Possible causes of apoptotic volume decrease: an attempt at quantitative review.

Cell shrinkage and dehydration are essential characteristics of apoptosis, and loss of as much as half of the initial cell volume is not uncommon. This phenomenon is usually explained by efflux of K(+) and Cl(-). We reexamine this hypothesis on the basis of the available data for ion concentrations and the requirements for osmotic equilibrium and electroneutrality. In addition to ion loss, we discuss the possible impacts of several other processes: efflux of low-molecular-weight osmolytes, acidification of the cytosol, effects of water channels and pumps, heterogeneity of intracellular water, and dissociation of apoptotic bodies. We conclude that most mammalian cells are theoretically capable of reducing their volume by 15-20% through ion loss or a decrease in cytosolic pH, although, in reality, the contribution of these mechanisms to apoptotic shrinkage may be smaller. Transitions between osmotically active and inactive water pools might influence cell volume as well; these mechanisms are poorly understood but are amenable to experimental study. Dissociation of apoptotic bodies is a separate mechanism of volume reduction and should be monitored closely; this can be best achieved by measurement of intracellular water, rather than cell volume.