Fig. 6: Model summarizing the effect of hyperammonemia at normal physiological pH (pH 7.5) versus low extracellular pH (pH 6.8).
From: Low extracellular pH protects cancer cells from ammonia toxicity
Panel 1. Increased glutaminolysis leads to a positive net production of NH4+, which is exported from the mitochondria to the extracellular space (green arrows). When perfusion of the interstitial fluid is normal, ammonia is constantly removed from the microenvironment. Panel 2. When perfusion is abrogated, ammonia accumulates in the extracellular space. Under normal physiological pH, 2.2% of the total ammonia pool will be in the form of NH3. As an alkaline gas, NH3 can traverse the plasma membrane and enter the more acidic cytosol (yellow arrow). When the influx of NH3 exceeds the efflux of NH4+, ammonia will accumulate in the cytosol, where it leads to a dose-dependent alkalinization of acidic organelles, which impedes their turnover and function. This indirectly represses cell growth and vitality. Panel 3. When the extracellular pH is 6.8, less (0.4%) of the total ammonia pool will be in the form of NH3. Therefore, less NH3 will be available to enter the cytoplasm. In addition, low extracellular pH instigates a reversed pH gradient, impeding the flux of NH3 to the cytosol (yellow arrow). Consequently, high extracellular ammonia levels are largely effectless when cells are subjected to low extracellular pH.
