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Mechanisms of increased mitochondria-dependent necrosis in Wiskott-Aldrich syndrome plateletsстатья
Статья опубликована в высокорейтинговом журнале
Информация о цитировании статьи получена из
Web of Science,
Scopus
Статья опубликована в журнале из списка Web of Science и/или Scopus
Дата последнего поиска статьи во внешних источниках: 8 сентября 2020 г.
- Авторы: Obydennyi S.I., Artemenko E.O., Sveshnikova A.N., Ignatova A.A., Varlamova T.V., Gambaryan S., Ugarova N.N., Lomakina G.Y., Kireev I.I., Ataullakhanov F.I., Novichkova G.A., Maschan A.A., Shcherbina A., Panteleev M.
- Журнал: Haematologica
- Том: 105
- Номер: 4
- Год издания: 2020
- Издательство: Ferrata Storti Foundation
- Местоположение издательства: Italy
- Первая страница: 1095
- Последняя страница: 1106
- DOI: 10.3324/haematol.2018.214460
- Аннотация: Wiskott-Aldrich syndrome (WAS) is associated with thrombocytopenia of unclear origin. We investigated real-time cytosolic calciumdynamics, mitochondrial membrane potential and phosphatidylserine (PS) exposure in single fibrinogen-bound platelets using confocalmicroscopy. The WAS platelets had higher resting calcium levels,more frequent spikes, and their mitochondria more frequently lost membranepotential followed by PS exposure (in 22.9% of platelets vs. 3.9% in controls; P<0.001) after the collapse of the last mitochondria. This phenomenonwas inhibited by the mitochondrial permeability transition pore inhibitor cyclosporine A, as well by xestospongin C and lack of extracellularcalcium. Thapsigargin by itself caused accelerated cell death in the WAS platelets. The number of mitochondria was predictive of PS exposure: 33%of platelets from WAS patients with fewer than five mitochondria exposed PS, while only 12% did among those that had five or more mitochondria.Interestingly, healthy donor platelets with fewer mitochondria also more readily became procoagulant upon PAR1/PAR4 stimulation. Collapse of singlemitochondria led to greater cytosolic calcium increase in WAS platelets if they had one to three mitochondria compared with platelets containinghigher numbers. A computer systems biology model of platelet calcium homeostasis showed that smaller platelets with fewer mitochondria couldhave impaired calcium homeostasis because of higher surface-to-volume ratio and greater metabolic load, respectively. There was a correlation (C=0.81, P<0.02) between the mean platelet size and platelet count in theWAS patients. We conclude that WAS platelets readily expose PS via a mitochondria-dependent necrotic mechanism caused by their smaller size,which could contribute to the development of thrombocytopenia
- Добавил в систему: Угарова Наталья Николаевна