An Incompatibility between a Mitochondrial tRNA and Its Nuclear-Encoded tRNA Synthetase Compromises Development and Fitness in Drosophila

Abstract

Mitochondrial transcription, translation, and respiration require interactions between genes encoded in two distinct genomes, generating the potential for mutations in nuclear and mitochondrial genomes to interact epistatically and cause incompatibilities that decrease fitness. Mitochondrial-nuclear epistasis for fitness has been documented within and between populations and species of diverse taxa, but rarely has the genetic or mechanistic basis of these mitochondrial–nuclear interactions been elucidated, limiting our understanding of which genes harbor variants causing mitochondrial–nuclear disruption and of the pathways and processes that are impacted by mitochondrial–nuclear coevolution. Here we identify an amino acid polymorphism in the Drosophila melanogaster nuclear-encoded mitochondrial tyrosyl–tRNA synthetase that interacts epistatically with a polymorphism in the D. simulans mitochondrial-encoded tRNA^Tyr to significantly delay development, compromise bristle formation, and decrease fecundity. The incompatible genotype specifically decreases the activities of oxidative phosphorylation complexes I, III, and IV that contain mitochondrial-encoded subunits. Combined with the identity of the interacting alleles, this pattern indicates that mitochondrial protein translation is affected by this interaction. Our findings suggest that interactions between mitochondrial tRNAs and their nuclear-encoded tRNA synthetases may be targets of compensatory molecular evolution. Human mitochondrial diseases are often genetically complex and variable in penetrance, and the mitochondrial–nuclear interaction we document provides a plausible mechanism to explain this complexity. The ancient symbiosis between two prokaryotes that gave rise to the eukaryotic cell has required genomic cooperation for at least a billion years. Eukaryotic cells respire through the coordinated expression of their nuclear and mitochondrial genomes, both of which encode the proteins and RNAs required for mitochondrial transcription, translation, and aerobic respiration. Genetic interactions between these genomes are hypothesized to influence the effects of mitochondrial mutations on disease and drive mitochondrial–nuclear coevolution. Here we characterize the molecular cause and the cellular and organismal consequences of a mitochondrial–nuclear interaction in Drosophila between naturally occurring mutations in a mitochondrial tRNA and a nuclear-encoded tRNA synthetase. These mutations have little effect on their own; but, when combined, they severely compromise development and reproduction. tRNA synthetases attach the appropriate amino acid onto their cognate tRNA, and this reaction is required for efficient and accurate protein synthesis. We show that disruption of this interaction compromises mitochondrial function, providing hypotheses for the variable penetrance of diseases associated with mitochondrial tRNAs and for which pathways and processes are likely to be affected by mitochondrial–nuclear interactions.