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

Abstract

Cancer and highly proliferating normal cells have high demand for energy but paradoxically switch energy production from the highly efficient mitochondrial respiration to the low efficient cytosolic glycolysis. This phenomenon is known as the Warburg effect, but the reason for which is not fully understood. This study found that low intracellular pH (pHi) induced apoptosis, whereas high pHi enhanced proliferation, of normal lymphocytes. In tumor cells, low pHi also induced apoptosis whereas high pHi maintained high rates of proliferation. In the draining mediastinal lymph nodes (MLNs) of mice sensitized and challenged with ovalbumin, lymphocytes had dramatically higher and more heterogeneous pHi values than lymphocytes in the non-draining lymph nodes. The pHi values of the lymphocytes were inversely related to mitochondrial energetic activities, and the rise of the lymphocyte pHi in the MLNs was accompanied by the reduction of mitochondrial energetic activities. Furthermore, high lymphocyte proliferation in the MLNs powered by strong mitochondrial energy led to low pHi thereby predestined the lymphocytes to death by apoptosis, thus prevented such cells from accumulating in the MLNs. Since unlike mitochondrial respiration, the Warburg effect does not increase protons in the cells, these findings support a proposed explanation for the Warburg effect as a substitution for mitochondrial respiration that allows the highly proliferating cells to avoid low pHi-induced apoptosis.