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.
Highlights
Genetic factors contribute to the risk of thrombotic diseases
The INVENT Consortium used GWAS to identify genetic variants associated with Venous thromboembolism (VTE) in a cohort of over 60,000 human subjects, including a genetic variant located within the gene SLC44A2 which was associated with a ~20% increased risk of thrombosis in replication and discovery cohorts[3,4]
The major findings of our study are that choline is a substrate for mitochondria, Slc44a2 regulates choline transport into mitochondria, and choline plays a key role in production of ATP necessary for maximal platelet activation (Fig. 5)
Summary
Recent genome wide association studies have identified genetic loci including SLC44A2 which may regulate thrombosis. We show that Slc44a2 controls platelet activation and thrombosis by regulating mitochondrial energetics. 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. The INVENT Consortium used GWAS to identify genetic variants associated with VTE in a cohort of over 60,000 human subjects, including a genetic variant located within the gene SLC44A2 which was associated with a ~20% increased risk of thrombosis in replication and discovery cohorts[3,4]. We show that Slc44a2 is a mitochondrial choline transporter that regulates mitochondrial synthesis of ATP, platelet activation and thrombosis
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