Thermodynamic limitations on brain oxygen metabolism: physiological implications

Recent thermodynamic modelling indicates that maintaining the brain tissue ratio of O₂ to CO₂ (abbreviated tissue O₂ /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. This provides a novel perspective for understanding physiological responses under different conditions in terms of preserving tissue O₂ /CO₂ . To enable estimation of tissue O₂ /CO₂ in the human brain, a detailed mathematical model of O₂ and CO₂ transport was developed, and applied to reported physiological responses to different challenges, asking: how well is tissue O₂ /CO₂ preserved? Reported experimental results for increased neural activity, hypercapnia and hypoxia due to high altitude are consistent with preserving tissue O₂ /CO₂ . The results highlight two physiological mechanisms that control tissue O₂ /CO₂ : cerebral blood flow, which modulates tissue O₂ ; and ventilation rate, which modulates tissue CO₂ . The hypoxia modelling focused on humans at high altitude, including acclimatized lowlanders and Tibetan and Andean adapted populations, with a primary finding that decreasing CO₂ by increasing ventilation rate is more effective for preserving tissue O₂ /CO₂ than increasing blood haemoglobin content to maintain O₂ delivery to tissue. This work focused on the function served by particular physiological responses, and the underlying mechanisms require further investigation. The modelling 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: Thermodynamic modelling indicates that preserving the O₂ /CO₂ ratio in brain tissue is critical for preserving the entropy change available from oxidative metabolism of glucose and the phosphorylation potential underlying energy metabolism. A detailed model of O₂ and CO₂ transport was developed to allow estimation of the tissue O₂ /CO₂ ratio in the human brain in different physiological states. Reported experimental results during hypoxia, hypercapnia and increased oxygen metabolic rate in response to increased neural activity are consistent with maintaining brain tissue O₂ /CO₂ ratio. The hypoxia modelling of high-altitude acclimatization and adaptation in humans demonstrates the critical role of reducing CO₂ with increased ventilation for preserving tissue O₂ /CO₂ . Preservation of tissue O₂ /CO₂ provides a novel 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.