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

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 and Yang Xia ()
Additional contact information
Kaiqi Sun: The University of Texas Health Science Center at Houston
Yujin Zhang: The University of Texas Health Science Center at Houston
Angelo D’Alessandro: University of Colorado School of Medicine
Travis Nemkov: University of Colorado School of Medicine
Anren Song: The University of Texas Health Science Center at Houston
Hongyu Wu: The University of Texas Health Science Center at Houston
Hong Liu: The University of Texas Health Science Center at Houston
Morayo Adebiyi: The University of Texas Health Science Center at Houston
Aji Huang: The University of Texas Health Science Center at Houston
Yuan E. Wen: The University of Texas Health Science Center at Houston
Mikhail V. Bogdanov: The University of Texas Health Science Center at Houston
Alejandro Vila: The University of Texas Health Science Center at Houston
John O’Brien: The University of Texas Health Science Center at Houston
Rodney E. Kellems: The University of Texas Health Science Center at Houston
William Dowhan: The University of Texas Health Science Center at Houston
Andrew W. Subudhi: Altitude Research Center, University of Colorado School of Medicine
Sonja Jameson- Van Houten: Altitude Research Center, University of Colorado School of Medicine
Colleen G. Julian: Altitude Research Center, University of Colorado School of Medicine
Andrew T. Lovering: University of Oregon
Martin Safo: Virginia Commonwealth University
Kirk C. Hansen: University of Colorado School of Medicine
Robert C. Roach: Altitude Research Center, University of Colorado School of Medicine
Yang Xia: The University of Texas Health Science Center at Houston

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12086

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