Erythrocyte adaptive metabolic reprogramming under physiological and pathological hypoxia.

Area of Science:

• Hematology
• Metabolomics
• Physiology

Background:

• Erythrocytes (red blood cells) are crucial for oxygen transport and sensing.
• Metabolic reprogramming in erythrocytes plays a key role in adapting to hypoxic conditions.
• Recent advances in metabolomics and genetics illuminate erythrocyte function in hypoxia.

Purpose of the Study:

• To summarize recent progress in understanding erythrocyte hypoxic metabolic reprogramming.
• To highlight potential therapeutic strategies for hypoxia-related conditions.
• To differentiate erythrocyte responses in healthy individuals at high altitude versus patients with sickle cell disease (SCD) and chronic kidney disease (CKD).

Main Methods:

• Human metabolomics screening.
• Mouse genetic studies.
• Analysis of purinergic signaling pathways involving adenosine and sphingosine-1-phosphate (S1P).

Main Results:

• Elevated soluble CD73 (sCD73) increases adenosine, activating ADORA2B, and with erythrocyte S1P, promotes 2,3-bisphosphoglycerate (2,3-BPG) production.
• In SCD, this pathway contributes to sickling and tissue damage.
• At high altitude and in CKD, erythrocyte metabolic reprogramming via 2,3-BPG enhances oxygen delivery.

Conclusions:

• Erythrocyte hypoxic metabolic reprogramming plays a differential role in various hypoxia-exposed groups.
• Distinct therapeutic approaches are suggested for high-altitude adaptation, CKD, and SCD.
• Targeting erythrocyte metabolism offers precision therapy potential for hypoxia-related disorders.