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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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    Fig. 1.

    Effects of the epistatic interaction on scutellar bristle length. The transgenic rescue strains pair the simw501 mtDNA with three alternative nuclear Aatm alleles: AatmOre, AatmAut or AatmOre_V275A. The sibling control strains are generated from the same cross (supplementary material Fig. S1). (A) Scutellar bristle length of transgenic rescue strains (mean±s.d., n=15, F2,42=79.48, ***PANOVA<5e-15). The incompatible interaction shortens scutellar bristle length. (B) Bristle length measured in transgenic control sibling strains does not differ (mean±s.d., n=15, F2,42=0.285, PANOVA=0.75).

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    Fig. 2.

    The mito-nuclear incompatibility alters flight and climbing ability. (A) Flight distributions of mito-nuclear introgression strains. The distribution of (simw501); OreR is downshifted and displays the lowest average flight score. (simw501); Aut and (ore); Aut distributions do not differ significantly (PWilcox=0.33). All other comparisons between genotypes are significantly different (pairwise contrasts in supplementary material Table S4). (B) Flight distributions of transgenic rescue strains. (simw501); AatmOre displays the lowest distribution of height scores. The distribution of (simw501); AatmOre differs significantly from (simw501); AatmAut and (simw501); AatmOre_V275A (pairwise contrasts in supplementary material Table S4). The distributions of (simw501); AatmAut and (simw501); AatmOre_V275A do not differ (PWilcox>0.7). (C) Climbing profile of mito-nuclear introgression strains. (simw501); OreR and (ore); OreR distributions do not differ significantly (PWilcox>0.1). All other comparisons between genotypes are significantly different (pairwise contrasts in supplementary material Table S4). (D) Climbing profile of transgenic rescue strains. The distribution of (simw501); AatmOre differs significantly from (simw501); AatmAut and (simw501); AatmOre_V275A (pairwise contrasts in supplementary material Table S4). The distributions of (simw501); AatmAut and (simw501); AatmOre_V275A are marginally different (PWilcox=0.04). All P-values associated with Wilcoxon tests are Bonferroni-corrected to account for multiple testing. Different letters signify significant differences in pairwise contrasts.

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    Fig. 3.

    Characterization of mitochondrial morphology in the mito-nuclear introgression strains. TEMs of indirect flight muscle reveal structural abnormalities in (simw501); OreR. (A-D) (simw501); OreR display a loose cristae structure and matrix gaps. (simw501); OreR contained the most mitochondria per unit area, and several examples of swirled concentric cristae structures were observed (A,D). (E,F) (ore); OreR displayed some loose cristae structure and matrix gaps, and on average contained the largest mitochondria. (G-J) (simw501); Aut and (ore); Aut displayed tight cristae packing and healthy mitochondrial morphology. (K) Quantification of mitochondrial morphology parameters in mito-nuclear introgression strains. Approximately 100 mitochondria per genotype were analyzed to generate size data. Different superscript letters signify significant differences in pairwise comparisons (values for PTukey pairwise contrasts are displayed in supplementary material Table S5). Mitochondria were counted in 50 μm×50 μm sections to generate density data. The average number of mitochondria per unit area of >3 sections are displayed. Scale bars: 2 μm (A,B,E-G,I); 500 nm (C,D,H,J).

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    Fig. 4.

    Characterization of mitochondrial morphology in the transgenic rescue strains. The incompatible mito-nuclear pair results in mitochondrial morphological defects. (A-D) Large matrix holes and unidentified inclusions were observed in (simw501); AatmOre. On average (simw501); AatmOre contains the smallest mitochondria, but the most per unit area. (E,F) (simw501); AatmAut displays some matrix holes, but maintains a relatively low ratio of empty matrix space to mitochondrial area. (G,H) The transgenic rescue genotype (simw501); AatmOre_V275A displays a healthy cristae structure and normal mitochondrial morphology. (I) Quantification of mitochondrial morphology parameters in transgenic rescue strains. Approximately 100 mitochondria per genotype were analyzed to generate size data. Different letters signify significant differences in pairwise comparisons (values for PTukey pairwise contrasts are displayed in supplementary material Table S5). Mitochondria were counted in 50 μm×50 μm sections to generate density data. The average number of mitochondria per unit area of >3 sections are displayed. Scale bars: 2 μm (A,C,E,G); 500 nm (B,D,F,H).

  • Table 1.
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    Fig. 5.

    OXPHOS enzyme abundance and activity is reduced in mitochondrially translated complexes containing the most tyrosines. BN-PAGE analysis of mitochondrial protein isolates. (A) Example of BN-PAGE gel for transgenic rescue strains (note: full lanes moved from original gel locations for genotype consistency, no manipulations within lanes). Quantification of individual band intensity corresponding to Complex I, III and V relative to BSA. Across all complexes (simw501); AatmOre displayed reduced protein levels to varied degrees (individual contrasts in supplementary material Table S7). (B) Enzymatic activity of OXPHOS complexes. (simw501); AatmOre has significantly reduced activity of Complex I compared to (simw501); AatmAut and (simw501); AatmOre_V275A (PTukey=3.18e-5 and PTukey<0.05, respectively). The (simw501); AatmOre_V275A rescue strain has marginally lower Complex I activity compared with (simw501); AatmAut (PTukey<0.05). Complex II and Complex III activity does not differ between the rescue strains (PANOVA>0.8, each complex). Complex IV activity is reduced by the incompatibility in (simw501); AatmOre (PANOVA<0.01). There is no difference in citrate synthase among the rescue genotypes (PANOVA=0.7). The complexes with more mitochondrially encoded tyrosines display the most severe defect (Complexes I and IV). Enzymes that are completely nuclearly encoded (Complex II and citrate synthase) or those with few mitochondrially encoded tyrosines (Complex III) show little disruption of enzyme capacity. *P<0.05; **P<0.01; ***P<0.001.

  • Fig. 6.
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    Fig. 6.

    Mitochondrial translation is upregulated by the mito-nuclear incompatibility. Quantification of de novo translation as assessed by 35S-methionine incorporation into newly synthesized proteins, normalized to total mitochondrial protein. (A) 35S-methionine incorporation in introgression strains. (simw501); OreR displays a mild increase compared to (ore); OreR, and no significant difference is seen between (simw501); OreR compared to either (simw501); Aut or (ore); Aut. (B) 35S-methionine incorporation is significantly increased in (simw501); AatmOre compared to the other transgenic rescue strains (PTukey<4e-6 for both comparisons). DPM, disintegrations per minute. **P<0.01; ***P<0.001.

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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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