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

Kaiqi Sun,Colleen G Julian,Travis Nemkov,John O’Brien,Yujin Zhang,William Dowhan,Yang Xia,Rodney E Kellems,Sonja Jameson-Van Houten,Andrew W Subudhi,Robert C Roach,Andrew T Lovering,Anren Song,Aji Huang,Angelo D’Alessandro,Kirk C Hansen,Yuan Edward Wen ,Morayo G Adebiyi ,A.j Vila ,Martin K Safo ,Wu H ,Mikhail Bogdanov ,Hong Li

doi:10.1038/ncomms12086

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.

Highlights

Sphingosine-1-phosphate (S1P) is a bioactive signalling lipid highly enriched in mature erythrocytes, with unknown functions pertaining to erythrocyte physiology
Our metabolomics profiling coupled with S1P level quantification revealed that erythrocyte S1P levels rapidly increased within 12 h at high altitude and further increased to approximately twofold on day 7 and threefold on day 16, consistent with the trends observed for 2,3-BPG and P50 (Fig. 1d)
We demonstrated the beneficial role of Sphk1dependent elevation of erythrocyte S1P by promoting 2,3-BPG production and O2 release to counteract tissue hypoxia

Summary

Introduction

Sphingosine-1-phosphate (S1P) is a bioactive signalling lipid highly enriched in mature erythrocytes, with unknown functions pertaining to erythrocyte physiology. There is an enormous gap in our understanding of the specific factors and signalling pathways involved in hypoxia adaptation and an even larger one in identifying strategies to reduce hypoxia-induced tissue damage Translating results from the human high-altitude study to a mouse model of hypoxia, we demonstrate that elevated RBCs’ Sphk[1] activity underlies increased S1P production within RBCs in hypoxia conditions and that elevated RBCs’ S1P is beneficial to counteract tissue hypoxia independent of S1P receptors. These results may provide the basis for novel therapeutic possibilities to counteract hypoxic conditions

Methods

Results

Conclusion