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 Lopez & 1 others Shaun P. Jackson

Research output: Contribution to journalArticleResearchpeer-review

18 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

Cite this

Schoenwaelder, S. M., Darbousset, R., Cranmer, S. L., Ramshaw, H. S., Orive, S. L., Sturgeon, S., ... Jackson, S. P. (2016). 14-3-3ζ regulates the mitochondrial respiratory reserve linked to platelet phosphatidylserine exposure and procoagulant function. Nature Communications, 7, [12862]. https://doi.org/10.1038/ncomms12862
Schoenwaelder, Simone M. ; Darbousset, Roxane ; Cranmer, Susan L. ; Ramshaw, Hayley S ; Orive, Stephanie L. ; Sturgeon, Sharelle ; Yuan, Yuping ; Yao, Yu ; Krycer, James R. ; Woodcock, Joanna M ; Maclean, Jessica ; Pitson, Stuart ; Zheng, Zhaohua ; Henstridge, Darren C. ; Van Der Wal, Dianne ; Gardiner, Elizabeth E. ; Berndt, Michael C. ; Andrews, Robert K. ; James, David E ; Lopez, Angel F ; Jackson, Shaun P. / 14-3-3ζ regulates the mitochondrial respiratory reserve linked to platelet phosphatidylserine exposure and procoagulant function. In: Nature Communications. 2016 ; Vol. 7.
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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.",
author = "Schoenwaelder, {Simone M.} and Roxane Darbousset and Cranmer, {Susan L.} and Ramshaw, {Hayley S} and Orive, {Stephanie L.} and Sharelle Sturgeon and Yuping Yuan and Yu Yao and Krycer, {James R.} and Woodcock, {Joanna M} and Jessica Maclean and Stuart Pitson and Zhaohua Zheng and Henstridge, {Darren C.} and {Van Der Wal}, Dianne and Gardiner, {Elizabeth E.} and Berndt, {Michael C.} and Andrews, {Robert K.} and James, {David E} and Lopez, {Angel F} and Jackson, {Shaun P.}",
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Schoenwaelder, SM, Darbousset, R, Cranmer, SL, Ramshaw, HS, Orive, SL, Sturgeon, S, Yuan, Y, Yao, Y, Krycer, JR, Woodcock, JM, Maclean, J, Pitson, S, Zheng, Z, Henstridge, DC, Van Der Wal, D, Gardiner, EE, Berndt, MC, Andrews, RK, James, DE, Lopez, AF & Jackson, SP 2016, '14-3-3ζ regulates the mitochondrial respiratory reserve linked to platelet phosphatidylserine exposure and procoagulant function', Nature Communications, vol. 7, 12862. https://doi.org/10.1038/ncomms12862

14-3-3ζ regulates the mitochondrial respiratory reserve linked to platelet phosphatidylserine exposure and procoagulant function. / Schoenwaelder, Simone M.; Darbousset, Roxane; Cranmer, Susan L.; Ramshaw, Hayley S; Orive, Stephanie L.; Sturgeon, Sharelle; Yuan, Yuping; Yao, Yu; Krycer, James R.; Woodcock, Joanna M; Maclean, Jessica; Pitson, Stuart; Zheng, Zhaohua; Henstridge, Darren C.; Van Der Wal, Dianne; Gardiner, Elizabeth E.; Berndt, Michael C.; Andrews, Robert K.; James, David E; Lopez, Angel F; Jackson, Shaun P.

In: Nature Communications, Vol. 7, 12862, 27.09.2016.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - 14-3-3ζ regulates the mitochondrial respiratory reserve linked to platelet phosphatidylserine exposure and procoagulant function

AU - Schoenwaelder, Simone M.

AU - Darbousset, Roxane

AU - Cranmer, Susan L.

AU - Ramshaw, Hayley S

AU - Orive, Stephanie L.

AU - Sturgeon, Sharelle

AU - Yuan, Yuping

AU - Yao, Yu

AU - Krycer, James R.

AU - Woodcock, Joanna M

AU - Maclean, Jessica

AU - Pitson, Stuart

AU - Zheng, Zhaohua

AU - Henstridge, Darren C.

AU - Van Der Wal, Dianne

AU - Gardiner, Elizabeth E.

AU - Berndt, Michael C.

AU - Andrews, Robert K.

AU - James, David E

AU - Lopez, Angel F

AU - Jackson, Shaun P.

PY - 2016/9/27

Y1 - 2016/9/27

N2 - 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.

AB - 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.

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