Genetic variation for ontogenetic shifts in metabolism underlies physiological homeostasis in Drosophila

Organismal physiology emerges from metabolic pathways and subcellular structures like the mitochondria that can vary across development and among individuals. Here, we tested whether genetic variation at one level of physiology can be buffered at higher levels of biological organization during development by the inherent capacity for homeostasis in physiological systems. We found that the fundamental scaling relationship between mass and metabolic rate, as well as the oxidative capacity per mitochondria, changed significantly across development in the fruit fly Drosophila. However, mitochondrial respiration rate was maintained at similar levels across development. Furthermore, larvae clustered into two types—those that switched to aerobic, mitochondrial ATP production before the second instar, and those that relied on anaerobic, glycolytic production of ATP through the second instar. Despite genetic variation for the timing of this metabolic shift, metabolic rate in second-instar larvae was more robust to genetic variation than was the metabolic rate of other instars. We found that larvae with a mitochondrial-nuclear incompatibility that disrupts mitochondrial function had increased aerobic capacity and relied more on anaerobic ATP production throughout development relative to larvae from wild-type strains. By taking advantage of both ways of making ATP, larvae with this mitochondrial–nuclear incompatibility maintained mitochondrial respiratory capacity, but also had higher levels of whole-body reactive oxygen species and decreased mitochondrial membrane potential, potentially as a physiological defense mechanism. Thus, genetic defects in core physiology can be buffered at the organismal level via physiological plasticity, and natural populations may harbor genetic variation for distinct metabolic strategies in development that generate similar organismal outcomes.