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

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 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.
AuthorsMarissa A Holmbeck, Julia R Donner, Eugenia Villa-Cuesta, David M Rand
JournalDisease models & mechanisms (Dis Model Mech) Vol. 8 Issue 8 Pg. 843-54 (Aug 01 2015) ISSN: 1754-8411 [Electronic] England
PMID26035388 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Copyright© 2015. Published by The Company of Biologists Ltd.
Chemical References
  • Tyrosine
  • RNA, Transfer
  • Amino Acyl-tRNA Synthetases
Topics
  • Amino Acyl-tRNA Synthetases (metabolism)
  • Animal Structures (anatomy & histology)
  • Animals
  • Animals, Genetically Modified
  • Cell Nucleus (metabolism)
  • Cell Respiration
  • Disease Models, Animal
  • Drosophila melanogaster (genetics, 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)

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