Open AccessSphingosine-1-phosphate promotes erythrocyte glycolysis and oxygen release for adaptation to high-altitude hypoxia
Author(s) -
Kaiqi Sun,
Yujin Zhang,
Angelo D’Alessandro,
Travis Nemkov,
Anren Song,
Wu H,
Hong Li,
Morayo G. Adebiyi,
Aji Huang,
Y. Edward Wen,
Mikhail Bogdanov,
A.J. Vila,
John O’Brien,
Rodney E. Kellems,
William Dowhan,
Andrew W. Subudhi,
Sonja Jameson-Van Houten,
Colleen G. Julian,
Andrew T. Lovering,
Martin K. Safo,
Kirk C. Hansen,
Robert C. Roach,
Yang Xia
Publication year - 2016
Publication title -
nature communications
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.559
H-Index - 365
ISSN - 2041-1723
DOI - 10.1038/ncomms12086
Subject(s) - glycolysis , sphingosine 1 phosphate , hypoxia (environmental) , microbiology and biotechnology , sphingosine , intracellular , biochemistry , cytosol , sphingosine kinase , sphingosine kinase 1 , biology , chemistry , metabolism , enzyme , oxygen , receptor , organic chemistry
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 (O 2 ) release capacity. Mouse genetic studies show that elevated erythrocyte Sphk1-induced S1P protects against tissue hypoxia by inducing O 2 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 O 2 release. Altogether, we reveal S1P as an intracellular hypoxia-responsive biolipid promoting erythrocyte glycolysis, O 2 delivery and thus new therapeutic opportunities to counteract tissue hypoxia.