Intracellular pH links energy metabolism to lymphocyte death and proliferation

Abstract

Many biological processes are controlled by cell death and proliferation. Previous evidence suggests that cell proliferation and death by apoptosis are regulated by separate pathways. The present study found that cellular pH was positively correlated with proliferation but negatively with apoptosis. Alkaline treatments enhanced lymphocyte proliferation in response to antigen challenge in vivo and in in vitro cultures, whereas acid treatments induced apoptosis. Low pH was incompatible with the survival of highly proliferating cells, and the susceptibility to the acid-induced death was determined in part by the proliferative status of the lymphocytes. Likewise, alkaline treatments maintained tumor cell proliferation whereas acid treatments induced apoptosis. These data support a unified theory for the regulation of apoptosis and proliferation where a cellular pH balance controls both events, and the mitochondria as proton generators act as pH-stats. Thus, the Warburg effect is viewed as necessary for proliferating cells to have a high cellular pH environment to both survive and accelerate proliferation.

Characterization of the Intracellular Acidity Regulation of Brain Tumor Cells and Consequences for Therapeutic Optimization of Temozolomide

“…Several studies have reported the existence of a link between the regulation of intracellular acidity and the reduction in cell death [ 58 , 59 , 60 , 61 ]. Therefore, in order to minimize toxic intracellular acidity, tumor cells must regulate the extrusion mechanisms of H ions, which increase pH .…”