AltitudeOmics: Red Blood Cell Metabolic Adaptation to High Altitude Hypoxia

Abstract

Red blood cells (RBCs) are key players in systemic oxygen transport. RBCs respond to in vitro hypoxia through the so-called oxygen-dependent metabolic regulation, which involves the competitive binding of deoxyhemoglobin and glycolytic enzymes to the N-terminal cytosolic domain of band 3. This mechanism promotes the accumulation of 2,3-DPG, stabilizing the deoxygenated state of hemoglobin, and cytosol acidification, triggering oxygen off-loading through the Bohr effect. Despite in vitro studies, in vivo adaptations to hypoxia have not yet been completely elucidated. Within the framework of the AltitudeOmics study, erythrocytes were collected from 21 healthy volunteers at sea level, after exposure to high altitude (5260m) for 1, 7 and 16days, and following reascent after 7days at 1525m. UHPLC-MS metabolomics results were correlated to physiological and athletic performance parameters. Immediate metabolic adaptations were noted as early as a few hours from ascending to >5000m, and maintained for 16 days at high altitude. Consistent with the mechanisms elucidated in vitro, hypoxia promoted glycolysis and deregulated the pentose phosphate pathway, as well purine catabolism, glutathione homeostasis, arginine/nitric oxide and sulphur/H2S metabolism. Metabolic adaptations were preserved one week after descent, consistently with improved physical performances in comparison to the first ascendance, suggesting a mechanism of metabolic memory.

Hypoxic storage of red blood cells improves metabolism and post‐transfusion recovery

“…Previous studies on metabolic responses to hypoxic storage in the laboratory setting highlighted an increase in glycolysis and a decrease in oxidant stress markers in comparison to standard, normoxic storage strategies . While some of these changes recapitulated observations from hypoxic exposure in vivo—e.g., following exposure to high‐altitude hypoxia —we wanted to test whether a commercially ready platform could phenocopy the benefits of hypoxic storage observed in our previous smaller scale, more controlled laboratory studies. We could thus confirm that hypoxic storage increased glucose consumption and lactate generation (Fig.…”

Methylation of protein aspartates and deamidated asparagines as a function of blood bank storage and oxidative stress in human red blood cells

“…For example, we report that the N‐terminal cytosolic domain of Band 3 is methylated along with other crucial regions of Band 3 that interact with deoxyhemoglobin, glycolytic enzymes, and structural proteins . Fine tuning of such interactions modulates metabolic responses to hypoxia, such as at high altitude . While the full picture of how such methylation impacts structure and protein–protein interactions is not yet known, it is interesting to speculate on the basis of computational models that esterification ablates negative charges in the N‐term of Band 3, perhaps destabilizing interactions with glycolytic enzymes and others .…”

Nitric oxide inhibits hypoxia‐induced impairment of human RBC deformability through reducing the cross‐linking of membrane protein band 3

“…As an anion channel protein, the normal structure and function of band 3 provide necessary conditions for regulating the intracellular pH, cell volume, and membrane potential . And maintaining RBC normal structure and function not only can improve tissue blood and oxygen supply and ischemic state, but also can help human adaptation to hypoxia . These experimental findings reflect a molecular mechanism underlying a role of NO in maintaining RBC deformability under hypoxia, and help to establish a new therapeutic approach for these ischemic and hypoxic patients.…”