Deletion of GLUT1 and GLUT3 Reveals Multiple Roles for Glucose Metabolism in Platelet and Megakaryocyte Function

Publication date: 25 July 2017
Source:Cell Reports, Volume 20, Issue 4
Author(s): Trevor P. Fidler, Robert A. Campbell, Trevor Funari, Nicholas Dunne, Enrique Balderas Angeles, Elizabeth A. Middleton, Dipayan Chaudhuri, Andrew S. Weyrch, E. Dale Abel
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.

Graphical abstract

Teaser

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.


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