Saccharomyces cerevisiae is often applied in large-scale bioreactors where gradients of dissolved CO2 exist. Under high CO2 pressure, the dissolved gas enters the microbe, causing multifold intracellular responses such as decrease of pH, increase of HCO3−, and changes of ion balance. Effects of varying CO2 concentrations are multifold, hard to scale and hardly investigated. Hence, the multi-level response to CO2-shifts was summarized in a predicting ODE model with mass action kinetics, balancing electrochemical charges in steady-state growth conditions. Compared to experimental observations the simulated dynamics of ion concentrations were found to be consistent. During CO2-shifts, the model predicts the initial depolarization of the membrane potential, the temporal pH drop and the activation of countermeasures such as Pma1-mediated H+ export and Trk1,2-mediated K+ import. In conclusion, extracellular cation concentrations and the cellular pH regulation are critical factors that determine physiology and cellular energy management. Consequently, pressure-induced CO2-gradients cause peaks of ATP demand which may occur in cells circulating in large-scale industrial bioreactors.