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
D
rosophila
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
D
rosophila
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.
Summary:
Interacting mutations in a mitochondrially encoded tRNA and nuclear-encoded tRNA synthetase result in a suite of pathologies, including altered locomotor capacity, mitochondrial function and morphology, and mitochondrial translation.