The mitonuclear genome is the most successful co-evolved mutualism in the history of life on Earth. The cross-talk between the mitochondrial and nuclear genomes has been shaped by conflict and cooperation for more than 1.5 billion years, yet this system has adapted to countless genomic reorganizations by each partner, and done so under changing environments that have placed dramatic biochemical and physiological pressures on evolving lineages. From putative anaerobic origins, mitochondria emerged as the defining aerobic organelle. During this transition, the two genomes resolved rules for sex determination and transmission that made uniparental inheritance the dominant, but not a universal pattern. Mitochondria are much more than energy-producing organelles and play crucial roles in nutrient and stress signalling that can alter how nuclear genes are expressed as phenotypes. All of these interactions are examples of genotype-by-environment (GxE) interactions, gene-by-gene (GxG) interactions (epistasis) or more generally context-dependent effects on the link between genotype and phenotype. We provide evidence from our own studies in Drosophila, and from those of other systems, that mitonuclear interactions-either conflicting or cooperative-are common features of GxE and GxG. We argue that mitonuclear interactions are an important model for how to better understand the pervasive context-dependent effects underlying the architecture of complex phenotypes. Future research in this area should focus on the quantitative genetic concept of effect size to place mitochondrial links to phenotype in a proper context. This article is part of the theme issue 'Linking the mitochondrial genotype to phenotype: a complex endeavour'.
Keywords: GxE; GxG; conflict; cooperation; epistasis; mitonuclear.