Targeting succinate metabolism to decrease brain injury upon mechanical thrombectomy treatment of ischemic stroke
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
Affiliations
Amin Mottahedin
MRC 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.
Hiran A. Prag
Department of Medicine, University of Cambridge, Cambridge University Hospitals, Cambridge, UK
Andreas Dannhorn
Imaging and Data Analytics, Clinical Pharmacology and Safety Sciences, R & D, AstraZeneca, Cambridge, UK
Richard Mair
Division of Neurosurgery, Department of Clinical Neurosciences, Cambridge University Hospitals, Cambridge, UK
Christina Schmidt
CECAD Research Center, Faculty of Medicine, University Hospital Cologne, Cologne, Germany
Ming Yang
CECAD Research Center, Faculty of Medicine, University Hospital Cologne, Cologne, Germany
Annabel Sorby-Adams
MRC Mitochondrial Biology Unit, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Cambridge, UK
Jordan J. Lee
Department of Medicine, University of Cambridge, Cambridge University Hospitals, Cambridge, UK
Nils Burger
MRC Mitochondrial Biology Unit, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Cambridge, UK
Duvaraka Kulaveerasingam
Department of Medicine, University of Cambridge, Cambridge University Hospitals, Cambridge, UK
Margaret M. Huang
MRC Mitochondrial Biology Unit, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Cambridge, UK
Stefano Pluchino
Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, UK
Luca Peruzzotti-Jametti
Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, UK
Richard Goodwin
Imaging and Data Analytics, Clinical Pharmacology and Safety Sciences, R & D, AstraZeneca, Cambridge, UK
Christian Frezza
CECAD Research Center, Faculty of Medicine, University Hospital Cologne, Cologne, Germany
Michael P. Murphy
MRC 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.
Thomas Krieg
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.
