Lost in Translation: mitochondrial and nuclear incompatibility results in reduced longevity and increased oxidative stress resistance in Drosophila. Marissa A. Holmbeck, David M. Rand. Bio-Med, Brown University, Providence, RI.

   Communication between the mitochondrial and nuclear genomes is vital for cellular function and influences aging. Coordinated expression of both genomes is required for the function of jointly encoded respiratory enzymes that produce the majority of energy for the cell. We have developed a model in which mitochondrial and nuclear genomes can be jointly manipulated in Drosophila. mtDNA from different strains of Drosophila simulans (Dsim) and D. melanogaster (Dmel) have been introduced into controlled Dmel nuclear backgrounds. We previously found that a specific Dsim mtDNA, simw⁵⁰¹, shows a strong epistatic interaction with the OreR nuclear background resulting in a suite of compromised phenotypes including developmental delay and reduced mitochondrial function. Genetic mapping studies have identified a mutation in the nuclear encoded mitochondrial tyrosyl-tRNA synthetase, and a mutation in the mtDNA encoded tyrosine-tRNA as the source of this epistatic interaction (C.D. Meiklejohn et al. manuscript in review). Our working model is that this mito-nuclear interaction compromises translation within mitochondria. We have examined the effects of this epistasis on mortality: the simw⁵⁰¹; OreR (mito; nuclear) genotype reduces lifespan, but does not have elevated reactive oxygen species (ROS) levels. Interestingly, simw⁵⁰¹; OreR displays increased resistance to paraquat treatment. These phenotypes are not seen when the simw⁵⁰¹ mtDNA is placed on an Aut nuclear background. To confirm the source of this epistasis, a transgenic approach was used to generate rescue strains with alternative OreR and Aut nuclear alleles of the identified tyrosyl-tRNA synthetase inserted into the genome at the same location. The strain containing the transgenic OreR allele also displays reduced lifespan when paired with the simw⁵⁰¹ mtDNA in a matched genetic background, supporting the model of epistasis. This study provides insight into the joint genetic architecture that regulates mitochondrial function and aging and suggests that mitochondrial defects can reduce longevity without increasing ROS.