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

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.

• Authors: 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, Shaun P Jackson
• Journal: Nature communications (Nat Commun) Vol. 7 Pg. 12862 (Sep 27 2016) ISSN: 2041-1723 [Electronic] England
• PMID: 27670677 (Publication Type: Journal Article)