Importance of pH homeostasis in metabolic health and diseases: crucial role of membrane proton transport

Abstract

Protons dissociated from organic acids in cells are partly buffered. If not, they are transported to the extracellular fluid through the plasma membrane and buffered in circulation or excreted in urine and expiration gas. Several transporters including monocarboxylate transporters and Na(+)/H(+) exchanger play an important role in uptake and output of protons across plasma membranes in cells of metabolic tissues including skeletal muscle and the liver. They also contribute to maintenance of the physiological pH of body fluid. Therefore, impairment of these transporters causes dysfunction of cells, diseases, and a decrease in physical performance associated with abnormal pH. Additionally, it is known that fluid pH in the interstitial space of metabolic tissues is easily changed due to little pH buffering capacitance in interstitial fluids and a reduction in the interstitial fluid pH may mediate the onset of insulin resistance unlike blood containing pH buffers such as Hb (hemoglobin) and albumin. In contrast, habitual exercise and dietary intervention regulate expression/activity of transporters and maintain body fluid pH, which could partly explain the positive effect of healthy lifestyle on disease prognosis.

Figure 1

Proton production and its transporting kinetics in intracellular and extracellular fluid in metabolic tissues. The production of organic acids such as lactic acid and ketone bodies is accelerated by elevating glycolytic anaerobic metabolism and β-oxidation in metabolic cells. Body fluid pH is strictly maintained by buffering systems, efflux across plasma membrane, and acid excretion. Monocarboxylate transporter (MCT) and Na⁺/H⁺ exchanger (NHE) contribute to proton extrusion from the cytosol to the extracellular space. In contrast to intracellular fluid and blood containing pH buffers such as Hb (hemoglobin) and albumin, the interstitial fluid pH could be easily reduced by acid stress owing to the limited availability of the buffering factors such as proteins.