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

Nat Commun. 2016 Jul 15;7:12086. doi: 10.1038/ncomms12086.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Lysophospholipids / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Oxygen / blood*
  • Oxygen / metabolism
  • Phosphotransferases (Alcohol Group Acceptor) / blood
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Sphingosine / analogs & derivatives*
  • Sphingosine / blood
  • Sphingosine / metabolism


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