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

J. Allen Bennett, Michael A. Mastrangelo, Sara K. Ture, Charles O. Smith, Shannon G. Loelius, Rachel A. Berg, Xu Shi, Ryan M. Burke, Sherry L. Spinelli, Scott J. Cameron, Thomas E. Carey, Paul S. Brookes, Robert E. Gerszten, Maria Sabater-Lleal, Paul S. de Vries, Jennifer E. Huffman, Nicholas L. Smith, Craig N. Morrell and Charles J. Lowenstein ()
Additional contact information
J. Allen Bennett: University of Rochester Medical Center
Michael A. Mastrangelo: University of Rochester Medical Center
Sara K. Ture: University of Rochester Medical Center
Charles O. Smith: University of Rochester Medical Center
Shannon G. Loelius: University of Rochester Medical Center
Rachel A. Berg: University of Rochester Medical Center
Xu Shi: Beth Israel Deaconess Medical Center
Ryan M. Burke: University of Rochester Medical Center
Sherry L. Spinelli: University of Rochester Medical Center
Scott J. Cameron: University of Rochester Medical Center
Thomas E. Carey: University of Michigan
Paul S. Brookes: University of Rochester Medical Center
Robert E. Gerszten: Beth Israel Deaconess Medical Center
Maria Sabater-Lleal: Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital
Paul S. de Vries: The University of Texas Health Science Center at Houston
Jennifer E. Huffman: MAVERIC, VA Boston Healthcare System
Nicholas L. Smith: University of Washington
Craig N. Morrell: University of Rochester Medical Center
Charles J. Lowenstein: University of Rochester Medical Center

Nature Communications, 2020, vol. 11, issue 1, 1-9

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17254-w

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