Metabolic alterations in erythrocytes associated with long-term hypoxia at high altitude

Red blood cell (RBC) plays a vital role in the adaptations to hypoxia at high altitudes, however, the metabolic pattern of RBC under long-term hypoxia remains unknown. Here, we employed broad- and energy-targeted metabolomics approaches to study the differences in the RBC among the three groups: lowlanders living in plain areas, lowlanders acclimatized to plateaus for more than 10 years, and native Tibetans. Compared with lowlanders, the glycolytic flux remained stable in acclimatized lowlanders and adapted Tibetans, and purine metabolism did not correspondingly increase. Notably, the oxidative pentose phosphate pathway was reduced in both acclimatized lowlanders and adapted Tibetans, and a consistent decrease was observed in the reduced glutathione, a key metabolite of the redox system. Next, reduced Superoxide dismutase activity and enhanced catalase activity exhibited distinct pattern in the antioxidant system. Further validation using proteomics confirmed that the major antioxidant enzymes have undergone extensive adaptive changes under long-term hypoxia, including a decrease in Superoxide dismutase 1, peroxiredoxin 1/2, and thioredoxin reductase 1, while catalase has increased. In conclusion, metabolomics and validation measurements reveal a distinct remodeling of the antioxidant defense system in erythrocytes under long-term hypoxia and suggest a pronounced influence of environmental factors on erythrocyte metabolism, offering new insights into hypoxic adaptations.