Thermodynamic limitations on brain oxygen metabolism: physiological implications

AbstractA recent hypothesis is that maintaining the brain tissue ratio of O2to CO2is critical for preserving the entropy increase available from oxidative metabolism of glucose, with a fall of that available entropy leading to a reduction of the phosphorylation potential and impairment of brain energy metabolism. The hypothesis suggests that physiological responses under different conditions can be understood as preserving tissue O2/CO2. To test this idea, a mathematical model of O2and CO2transport was used to calculate how well different physiological responses maintain tissue O2/CO2, showing good agreement with reported experimental measurements for increased neural activity, hypercapnia and hypoxia. The results highlight the importance of thinking about brain blood flow as a way to modulate tissue O2/CO2, rather than simply in terms of O2delivery to the capillary bed. The hypoxia modeling focused on humans at high altitude, including acclimatized lowlanders and adapted populations, with a primary finding that decreasing CO2by increasing ventilation rate is much more effective for preserving tissue O2/CO2than increasing blood hemoglobin content. The modeling provides a new framework and perspective for understanding how blood flow and other physiological factors support energy metabolism in the brain under a wide range of conditions.Key points summaryRecent thermodynamic modeling suggests that preserving the O2/CO2ratio in brain tissue is critical for preserving the entropy change available from the oxidative metabolism of glucose and the phosphorylation potential underlying energy metabolism.The hypothesis tested is that normal physiological responses (notably blood flow changes) often act to preserve this ratio under changing conditions.Using a detailed model to calculate tissue O2/CO2we found good agreement with the predictions of the hypothesis and reported experimental results during hypoxia, hypercapnia and increased oxygen metabolic rate in response to increased neural activity.For the hypoxia modeling we considered high altitude acclimatization and adaptation in humans, showing the critical role of reducing CO2in preserving tissue O2/CO2.The tissue O2/CO2hypothesis provides a useful perspective for understanding the function of observed physiological responses under different conditions in terms of preserving brain energy metabolism, although the mechanisms underlying these functions are not well understood.