Platelets of COVID-19 patients display mitochondrial dysfunction, oxidative stress, and energy metabolism failure compatible with cell death.

Autor:	Léopold V; Amsterdam University Medical Center, University of Amsterdam, Center for Experimental and Molecular Medicine (CEMM), Meibergdreef 9, Amsterdam, The Netherlands.; Université Paris Cité, INSERM UMR-S 942 (MASCOT), Paris, France.; Department of Anesthesiology and Critical Care and Burn Unit, Saint-Louis and Lariboisière Hospitals, Assistance Publique des Hôpitaux de Paris Nord, Paris, France., Chouchane O; Amsterdam University Medical Center, University of Amsterdam, Center for Experimental and Molecular Medicine (CEMM), Meibergdreef 9, Amsterdam, The Netherlands., Butler JM; Amsterdam University Medical Center, University of Amsterdam, Center for Experimental and Molecular Medicine (CEMM), Meibergdreef 9, Amsterdam, The Netherlands., Schuurman AR; Amsterdam University Medical Center, University of Amsterdam, Center for Experimental and Molecular Medicine (CEMM), Meibergdreef 9, Amsterdam, The Netherlands., Michels EHA; Amsterdam University Medical Center, University of Amsterdam, Center for Experimental and Molecular Medicine (CEMM), Meibergdreef 9, Amsterdam, The Netherlands., de Brabander J; Amsterdam University Medical Center, University of Amsterdam, Center for Experimental and Molecular Medicine (CEMM), Meibergdreef 9, Amsterdam, The Netherlands., Schomakers BV; Amsterdam University Medical Center, University of Amsterdam, Laboratory Genetic Metabolic Diseases, Meibergdreef 9, Amsterdam, The Netherlands.; Amsterdam Gastroenterology Endocrinology and Metabolism Institute, Meibergdreef 9, Amsterdam, The Netherlands.; Amsterdam Cardiovascular Sciences Institute, Meibergdreef 9, Amsterdam, The Netherlands.; Amsterdam University Medical Center, University of Amsterdam, Core Facility Metabolomics, Meibergdreef 9, Amsterdam, The Netherlands., van Weeghel M; Amsterdam University Medical Center, University of Amsterdam, Laboratory Genetic Metabolic Diseases, Meibergdreef 9, Amsterdam, The Netherlands.; Amsterdam Gastroenterology Endocrinology and Metabolism Institute, Meibergdreef 9, Amsterdam, The Netherlands.; Amsterdam Cardiovascular Sciences Institute, Meibergdreef 9, Amsterdam, The Netherlands.; Amsterdam University Medical Center, University of Amsterdam, Core Facility Metabolomics, Meibergdreef 9, Amsterdam, The Netherlands., Picavet-Havik DI; Amsterdam University Medical Center, University of Amsterdam, Electron Microscopy Centre Amsterdam, Medical Biology, Meibergdreef 9, Amsterdam, The Netherlands., Grootemaat AE; Amsterdam University Medical Center, University of Amsterdam, Electron Microscopy Centre Amsterdam, Medical Biology, Meibergdreef 9, Amsterdam, The Netherlands., Douma RA; Flevo Hospital, Department of Internal Medicine, Almere, The Netherlands., Reijnders TDY; Amsterdam University Medical Center, University of Amsterdam, Center for Experimental and Molecular Medicine (CEMM), Meibergdreef 9, Amsterdam, The Netherlands., Klarenbeek AM; Amsterdam University Medical Center, University of Amsterdam, Center for Experimental and Molecular Medicine (CEMM), Meibergdreef 9, Amsterdam, The Netherlands., Appelman B; Amsterdam University Medical Center, University of Amsterdam, Center for Experimental and Molecular Medicine (CEMM), Meibergdreef 9, Amsterdam, The Netherlands., Wiersinga WJ; Amsterdam University Medical Center, University of Amsterdam, Center for Experimental and Molecular Medicine (CEMM), Meibergdreef 9, Amsterdam, The Netherlands.; Amsterdam University Medical Center, University of Amsterdam, Division of Infectious Diseases, Meibergdreef 9, Amsterdam, The Netherlands., van der Wel NN; Amsterdam University Medical Center, University of Amsterdam, Electron Microscopy Centre Amsterdam, Medical Biology, Meibergdreef 9, Amsterdam, The Netherlands., den Dunnen J; Amsterdam University Medical Center, University of Amsterdam, Center for Experimental and Molecular Medicine (CEMM), Meibergdreef 9, Amsterdam, The Netherlands., Houtkooper RH; Amsterdam University Medical Center, University of Amsterdam, Laboratory Genetic Metabolic Diseases, Meibergdreef 9, Amsterdam, The Netherlands.; Amsterdam Gastroenterology Endocrinology and Metabolism Institute, Meibergdreef 9, Amsterdam, The Netherlands.; Amsterdam Cardiovascular Sciences Institute, Meibergdreef 9, Amsterdam, The Netherlands.; Amsterdam University Medical Center, University of Amsterdam, Core Facility Metabolomics, Meibergdreef 9, Amsterdam, The Netherlands., Van't Veer C; Amsterdam University Medical Center, University of Amsterdam, Center for Experimental and Molecular Medicine (CEMM), Meibergdreef 9, Amsterdam, The Netherlands., van der Poll T; Amsterdam University Medical Center, University of Amsterdam, Center for Experimental and Molecular Medicine (CEMM), Meibergdreef 9, Amsterdam, The Netherlands.; Amsterdam University Medical Center, University of Amsterdam, Division of Infectious Diseases, Meibergdreef 9, Amsterdam, The Netherlands.
Jazyk:	angličtina
Zdroj:	Research and practice in thrombosis and haemostasis [Res Pract Thromb Haemost] 2023 Sep 28; Vol. 7 (7), pp. 102213. Date of Electronic Publication: 2023 Sep 28 (Print Publication: 2023).
DOI:	10.1016/j.rpth.2023.102213
Abstrakt:	Background: Alterations in platelet function have been implicated in the pathophysiology of COVID-19 since the beginning of the pandemic. While early reports linked hyperactivated platelets to thromboembolic events in COVID-19, subsequent investigations demonstrated hyporeactive platelets with a procoagulant phenotype. Mitochondria are important for energy metabolism and the function of platelets. Objectives: Here, we sought to map the energy metabolism of platelets in a cohort of noncritically ill COVID-19 patients and assess platelet mitochondrial function, activation status, and responsiveness to external stimuli. Methods: We enrolled hospitalized COVID-19 patients and controls between October 2020 and December 2021. Platelets function and metabolism was analyzed by flow cytometry, metabolomics, glucose fluxomics, electron and fluorescence microscopy and western blot. Results: Platelets from COVID-19 patients showed increased phosphatidylserine externalization indicating a procoagulant phenotype and hyporeactivity to ex vivo stimuli, associated with profound mitochondrial dysfunction characterized by mitochondrial depolarization, lower mitochondrial DNA-encoded transcript levels, an altered mitochondrial morphology consistent with increased mitochondrial fission, and increased pyruvate/lactate ratios in platelet supernatants. Metabolic profiling by untargeted metabolomics revealed NADH, NAD + , and ATP among the top decreased metabolites in patients' platelets, suggestive of energy metabolism failure. Consistently, platelet fluxomics analyses showed a strongly reduced utilization of 13 C-glucose in all major energy pathways together with a rerouting of glucose to de novo generation of purine metabolites. Patients' platelets further showed evidence of oxidative stress, together with increased glutathione oxidation and synthesis. Addition of plasma from COVID-19 patients to normal platelets partially reproduced the phenotype of patients' platelets and disclosed a temporal relationship between mitochondrial decay and (subsequent) phosphatidylserine exposure and hyporeactivity. Conclusion: These data link energy metabolism failure in platelets from COVID-19 patients with a prothrombotic platelet phenotype with features matching cell death. (© 2023 The Authors.)
Databáze:	MEDLINE
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