise intolerance in humans, this mitochondrial-nuclear introgression model in Drosophila provides a means to dissect the molecular basis of these, and other, mitochondrial diseases that are a consequence of the joint genetic architecture of mitochondrial function.

Footnotes

  • Competing interests

    The authors declare no competing or financial interests.

  • Author contributions

    M.A.H. and D.M.R. designed the experiments and wrote the manuscript. M.A.H. and J.R.D. performed the experiments. E.V.-C. optimized methods and provided experimental feedback. M.A.H. analyzed the data prepared the figures.

  • Funding

    This work was supported by grants 1F31AG040925-02 awarded to M.A.H., grant R15GM113156 from NIGMS awarded to E.V.-C., and grant R01GM067862 from NIGMS and grant R01AG027849 from NIA awarded to D.M.R.

  • Supplementary material

    Supplementary material available online at http://dmm.biologists.org/lookup/suppl/doi:10.1242/dmm.019323/-/DC1

  • Received December 2, 2014.
  • Accepted April 23, 2015.
  • © 2015. 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

  • Disease
  • Epistasis
  • Mitochondria

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RESEARCH ARTICLE
A Drosophila model for mito-nuclear diseases generated by an incompatible interaction between tRNA and tRNA synthetase
Marissa A. Holmbeck, Julia R. Donner, Eugenia Villa-Cuesta, David M. Rand
Disease Models & Mechanisms 2015 8: 843-854; doi: 10.1242/dmm.019323
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RESEARCH ARTICLE
A Drosophila model for mito-nuclear diseases generated by an incompatible interaction between tRNA and tRNA synthetase
Marissa A. Holmbeck, Julia R. Donner, Eugenia Villa-Cuesta, David M. Rand
Disease Models & Mechanisms 2015 8: 843-854; doi: 10.1242/dmm.019323

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