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

Author

Listed:
  • 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
    Research Institute of Hospital de la Santa Creu i Sant Pau (IIB Sant Pau))

  • 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
    Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development)

  • Craig N. Morrell

    (University of Rochester Medical Center)

  • Charles J. Lowenstein

    (University of Rochester Medical Center)

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.

Suggested Citation

  • 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 & P, 2020. "The choline transporter Slc44a2 controls platelet activation and thrombosis by regulating mitochondrial function," Nature Communications, Nature, vol. 11(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17254-w
    DOI: 10.1038/s41467-020-17254-w
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