The choline transporter Slc44a2 controls platelet activation and thrombosis by regulating mitochondrial function
Bennett, J.A. (University of Rochester Medical Center)
Mastrangelo, M.A. (University of Rochester Medical Center)
Ture, S.K. (University of Rochester Medical Center)
Smith, C.O. (University of Rochester Medical Center)
Loelius, S.G. (University of Rochester Medical Center)
Berg, R.A. (University of Rochester Medical Center)
Shi, X. (Beth Israel Deaconess Medical Center)
Burke, R.M. (University of Rochester Medical Center)
Spinelli, S.L. (University of Rochester Medical Center)
Cameron, S.J. (University of Rochester Medical Center)
Carey, T.E. (University of Michigan)
Brookes, Paul S (University of Rochester Medical Center)
Gerszten, R.E. (Beth Israel Deaconess Medical Center)
Sabater-Lleal, Maria (Institut d'Investigació Biomèdica Sant Pau)
de Vries, P.S. (The University of Texas Health Science Center at Houston)
Huffman, Jennifer E (VA Boston Healthcare System)
Smith, N.L. (Seattle Epidemiologic Research and Information Center)
Morrell, C.N. (University of Rochester Medical Center)
Lowenstein, C.J. (University of Rochester Medical Center)
Universitat Autònoma de Barcelona

Fecha:	2020
Resumen:	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.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Platelets ; Experimental models of disease
Publicado en:	Nature communications, Vol. 11 Núm. 1 (january 2020) , p. 3479, ISSN 2041-1723

DOI: 10.1038/s41467-020-17254-w
PMID: 32661250

9 p, 1.3 MB

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Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut de Recerca Sant Pau
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