Diet’s impact dictated by synonymous mitochondrial SNP interacting with nucleotype

Epistasis between mitochondrial and nuclear genomes can modulate fitness effects of nutrition. Are these “mitonuclear” effects deterministic with regard to optimal nutrition? Which nutrients and genetic loci participate? Here, in fruitflies, we show that mitonuclear epistasis repeatably dictates fitness effects of dietary lipids and amino acids, with a tripartite interaction emerging as an unprecedented source of quantitative variation. We also observed diet-dependent developmental lethality and parental effects, but only in specific mitonucleotypes. Associating phenotype to mtDNA variation implicated a non-coding RNA (mt:lrRNA), suggesting a novel mechanism, with epistasis between mitochondria-derived regulatory factors and the nuclear genome producing qualitative differences in how diet impacts fitness.