Mitochondrial Calcium and Reactive Oxygen Species Regulate Agonist-Initiated Platelet Phosphatidylserine Exposure
- 1 December 2012
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Arteriosclerosis, Thrombosis, and Vascular Biology
- Vol. 32 (12), 2946-2955
- https://doi.org/10.1161/atvbaha.112.300433
Abstract
Objective—: To study the interactions of cytoplasmic calcium elevation, mitochondrial permeability transition pore (mPTP) formation, and reactive oxygen species formation in the regulation of phosphatidylserine (PS) exposure in platelets. Methods and Results—: mPTP formation, but not the degree of cytoplasmic calcium elevation, was associated with PS exposure in wild-type, cyclophilin D–null, ionomycin-treated, and reactive oxygen species–treated platelets. In the absence of the mPTP regulator cyclophilin D, agonist-initiated mPTP formation and high-level PS exposure were markedly blunted, but cytoplasmic calcium transients were unchanged. Mitochondrial calcium (Ca 2+ mit ) transients and reactive oxygen species, key regulators of mPTP formation, were examined in strongly stimulated platelets. Increased reactive oxygen species production occurred in strongly stimulated platelets and was dependent on extracellular calcium entry, but not the presence of cyclophilin D. Ca 2+ mit increased significantly in strongly stimulated platelets. Abrogation of Ca 2+ mit entry, either by inhibition of the Ca 2+ mit uniporter or mitochondrial depolarization, prevented mPTP formation and exposure but not platelet aggregation or granule release. Conclusion—: Sustained cytoplasmic calcium levels are necessary, but not sufficient, for high-level PS exposure in response to agonists. Increased Ca 2+ mit levels are a key signal initiating mPTP formation and PS exposure. Blockade of Ca 2+ mit entry allows the specific inhibition of platelet procoagulant activity.Keywords
This publication has 54 references indexed in Scilit:
- Inhibiting platelet-stimulated blood coagulation by inhibition of mitochondrial respirationProceedings of the National Academy of Sciences of the United States of America, 2012
- Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporterNature, 2011
- A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporterNature, 2011
- An intimate liaison: spatial organization of the endoplasmic reticulum–mitochondria relationshipThe EMBO Journal, 2010
- Roles of Platelet STIM1 and Orai1 in Glycoprotein VI- and Thrombin-dependent Procoagulant Activity and Thrombus FormationOnline Journal of Public Health Informatics, 2010
- Mitochondrial cyclophilin-D as a critical mediator of ischaemic preconditioningCardiovascular Research, 2010
- What is the mitochondrial permeability transition pore?Journal of Molecular and Cellular Cardiology, 2009
- The calcium sensor STIM1 is an essential mediator of arterial thrombosis and ischemic brain infarctionThe Journal of Experimental Medicine, 2008
- Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell deathNature, 2005
- Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell deathNature, 2005