Understanding the link between genotype to fitness has been a major challenge over the past decades. However, to fully understand how a genotype modulates fitness we need to investigate the intermediate steps that drive these phenotypic responses – physiology. Here I will explore how different genotypes across both sexes respond to metabolic changes (via nutrition) and the fitness consequences they elicit. I will then break down the level of the genotype to mitochondrial and nuclear DNA. I will present evidence on how mito-nuclear incompatibilities impact the intermediate metabolic phenotype, plus how these responses impact fitness and adaptive traits.