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 M 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 LopezShaun P. Jackson

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25 Citations (Scopus)

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.

Original languageEnglish
Article number12862
Number of pages17
JournalNature Communications
Volume7
DOIs
Publication statusPublished - 27 Sep 2016

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