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

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 th...

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Bibliographic Details
Published in:	Nature communications 2020-07, Vol.11 (1), p.3479-9, Article 3479
Main Authors:	Bennett, J Allen, Mastrangelo, Michael A, Ture, Sara K, Smith, Charles O, Loelius, Shannon G, Berg, Rachel A, Shi, Xu, Burke, Ryan M, Spinelli, Sherry L, Cameron, Scott J, Carey, Thomas E, Brookes, Paul S, Gerszten, Robert E, Sabater-Lleal, Maria, de Vries, Paul S, Huffman, Jennifer E, Smith, Nicholas L, Morrell, Craig N, Lowenstein, Charles J
Format:	Article
Language:	eng
Subjects:	Adenosine diphosphate Adenosine Triphosphate - metabolism Animals ATP Bleeding Blotting, Western Choline Disease Models, Animal Genetic factors Genome-wide association studies Genome-Wide Association Study Genomes Health risks Loci Male Mass Spectrometry Medicin och hälsovetenskap Membrane Transport Proteins - genetics Membrane Transport Proteins - metabolism Metabolism Mice Mice, Knockout Mitochondria Mitochondria - genetics Mitochondria - metabolism Oxygen consumption Platelet Activation - genetics Platelet Activation - physiology Platelet Aggregation - genetics Platelet Aggregation - physiology Platelets Real-Time Polymerase Chain Reaction Thrombin Thromboembolism Thrombosis Thrombosis - genetics Thrombosis - metabolism
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Summary:	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.
ISSN:	2041-1723 2041-1723