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

Abstract

Model MA. Possible causes of apoptotic volume decrease: an attempt at quantitative review. Am J Physiol Cell Physiol 306: C417-C424, 2014. First published November 6, 2013; doi:10.1152/ajpcell.00328.2013.-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 ϩ and Cl Ϫ . 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. cell volume regulation; apoptosis; apoptotic volume decrease; intracellular water CELL SHRINKAGE is one the most reproducible signs of apoptosis (33,103). It has at least three distinct aspects: 1) weakening of the substrate attachment, resulting in cell rounding and reduced spreading, 2) dissociation of cell fragments known as apoptotic bodies, and 3) loss of intracellular water. Apoptotic body formation and the loss of water bring about a decrease in total cell volume. Volume changes in apoptotic cells have been measured by various techniques, and shrinkage by as much as 40 -85% has been reported (11,16,34,53,76,90). Shrinkage due to dehydration has received the most attention in the literature and is sometimes referred to as "apoptotic volume decrease" (AVD).The place of AVD in the sequence of apoptotic events and its significance for the rest of apoptosis have been addressed in numerous research papers and reviews (46,70,71,92,94). Apparently, AVD can be an early (5,8,15,28,34,49,53,81) or a late (26,60,85,90,117) response, depending on the particular system. A few exceptions to the rule that AVD must accompany apoptosis have also been described (11,13,56,65,121,127); nevertheless, it appears that, in the vast majority of apoptotic models, AVD does occur sooner or later.It has been hypothesized that the main purpose of AVD is to facilitate detachment of apoptotic bodies (91) or to oppose cell swelling and rupture that might develop otherwise (128). Although the definitive answer to this question is lacking, there can be little doubt that such a highly conserved property...

How Cells Can Control Their Size by Pumping Ions

“…The estimates are of course only as good as the intracellular concentration estimates, which as yet are difficult to obtain, absent sensitive and accurate monovalent ion sensors. Estimates of z have been made for muscle and some cell lines and ranges between −2 and −0.7 (Burton, 1983a; Model, 2014). Both x and z are unlikely to be fixed and will vary as impermeant molecules are metabolized or transported and as the pH changes.…”

Channels and Volume Changes in the Life and Death of the Cell

“…In contrast, evidence regarding organic osmolyte contribution to volume decrease during apoptosis is rather scarce (Wehner et al, 2003). However, the importance of organic osmolytes was emphasized in the quantitative analysis made by Model (2014), which demonstrated that the loss of organic molecules is necessary to account for the Channels and Cell Volume osmotically obligated water exit in AVD. Taurine cell loss is documented in apoptosis in Jurkat lymphocytes (Lang et al, 1998) and in cerebellar granule neurons (Morán et al, 2000).…”

DIDS Reduces Ischemia/Reperfusion-Induced Myocardial Injury in Rats

“…For example, early cell shrinkage or apoptotic volume decrease (AVD), a marked morphological characteristic of apoptosis [12,13,14], is accompanied with activation of potassium channels, chloride channels and H 2 O outflow [14,15]. Activation of anion channels such as chloride currents has been depicted to play a role in the regulation of cell volume, migration, proliferation, and apoptosis in various types of cells [14,16,17,18,19]. Findings from our group revealed that chloride channels participated in apoptosis while chloride channel blockade alleviated staurosporine-induced apoptosis in cardiomyocytes [20,21,22,23,24].…”