Cell acidification in apoptosis

Abstract

Programmed cell death is a stereotyped and highly conserved process leading to deletion of unwanted cells. The process may be initiated in response to physiologic signals (Fas ligation, removal of extra-cellular matrix or growth factors), or pathologic events (DNA damage, hypoxia/reperfusion injury, viral infection). Some of the signal transduction pathways between a specific stimulus and the commitment to apoptosis are being worked out, although these may not represent general pathways for all triggers of apoptosis. In addition, the cell is able to integrate a variety of signals, some favoring apoptosis and some favoring survival, and to make a life-or-death decision. This has been termed the ‘judgment phase’, whereas once the cell is irreversibly committed to apoptosis, the ‘execution phase’ is initiated. The biochemical features of the ‘execution phase’ are still unclear; DNA cleavage probably represents one of the final events of the execution phase, but what about the multitude of proteases that participate in the process, phosphatidylserine externalization, transglutaminase activation, and, of course, the subject of this discussion, cytoplasmic acidification? Where do these events fit into the process, and what are the relationships of one to the other? This review will address the following points: (1) Is cytoplasmic acidification a universal feature of apoptosis, and is it essential? The reported cases examined to date will be evaluated. (2) How is cytoplasmic acidification accomplished? Is acidification sufficient for apoptosis to occur? (3) What are the consequences of acidification, particularly with respect to other biochemical features of apoptosis? (4) Finally, I would like to advance the hypothesis that acidification may represent the cellular mechanism for integration of multiple signals; cytoplasmic acidification could represent the point of no return on the road to apoptosis.