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

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

Author information

1
Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
2
Graduate School of Biomedical Sciences, Biochemistry and Molecular Biology Program, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
3
Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
4
Department of Ophthalmology and Visual Science, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
5
Altitude Research Center, Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
6
Department of Human Physiology, University of Oregon, Eugene, Oregon 97403, USA.
7
Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
8
Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.

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.

PMID:
27417539
PMCID:
PMC4947158
DOI:
10.1038/ncomms12086
[Indexed for MEDLINE]
Free PMC Article

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