14-3-3ζ regulates the mitochondrial respiratory reserve linked to platelet phosphatidylserine exposure and procoagulant function

Simone M. Schoenwaelder, Roxane Darbousset, Susan L. Cranmer, Hayley S. Ramshaw, Stephanie L. Orive, Sharelle Sturgeon, Yuping Yuan, Yu Yao, James R. Krycer, Joanna Woodcock, Jessica Maclean, Stuart Pitson, Zhaohua Zheng, Darren C. Henstridge, Dianne van der Wal, Elizabeth E. Gardiner, Michael C. Berndt, Robert K. Andrews, David E. James, Angel F. Lopez and Shaun P. Jackson ()
Additional contact information
Simone M. Schoenwaelder: Heart Research Institute, Thrombosis Group
Roxane Darbousset: Heart Research Institute, Thrombosis Group
Susan L. Cranmer: Australian Centre for Blood Diseases, Alfred Medical Research and Education Precinct (AMREP), Monash University
Hayley S. Ramshaw: Centre for Cancer Biology, SA Pathology and the University of South Australia
Stephanie L. Orive: Australian Centre for Blood Diseases, Alfred Medical Research and Education Precinct (AMREP), Monash University
Sharelle Sturgeon: Australian Centre for Blood Diseases, Alfred Medical Research and Education Precinct (AMREP), Monash University
Yuping Yuan: Heart Research Institute, Thrombosis Group
Yu Yao: Australian Centre for Blood Diseases, Alfred Medical Research and Education Precinct (AMREP), Monash University
James R. Krycer: Charles Perkins Centre, The University of Sydney
Joanna Woodcock: Centre for Cancer Biology, SA Pathology and the University of South Australia
Jessica Maclean: Heart Research Institute, Thrombosis Group
Stuart Pitson: Centre for Cancer Biology, SA Pathology and the University of South Australia
Zhaohua Zheng: Australian Centre for Blood Diseases, Alfred Medical Research and Education Precinct (AMREP), Monash University
Darren C. Henstridge: Baker IDI Heart and Diabetes Institute
Dianne van der Wal: Australian Centre for Blood Diseases, Alfred Medical Research and Education Precinct (AMREP), Monash University
Elizabeth E. Gardiner: Australian Centre for Blood Diseases, Alfred Medical Research and Education Precinct (AMREP), Monash University
Michael C. Berndt: Faculty of Health Sciences, Curtin University
Robert K. Andrews: Australian Centre for Blood Diseases, Alfred Medical Research and Education Precinct (AMREP), Monash University
David E. James: Charles Perkins Centre, The University of Sydney
Angel F. Lopez: Centre for Cancer Biology, SA Pathology and the University of South Australia
Shaun P. Jackson: Heart Research Institute, Thrombosis Group

Nature Communications, 2016, vol. 7, issue 1, 1-17

Abstract: Abstract The 14-3-3 family of adaptor proteins regulate diverse cellular functions including cell proliferation, metabolism, adhesion and apoptosis. Platelets express numerous 14-3-3 isoforms, including 14-3-3ζ, which has previously been implicated in regulating GPIbα function. Here we show an important role for 14-3-3ζ in regulating arterial thrombosis. Interestingly, this thrombosis defect is not related to alterations in von Willebrand factor (VWF)–GPIb adhesive function or platelet activation, but instead associated with reduced platelet phosphatidylserine (PS) exposure and procoagulant function. Decreased PS exposure in 14-3-3ζ-deficient platelets is associated with more sustained levels of metabolic ATP and increased mitochondrial respiratory reserve, independent of alterations in cytosolic calcium flux. Reduced platelet PS exposure in 14-3-3ζ-deficient mice does not increase bleeding risk, but results in decreased thrombin generation and protection from pulmonary embolism, leading to prolonged survival. Our studies define an important role for 14-3-3ζ in regulating platelet bioenergetics, leading to decreased platelet PS exposure and procoagulant function.

Date: 2016
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DOI: 10.1038/ncomms12862

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