Cellular allometry of mitochondrial functionality establishes the optimal cell size

Eukaryotic cells attempt to maintain an optimal size resulting in size homeostasis. While cellular content scales isometrically with cell size, allometric laws indicate that metabolism per mass unit should decline with increasing size. Here we use elutriation and single-cell flow cytometry to analyse mitochondrial scaling with cell size. While mitochondrial content increases monotonously, mitochondrial membrane potential and oxidative phosphorylation are highest at intermediate cell sizes. Thus mitochondrial content and functional scaling are uncoupled. The nonlinearity of mitochondrial functionality is cell size, not cell cycle, dependent and results in an optimal cell size where cellular fitness and proliferative capacity is maximised. While optimal cell size is controlled by growth factor signalling, its establishment and maintenance requires mitochondrial dynamics, which can be controlled by the mevalonate pathway. Thus, optimisation of cellular fitness and functionality through mitochondria can explain the requirement for size control, as well as provide means for its maintenance.