Intracellular pH-regulated Cell Intrinsic Control of Death and Proliferation of Lymphocytes in Immune Response and Tumor Cells

Summary Previous studies have extensively investigated the biological consequences of extracellular acidosis caused by the Warburg effect. This article focuses on intracellular pH (pHi) and its regulation by mitochondrial respiration. It shows that low and high pHi induced apoptosis and enhanced proliferation of normal lymphocytes, respectively. In tumor cells, low pHi also induced apoptosis whereas high pHi maintained cell proliferation. In the draining mediastinal lymph nodes (MLNs) of mice sensitized and challenged with ovalbumin, lymphocyte pHi was dramatically higher and more heterogeneous than that in the non-draining lymph nodes, and was accompanied by reduction of, and inversely related to, mitochondrial energetic activities. The MLN lymphocytes with the highest mitochondrial energetic activities had the lowest pHi and highest proliferation, but exclusively contained the early apoptotic cells. These findings support a proposed explanation for the Warburg effect as a substitution for mitochondrial respiration that allows highly proliferating cells to avoid low pHi-induced apoptosis.