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.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Bennett JA,Mastrangelo MA,Ture SK,Smith CO,Loelius SG,Berg RA,Shi X,Burke RM,Spinelli SL,Cameron SJ,Carey TE,Brookes PS,Gerszten RE,Sabater-Lleal M,de Vries PS,Huffman JE,Smith NL,Morrell CN,Lowenstein CJdoi
10.1038/s41467-020-17254-wsubject
Has Abstractpub_date
2020-07-13 00:00:00pages
3479issue
1issn
2041-1723pii
10.1038/s41467-020-17254-wjournal_volume
11pub_type
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