Sphingosine-1-phosphate promotes erythrocyte glycolysis and oxygen release for adaptation to high-altitude hypoxia.

Abstract

Sphingosine-1-phosphate (S1P) is a bioactive signalling lipid highly enriched in mature erythrocytes, with unknown functions pertaining to erythrocyte physiology. Here by employing nonbiased high-throughput metabolomic profiling, we show that erythrocyte S1P levels rapidly increase in 21 healthy lowland volunteers at 5,260 m altitude on day 1 and continue increasing to 16 days with concurrently elevated erythrocyte sphingonisne kinase 1 (Sphk1) activity and haemoglobin (Hb) oxygen (O2) release capacity. Mouse genetic studies show that elevated erythrocyte Sphk1-induced S1P protects against tissue hypoxia by inducing O2 release. Mechanistically, we show that intracellular S1P promotes deoxygenated Hb anchoring to the membrane, enhances the release of membrane-bound glycolytic enzymes to the cytosol, induces glycolysis and thus the production of 2,3-bisphosphoglycerate (2,3-BPG), an erythrocyte-specific glycolytic intermediate, which facilitates O2 release. Altogether, we reveal S1P as an intracellular hypoxia-responsive biolipid promoting erythrocyte glycolysis, O2 delivery and thus new therapeutic opportunities to counteract tissue hypoxia.

• Authors: Kaiqi Sun, Yujin Zhang, Angelo D'Alessandro, Travis Nemkov, Anren Song, Hongyu Wu, Hong Liu, Morayo Adebiyi, Aji Huang, Yuan E Wen, Mikhail V Bogdanov, Alejandro Vila, John O'Brien, Rodney E Kellems, William Dowhan, Andrew W Subudhi, Sonja Jameson-Van Houten, Colleen G Julian, Andrew T Lovering, Martin Safo, Kirk C Hansen, Robert C Roach, Yang Xia
• Journal: Nature communications (Nat Commun) Vol. 7 Pg. 12086 (07 15 2016) ISSN: 2041-1723 [Electronic] England
• PMID: 27417539 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Lysophospholipids
• 2,3-Diphosphoglycerate
• sphingosine 1-phosphate
• Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)
• Phosphotransferases (Alcohol Group Acceptor)
• sphingosine kinase
• Sphingosine
• Oxygen

Topics

• 2,3-Diphosphoglycerate (metabolism)
• Adaptation, Physiological
• Adult
• Altitude Sickness (metabolism)
• Animals
• Erythrocytes (metabolism)
• Female
• Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) (metabolism)
• Glycolysis
• Humans
• Hypoxia (metabolism)
• Lysophospholipids (blood, metabolism)
• Male
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Oxygen (blood, metabolism)
• Phosphotransferases (Alcohol Group Acceptor) (blood, genetics)
• Sphingosine (analogs & derivatives, blood, metabolism)