A Reverse-Osmosis Model of Apoptotic Shrinkage

Abstract

The standard theory of apoptotic volume decrease (AVD) posits activation of potassium and/or chloride channels, causing an efflux of ions and osmotic loss of water. However, in view of the multitude of possible channels that are known to support apoptosis, a model based on specific signaling to a channel presents certain problems. We propose another mechanism of apoptotic dehydration based on cytoskeletal compression. As is well known, cytoskeleton is not strong enough to expel a substantial amount of water against an osmotic gradient. It is possible, however, that an increase in intracellular pressure may cause an initial small efflux of water, and that will create a small concentration gradient of ions, favoring their exit. If the channels are open, some ions will exit the cell, relieving the osmotic gradient; in this way, the process will be able to continue. Calculations confirm the possibility of such a mechanism. An increase in membrane permeability for water or ions may also result in dehydration if accompanied even by a constant cytoskeletal pressure. We review the molecular processes that may lead to apoptotic dehydration in the context of this model.

Keywords: apoptotic volume decrease; cytoskeletal contraction; cytoskeleton; intracellular pressure; osmolytes; potassium channels.

FIGURE 1

A bright-field transmission image of HeLa cells treated with actinomycin D. Two apoptotic and apparently dehydrated HeLa cells indicated by the arrows have much darker borders. However, this feature alone can only serve as a suggestion, but not as a definitive proof of dehydration. Water content can be accurately quantified under a transmission microscope as described by Mudrak et al. (2018).

FIGURE 2

Uniform pulling on the membrane (either by the radial component of cortical tension or by non-cortical fibers oriented perpendicular to the membrane) produces IP that would slowly push water and ions out of the cell. When gaps in the cytoskeleton-membrane linkages are present, water is squeezed out into the bleb instead.