Targeting succinate metabolism to decrease brain injury upon mechanical thrombectomy treatment of ischemic stroke
Current treatments for acute ischemic stroke aim to reinstate a normal perfusion in the ischemic territory but can also cause significant ischemia-reperfusion (IR) injury. Previous data in experimental models of stroke show that ischemia leads to the accumulation of succinate, and, upon reperfusion,...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-02-01
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| Series: | Redox Biology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231723000010 |
| _version_ | 1797954091462164480 |
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| author | Amin Mottahedin Hiran A. Prag Andreas Dannhorn Richard Mair Christina Schmidt Ming Yang Annabel Sorby-Adams Jordan J. Lee Nils Burger Duvaraka Kulaveerasingam Margaret M. Huang Stefano Pluchino Luca Peruzzotti-Jametti Richard Goodwin Christian Frezza Michael P. Murphy Thomas Krieg |
| author_facet | Amin Mottahedin Hiran A. Prag Andreas Dannhorn Richard Mair Christina Schmidt Ming Yang Annabel Sorby-Adams Jordan J. Lee Nils Burger Duvaraka Kulaveerasingam Margaret M. Huang Stefano Pluchino Luca Peruzzotti-Jametti Richard Goodwin Christian Frezza Michael P. Murphy Thomas Krieg |
| author_sort | Amin Mottahedin |
| collection | DOAJ |
| description | Current treatments for acute ischemic stroke aim to reinstate a normal perfusion in the ischemic territory but can also cause significant ischemia-reperfusion (IR) injury. Previous data in experimental models of stroke show that ischemia leads to the accumulation of succinate, and, upon reperfusion, the accumulated succinate is rapidly oxidized by succinate dehydrogenase (SDH) to drive superoxide production at mitochondrial complex I. Despite this process initiating IR injury and causing further tissue damage, the potential of targeting succinate metabolism to minimize IR injury remains unexplored. Using both quantitative and untargeted high-resolution metabolomics, we show a time-dependent accumulation of succinate in both human and mouse brain exposed to ischemia ex vivo. In a mouse model of ischemic stroke/mechanical thrombectomy mass spectrometry imaging (MSI) shows that succinate accumulation is confined to the ischemic region, and that the accumulated succinate is rapidly oxidized upon reperfusion. Targeting succinate oxidation by systemic infusion of the SDH inhibitor malonate upon reperfusion leads to a dose-dependent decrease in acute brain injury. Together these findings support targeting succinate metabolism upon reperfusion to decrease IR injury as a valuable adjunct to mechanical thrombectomy in ischemic stroke. |
| first_indexed | 2024-04-10T23:13:11Z |
| format | Article |
| id | doaj.art-41b646b7b62b4c0d9fe37775e8348c63 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-04-10T23:13:11Z |
| publishDate | 2023-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-41b646b7b62b4c0d9fe37775e8348c632023-01-13T04:16:24ZengElsevierRedox Biology2213-23172023-02-0159102600Targeting succinate metabolism to decrease brain injury upon mechanical thrombectomy treatment of ischemic strokeAmin Mottahedin0Hiran A. Prag1Andreas Dannhorn2Richard Mair3Christina Schmidt4Ming Yang5Annabel Sorby-Adams6Jordan J. Lee7Nils Burger8Duvaraka Kulaveerasingam9Margaret M. Huang10Stefano Pluchino11Luca Peruzzotti-Jametti12Richard Goodwin13Christian Frezza14Michael P. Murphy15Thomas Krieg16MRC Mitochondrial Biology Unit, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Cambridge, UK; Department of Physiology, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden; Corresponding author. Nuffield Department of Clinical Neurosciences, University of Oxford, Dorothy Crowfoot Hodgkin Building, Oxford, UK.Department of Medicine, University of Cambridge, Cambridge University Hospitals, Cambridge, UKImaging and Data Analytics, Clinical Pharmacology and Safety Sciences, R & D, AstraZeneca, Cambridge, UKDivision of Neurosurgery, Department of Clinical Neurosciences, Cambridge University Hospitals, Cambridge, UKCECAD Research Center, Faculty of Medicine, University Hospital Cologne, Cologne, GermanyCECAD Research Center, Faculty of Medicine, University Hospital Cologne, Cologne, GermanyMRC Mitochondrial Biology Unit, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Cambridge, UKDepartment of Medicine, University of Cambridge, Cambridge University Hospitals, Cambridge, UKMRC Mitochondrial Biology Unit, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Cambridge, UKDepartment of Medicine, University of Cambridge, Cambridge University Hospitals, Cambridge, UKMRC Mitochondrial Biology Unit, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Cambridge, UKDepartment of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, UKDepartment of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, UKImaging and Data Analytics, Clinical Pharmacology and Safety Sciences, R & D, AstraZeneca, Cambridge, UKCECAD Research Center, Faculty of Medicine, University Hospital Cologne, Cologne, GermanyMRC Mitochondrial Biology Unit, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Cambridge, UK; Department of Medicine, University of Cambridge, Cambridge University Hospitals, Cambridge, UK; Corresponding author. MRC Mitochondria Biology Unit, University of Cambridge, Cambridge, UK.Department of Medicine, University of Cambridge, Cambridge University Hospitals, Cambridge, UK; Corresponding author.Current treatments for acute ischemic stroke aim to reinstate a normal perfusion in the ischemic territory but can also cause significant ischemia-reperfusion (IR) injury. Previous data in experimental models of stroke show that ischemia leads to the accumulation of succinate, and, upon reperfusion, the accumulated succinate is rapidly oxidized by succinate dehydrogenase (SDH) to drive superoxide production at mitochondrial complex I. Despite this process initiating IR injury and causing further tissue damage, the potential of targeting succinate metabolism to minimize IR injury remains unexplored. Using both quantitative and untargeted high-resolution metabolomics, we show a time-dependent accumulation of succinate in both human and mouse brain exposed to ischemia ex vivo. In a mouse model of ischemic stroke/mechanical thrombectomy mass spectrometry imaging (MSI) shows that succinate accumulation is confined to the ischemic region, and that the accumulated succinate is rapidly oxidized upon reperfusion. Targeting succinate oxidation by systemic infusion of the SDH inhibitor malonate upon reperfusion leads to a dose-dependent decrease in acute brain injury. Together these findings support targeting succinate metabolism upon reperfusion to decrease IR injury as a valuable adjunct to mechanical thrombectomy in ischemic stroke.http://www.sciencedirect.com/science/article/pii/S2213231723000010 |
| spellingShingle | Amin Mottahedin Hiran A. Prag Andreas Dannhorn Richard Mair Christina Schmidt Ming Yang Annabel Sorby-Adams Jordan J. Lee Nils Burger Duvaraka Kulaveerasingam Margaret M. Huang Stefano Pluchino Luca Peruzzotti-Jametti Richard Goodwin Christian Frezza Michael P. Murphy Thomas Krieg Targeting succinate metabolism to decrease brain injury upon mechanical thrombectomy treatment of ischemic stroke Redox Biology |
| title | Targeting succinate metabolism to decrease brain injury upon mechanical thrombectomy treatment of ischemic stroke |
| title_full | Targeting succinate metabolism to decrease brain injury upon mechanical thrombectomy treatment of ischemic stroke |
| title_fullStr | Targeting succinate metabolism to decrease brain injury upon mechanical thrombectomy treatment of ischemic stroke |
| title_full_unstemmed | Targeting succinate metabolism to decrease brain injury upon mechanical thrombectomy treatment of ischemic stroke |
| title_short | Targeting succinate metabolism to decrease brain injury upon mechanical thrombectomy treatment of ischemic stroke |
| title_sort | targeting succinate metabolism to decrease brain injury upon mechanical thrombectomy treatment of ischemic stroke |
| url | http://www.sciencedirect.com/science/article/pii/S2213231723000010 |
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