Mitonuclear interactions: Evolutionary consequences over multiple biological scales

Fundamental biological processes hinge on coordinated interactions between genes spanning two obligate genomes-mitochondrial and nuclear. These interactions are key to complex life, and allelic variation that accumulates and persists at the loci embroiled in such intergenomic interactions should therefore be subjected to intense selection to maintain integrity of the mitochondrial electron transport system. Here, we compile evidence that suggests that mitochondrial-nuclear (mitonuclear) allelic interactions are evolutionarily significant modulators of the expression of key health-related and life-history phenotypes, across several biological scales-within species (intraand interpopulational) and between species.We then introduce a new frontier for the study of mitonuclear interactions-those that occur within individuals, and are fuelled by the mtDNA heteroplasmy and the existence of nuclearencoded mitochondrial gene duplicates and isoforms. Empirical evidence supports the idea of high-resolution tissue- and environment-specific modulation of intraindividual mitonuclear interactions. Predicting the penetrance, severity and expression patterns of mtDNA-induced mitochondrial diseases remains a conundrum. We contend that a deeper understanding of the dynamics and ramifications of mitonuclear interactions, across all biological levels, will provide key insights that tangibly advance our understanding, not only of core evolutionary processes, but also of the complex genetics underlying human mitochondrial disease.