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.