A Drosophila model for mito-nuclear diseases generated by an incompatible interaction between tRNA and tRNA synthetase

Dis Model Mech. 2015 Aug 1;8(8):843-54. doi: 10.1242/dmm.019323. Epub 2015 May 5.


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 simw(501) mtDNA-encoded transfer RNA (tRNA) for tyrosine (tRNA(Tyr)) 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 simw(501) 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 tRNA(Tyr) 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.

Keywords: Disease; Epistasis; Mitochondria.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acyl-tRNA Synthetases / metabolism*
  • Animal Structures / anatomy & histology
  • Animals
  • Animals, Genetically Modified
  • Cell Nucleus / metabolism*
  • Cell Respiration
  • Disease Models, Animal
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism*
  • Epistasis, Genetic
  • Flight, Animal
  • Genotype
  • Mitochondria, Muscle / ultrastructure
  • Mitochondrial Diseases / metabolism*
  • Motor Activity
  • Muscles / ultrastructure
  • Oxidative Phosphorylation
  • Peptide Chain Initiation, Translational
  • RNA, Transfer / metabolism*
  • Tyrosine / metabolism


  • Tyrosine
  • RNA, Transfer
  • Amino Acyl-tRNA Synthetases