Journal article
Deletion of GLUT1 and GLUT3 Reveals Multiple Roles for Glucose Metabolism in Platelet and Megakaryocyte Function
Cell reports (Cambridge), Vol.20(4), pp.881-894
07/25/2017
DOI: 10.1016/j.celrep.2017.06.083
PMID: 28746873
Abstract
Anucleate platelets circulate in the blood to facilitate thrombosis and diverse immune functions. Platelet activation leading to clot formation correlates with increased glycogenolysis, glucose uptake, glucose oxidation, and lactic acid production. Simultaneous deletion of glucose transporter (GLUT) 1 and GLUT3 (double knockout [DKO]) specifically in platelets completely abolished glucose uptake. In DKO platelets, mitochondrial oxidative metabolism of non-glycolytic substrates, such as glutamate, increased. Thrombosis and platelet activation were decreased through impairment at multiple activation nodes, including Ca2+ signaling, degranulation, and integrin activation. DKO mice developed thrombocytopenia, secondary to impaired pro-platelet formation from megakaryocytes, and increased platelet clearance resulting from cytosolic calcium overload and calpain activation. Systemic treatment with oligomycin, inhibiting mitochondrial metabolism, induced rapid clearance of platelets, with circulating counts dropping to zero in DKO mice, but not wild-type mice, demonstrating an essential role for energy metabolism in platelet viability. Thus, substrate metabolism is essential for platelet production, activation, and survival.
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•Glucose metabolism is required for megakaryocyte-mediated platelet production•Platelet metabolism is essential for platelet survival•Energetically stressed platelets undergo Ca2+-calpain-mediated necrosis and clearance•Glucose metabolism modulates multiple nodes of platelet activation
Fidler et al. show that glucose metabolism is essential for platelet production, activation, and clearance. Their findings reveal complementary roles for glycolysis versus mitochondrial metabolism in platelet viability. Blocking both metabolic pathways leads to complete clearance of platelets from the circulation, due to calcium overload and calpain activation.
Details
- Title: Subtitle
- Deletion of GLUT1 and GLUT3 Reveals Multiple Roles for Glucose Metabolism in Platelet and Megakaryocyte Function
- Creators
- Trevor P Fidler - Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112, USARobert A Campbell - Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112, USATrevor Funari - Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USANicholas Dunne - Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAEnrique Balderas Angeles - Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USAElizabeth A Middleton - Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112, USADipayan Chaudhuri - Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USAAndrew S Weyrich - Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112, USAE. Dale Abel - Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112, USA
- Resource Type
- Journal article
- Publication Details
- Cell reports (Cambridge), Vol.20(4), pp.881-894
- DOI
- 10.1016/j.celrep.2017.06.083
- PMID
- 28746873
- NLM abbreviation
- Cell Rep
- ISSN
- 2211-1247
- eISSN
- 2211-1247
- Publisher
- Elsevier Inc
- Grant note
- DOI: 10.13039/100000002, name: NIH, award: U01HG004085, U01HG004080, U42RR024244; DOI: 10.13039/100000002, name: NIH, award: T32 DK 007115; DOI: 10.13039/100000002, name: NIH, award: R00HL124070; DOI: 10.13039/100000002, name: NIH, award: R01 HL 126547; DOI: 10.13039/100000002, name: NIH, award: U54 HL112311
- Language
- English
- Date published
- 07/25/2017
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984024401702771
Metrics
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