Platelets of COVID-19 patients display mitochondrial dysfunction, oxidative stress, and energy metabolism failure compatible with cell death
© 2023 The Authors..
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 13C-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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:7 |
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| Enthalten in: |
Research and practice in thrombosis and haemostasis - 7(2023), 7 vom: 15. Okt., Seite 102213 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Léopold, Valentine [VerfasserIn] |
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| Links: |
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| Themen: |
Blood platelets |
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| Anmerkungen: |
Date Revised 11.12.2023 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1016/j.rpth.2023.102213 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM365686379 |
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| 100 | 1 | |a Léopold, Valentine |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Platelets of COVID-19 patients display mitochondrial dysfunction, oxidative stress, and energy metabolism failure compatible with cell death |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Revised 11.12.2023 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a © 2023 The Authors. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 13C-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 | ||
| 520 | |a Conclusion: These data link energy metabolism failure in platelets from COVID-19 patients with a prothrombotic platelet phenotype with features matching cell death | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a COVID-19 | |
| 650 | 4 | |a blood platelets | |
| 650 | 4 | |a cell death | |
| 650 | 4 | |a energy metabolism | |
| 650 | 4 | |a mitochondria | |
| 650 | 4 | |a oxidative stress | |
| 700 | 1 | |a Chouchane, Osoul |e verfasserin |4 aut | |
| 700 | 1 | |a Butler, Joe M |e verfasserin |4 aut | |
| 700 | 1 | |a Schuurman, Alex R |e verfasserin |4 aut | |
| 700 | 1 | |a Michels, Erik H A |e verfasserin |4 aut | |
| 700 | 1 | |a de Brabander, Justin |e verfasserin |4 aut | |
| 700 | 1 | |a Schomakers, Bauke V |e verfasserin |4 aut | |
| 700 | 1 | |a van Weeghel, Michel |e verfasserin |4 aut | |
| 700 | 1 | |a Picavet-Havik, Daisy I |e verfasserin |4 aut | |
| 700 | 1 | |a Grootemaat, Anita E |e verfasserin |4 aut | |
| 700 | 1 | |a Douma, Renée A |e verfasserin |4 aut | |
| 700 | 1 | |a Reijnders, Tom D Y |e verfasserin |4 aut | |
| 700 | 1 | |a Klarenbeek, Augustijn M |e verfasserin |4 aut | |
| 700 | 1 | |a Appelman, Brent |e verfasserin |4 aut | |
| 700 | 0 | |a Amsterdam University Medical Center COVID-19 Biobank Study Groupd.vandebeek@amsterdamumc.nl |e verfasserin |4 aut | |
| 700 | 1 | |a Wiersinga, W Joost |e verfasserin |4 aut | |
| 700 | 1 | |a van der Wel, Nicole N |e verfasserin |4 aut | |
| 700 | 1 | |a den Dunnen, Jeroen |e verfasserin |4 aut | |
| 700 | 1 | |a Houtkooper, Riekelt H |e verfasserin |4 aut | |
| 700 | 1 | |a Van't Veer, Cornelis |e verfasserin |4 aut | |
| 700 | 1 | |a van der Poll, Tom |e verfasserin |4 aut | |
| 700 | 0 | |a Amsterdam University Medical Center COVID-19 Biobank Study Group |e verfasserin |4 aut | |
| 700 | 1 | |a Agtmael, Michiel van |e investigator |4 oth | |
| 700 | 1 | |a Algera, Anne Geke |e investigator |4 oth | |
| 700 | 1 | |a Appelman, Brent |e investigator |4 oth | |
| 700 | 1 | |a van Baarle, Floor |e investigator |4 oth | |
| 700 | 1 | |a Beudel, Martijn |e investigator |4 oth | |
| 700 | 1 | |a Bogaard, Harm Jan |e investigator |4 oth | |
| 700 | 1 | |a Bomers, Marije |e investigator |4 oth | |
| 700 | 1 | |a Bonta, Peter |e investigator |4 oth | |
| 700 | 1 | |a Bos, Lieuwe |e investigator |4 oth | |
| 700 | 1 | |a Botta, Michela |e investigator |4 oth | |
| 700 | 1 | |a de Brabander, Justin |e investigator |4 oth | |
| 700 | 1 | |a de Bree, Godelieve |e investigator |4 oth | |
| 700 | 1 | |a de Bruin, Sanne |e investigator |4 oth | |
| 700 | 1 | |a Bugiani, Marianna |e investigator |4 oth | |
| 700 | 1 | |a Bulle, Esther |e investigator |4 oth | |
| 700 | 1 | |a Buis, David Tp |e investigator |4 oth | |
| 700 | 1 | |a Chouchane, Osoul |e investigator |4 oth | |
| 700 | 1 | |a Clohert, Alex |e investigator |4 oth | |
| 700 | 1 | |a Dijkstra, Mirjam |e investigator |4 oth | |
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