Thermodynamic limitations on brain oxygen metabolism: physiological implications

Abstract

A recent hypothesis is that maintaining the brain tissue ratio of O2 to CO2 is 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 O2 and CO2 transport 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 O2 delivery 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 CO2 by increasing ventilation rate is much more effective for preserving tissue O2/CO2 than 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 summaryO_LIRecent thermodynamic modeling suggests that preserving the O2/CO2 ratio in brain tissue is critical for preserving the entropy change available from the oxidative metabolism of glucose and the phosphorylation potential underlying energy metabolism. C_LIO_LIThe hypothesis tested is that normal physiological responses (notably blood flow changes) often act to preserve this ratio under changing conditions. C_LIO_LIUsing a detailed model to calculate tissue O2/CO2 we 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. C_LIO_LIFor the hypoxia modeling we considered high altitude acclimatization and adaptation in humans, showing the critical role of reducing CO2 in preserving tissue O2/CO2. C_LIO_LIThe tissue O2/CO2 hypothesis 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. C_LI