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The choline transporter Slc44a2 controls platelet activation and thrombosis by regulating mitochondrial function.

ABSTRACT: Genetic factors contribute to the risk of thrombotic diseases. Recent genome wide association studies have identified genetic loci including SLC44A2 which may regulate thrombosis. Here we show that Slc44a2 controls platelet activation and thrombosis by regulating mitochondrial energetics. We find that Slc44a2 null mice (Slc44a2(KO)) have increased bleeding times and delayed thrombosis compared to wild-type (Slc44a2(WT)) controls. Platelets from Slc44a2(KO) mice have impaired activation in response to thrombin. We discover that Slc44a2 mediates choline transport into mitochondria, where choline metabolism leads to an increase in mitochondrial oxygen consumption and ATP production. Platelets lacking Slc44a2 contain less ATP at rest, release less ATP when activated, and have an activation defect that can be rescued by exogenous ADP. Taken together, our data suggest that mitochondria require choline for maximum function, demonstrate the importance of mitochondrial metabolism to platelet activation, and reveal a mechanism by which Slc44a2 influences thrombosis.

SUBMITTER: Bennett JA

PROVIDER: S-EPMC7359028 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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The choline transporter Slc44a2 controls platelet activation and thrombosis by regulating mitochondrial function.

Bennett J Allen JA Mastrangelo Michael A MA Ture Sara K SK Smith Charles O CO Loelius Shannon G SG Berg Rachel A RA Shi Xu X Burke Ryan M RM Spinelli Sherry L SL Cameron Scott J SJ Carey Thomas E TE Brookes Paul S PS Gerszten Robert E RE Sabater-Lleal Maria M de Vries Paul S PS Huffman Jennifer E JE Smith Nicholas L NL Morrell Craig N CN Lowenstein Charles J CJ

Nature communications 20200713 1

Genetic factors contribute to the risk of thrombotic diseases. Recent genome wide association studies have identified genetic loci including SLC44A2 which may regulate thrombosis. Here we show that Slc44a2 controls platelet activation and thrombosis by regulating mitochondrial energetics. We find that Slc44a2 null mice (Slc44a2(KO)) have increased bleeding times and delayed thrombosis compared to wild-type (Slc44a2(WT)) controls. Platelets from Slc44a2(KO) mice have impaired activation in respon ...[more]

PMID: 32661250

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Project description:Resting platelets rely on oxidative phosphorylation (OXPHOS) and aerobic glycolysis (conversion of glucose to lactate in the presence of oxygen) for their energy requirements. In contrast, platelet activation exhibits an increased rate of aerobic glycolysis relative to OXPHOS. Mitochondrial enzymes pyruvate dehydrogenase kinases (PDKs) phosphorylate the pyruvate dehydrogenase (PDH) complex to inhibit its activity, thereby diverting the pyruvate flux from OXPHOS to aerobic glycolysis upon platelet activation. Of 4 PDK isoforms, PDK2 and PDK4 (PDK2/4) are predominantly associated with metabolic diseases. Herein, we report that the combined deletion of PDK2/4 inhibits agonist-induced platelet functions, including aggregation, integrin αIIbβ3 activation, degranulation, spreading, and clot retraction. In addition, collagen-mediated PLCγ2 phosphorylation and calcium mobilization were significantly reduced in PDK2/4-/- platelets, suggesting impaired GPVI signaling. The PDK2/4-/- mice were less susceptible to FeCl3-induced carotid and laser-induced mesenteric artery thrombosis without any effect on hemostasis. In adoptive transfer experiments, thrombocytopenic hIL-4Rα/GPIbα-transgenic mice transfused with PDK2/4-/- platelets exhibited less susceptibility to FeCl3 injury-induced carotid thrombosis compared with hIL-4Rα/GPIbα-Tg mice transfused with WT platelets, suggesting a platelet-specific role of PDK2/4 in thrombosis. Mechanistically, the inhibitory effects of PDK2/4 deletion on platelet function were associated with reduced PDH phosphorylation and glycoPER in activated platelets, suggesting that PDK2/4 regulates aerobic glycolysis. Finally, using PDK2 or PDK4 single KO mice, we identified that PDK4 plays a more prominent role in regulating platelet secretion and thrombosis compared with PDK2. This study identifies the fundamental role of PDK2/4 in regulating platelet functions and identifies the PDK/PDH axis as a potentially novel antithrombotic target.

Dataset Information

The choline transporter Slc44a2 controls platelet activation and thrombosis by regulating mitochondrial function.

Publications

The choline transporter Slc44a2 controls platelet activation and thrombosis by regulating mitochondrial function.

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