Membrane potential mediates the cellular response to mechanical pressure

Mechanical forces have been shown to influence cellular decisions to grow, die, or differentiate, through largely mysterious mechanisms. Separately, changes in resting membrane potential have been observed in development, differentiation, regeneration, and cancer. We now demonstrate that membrane potential is the central mediator of cellular response to mechanical pressure. We show that mechanical forces acting on the cell change cellular biomass density, which in turn alters membrane potential. These changes in membrane potential directly regulate growth by controlling signaling through the MAPK and Hippo pathways. By experimentally altering membrane potential, we show that membrane potential signaling regulates cell number density in epithelia by homeostatically controlling cell growth, proliferation, and cell elimination. This role of membrane potential in growth control may explain the frequent occurrence of mutations and aberrant expression of ion channels and transporters in cancer that result membrane potential depolarization.