Dependence of proton generation on aerobic or anaerobic metabolism and implications for tumour pH

Since low intracellular pH potentiates the hyperthermia response, the number of protons generated within the cell is calculated for both aerobic and anaerobic metabolism. The calculations incorporate the most recent estimates for the P: O ratio in mitochondrial oxidative phosphorylation, and include the hydrolysis of ATP as well as its synthesis. Anaerobic glycolysis of glucose to lactate generates two proton equivalents per mol of glucose, due to the complete dissociation of lactic acid. This corresponds to 1.00 proton per ATP, and is independent of pH. For aerobic metabolism of glucose to CO2 and water, protons are generated in the cell by dissociation of carbonic acid, and the exact number depends upon cytosolic pH. In the physiological pH range, one finds 4.1-5.9 mol of hydrogen ion per mol of glucose, which corresponds to 0.14-0.20 per ATP. Thus, anaerobic metabolism generates 5-7x as much acid within the cell as aerobic metabolism if the two are operating at the same rate in terms of ATP generation per unit time.