title: Sphingosine-1-phosphate promotes erythrocyte glycolysis and oxygen release for adaptation to high-altitude hypoxia.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.|Graduate School of Biomedical Sciences, Biochemistry and Molecular Biology Program, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
authors.forename: Kaiqi
authors.initials: K
authors.lastname: Sun
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
authors.forename: Yujin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
authors.forename: Angelo
authors.initials: A
authors.lastname: D'Alessandro
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
authors.forename: Travis
authors.initials: T
authors.lastname: Nemkov
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
authors.forename: Anren
authors.initials: A
authors.lastname: Song
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.|Graduate School of Biomedical Sciences, Biochemistry and Molecular Biology Program, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.|Graduate School of Biomedical Sciences, Biochemistry and Molecular Biology Program, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
authors.forename: Morayo
authors.initials: M
authors.lastname: Adebiyi
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
authors.forename: Aji
authors.initials: A
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
authors.forename: Yuan E
authors.initials: YE
authors.lastname: Wen
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Bogdanov
authors.affiliation: Department of Ophthalmology and Visual Science, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Vila
authors.affiliation: Department of Ophthalmology and Visual Science, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
authors.forename: John
authors.initials: J
authors.lastname: O'Brien
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.|Graduate School of Biomedical Sciences, Biochemistry and Molecular Biology Program, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
authors.forename: Rodney E
authors.initials: RE
authors.lastname: Kellems
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
authors.forename: William
authors.initials: W
authors.lastname: Dowhan
authors.affiliation: Altitude Research Center, Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Subudhi
authors.affiliation: Altitude Research Center, Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
authors.forename: Sonja
authors.initials: S
authors.lastname: Jameson-Van Houten
authors.affiliation: Altitude Research Center, Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
authors.forename: Colleen G
authors.initials: CG
authors.lastname: Julian
authors.affiliation: Department of Human Physiology, University of Oregon, Eugene, Oregon 97403, USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Lovering
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Safo
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
authors.forename: Kirk C
authors.initials: KC
authors.lastname: Hansen
authors.affiliation: Altitude Research Center, Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Roach
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.|Graduate School of Biomedical Sciences, Biochemistry and Molecular Biology Program, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.|Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
mesh_terms: D019794:2,3-Diphosphoglycerate / Q000378:metabolism; D000222:Adaptation, Physiological; D000328:Adult; D000532:Altitude Sickness / Q000378:metabolism*; D000818:Animals; D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D008246:Lysophospholipids / Q000097:blood* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010100:Oxygen / Q000097:blood* / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000097:blood / Q000235:genetics; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D019794:2,3-Diphosphoglycerate; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D008246:Lysophospholipids; D010100:Oxygen; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate