Thermodynamic limitations on brain oxygen metabolism: physiological implications

A recent hypothesis is that maintaining the brain tissue ratio of O 2 to CO 2 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 O 2 /CO 2 . To test this idea, a mathematical model of O 2 and CO 2 transport was used to calculate how well different physiological responses maintain tissue O 2 /CO 2 , 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 O 2 /CO 2 , rather than simply in terms of O 2 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 CO 2 by increasing ventilation rate is much more effective for preserving tissue O 2 /CO 2 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 summary Recent thermodynamic modeling suggests that preserving the O 2 /CO 2 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. 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 O 2 /CO 2 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. For the hypoxia modeling we considered high altitude acclimatization and adaptation in humans, showing the critical role of reducing CO 2 in preserving tissue O 2 /CO 2 . The tissue O 2 /CO 2 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.