Hiran A Prag1,2, Anja V Gruszczyk1,3, Margaret M Huang3, Timothy E Beach3, Timothy Young2,4, Laura Tronci4, Efterpi Nikitopoulou4, John F Mulvey2, Raimondo Ascione5, Anna Hadjihambi6, Michael J Shattock7, Luc Pellerin6,8,9, Kourosh Saeb-Parsy3, Christian Frezza4, Andrew M James1, Thomas Krieg2, Michael P Murphy1,2, Dunja Aksentijević10,11. 1. MRC Mitochondrial Biology Unit, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK. 2. Department of Medicine, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge CB2 0QQ, UK. 3. Department of Surgery, University of Cambridge, Cambridge NIHR Biomedical Research Centre, Biomedical Campus, Hills Road, Cambridge CB2 0QQ, UK. 4. MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, PO Box 197, Cambridge CB2 0XZ, UK. 5. Bristol Medical School and Translational Biomedical Research Centre, Faculty of Health Science, University of Bristol, Level 7, Bristol Royal Infirmary, Upper Maudlin Street, Bristol BS2 8HW, UK. 6. Département de Physiologie, Université de Lausanne, 7 Rue du Bugnon, 1005 Lausanne, Switzerland. 7. King's College London, British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK. 8. Centre de Résonance Magnétique des Systèmes Biologiques, UMR5536 CNRS, LabEx TRAIL-IBIO, Université de Bordeaux, 146 Rue Leo Saignat, Bordeaux 33076, France. 9. Inserm U1082, Université de Poitiers, 2 Rue de la Miletrie, Poitiers 86021, France. 10. William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, UK. 11. Centre for inflammation and Therapeutic Innovation, Queen Mary University of London, Charterhouse Square, London, UK.
Abstract
AIMS: Succinate accumulates several-fold in the ischaemic heart and is then rapidly oxidized upon reperfusion, contributing to reactive oxygen species production by mitochondria. In addition, a significant amount of the accumulated succinate is released from the heart into the circulation at reperfusion, potentially activating the G-protein-coupled succinate receptor (SUCNR1). However, the factors that determine the proportion of succinate oxidation or release, and the mechanism of this release, are not known. METHODS AND RESULTS: To address these questions, we assessed the fate of accumulated succinate upon reperfusion of anoxic cardiomyocytes, and of the ischaemic heart both ex vivo and in vivo. The release of accumulated succinate was selective and was enhanced by acidification of the intracellular milieu. Furthermore, pharmacological inhibition, or haploinsufficiency of the monocarboxylate transporter 1 (MCT1) significantly decreased succinate efflux from the reperfused heart. CONCLUSION: Succinate release upon reperfusion of the ischaemic heart is mediated by MCT1 and is facilitated by the acidification of the myocardium during ischaemia. These findings will allow the signalling interaction between succinate released from reperfused ischaemic myocardium and SUCNR1 to be explored.
AIMS: Succinate accumulates several-fold in the ischaemic heart and is then rapidly oxidized upon reperfusion, contributing to reactive oxygen species production by mitochondria. In addition, a significant amount of the accumulated succinate is released from the heart into the circulation at reperfusion, potentially activating the G-protein-coupled succinate receptor (SUCNR1). However, the factors that determine the proportion of succinate oxidation or release, and the mechanism of this release, are not known. METHODS AND RESULTS: To address these questions, we assessed the fate of accumulated succinate upon reperfusion of anoxic cardiomyocytes, and of the ischaemic heart both ex vivo and in vivo. The release of accumulated succinate was selective and was enhanced by acidification of the intracellular milieu. Furthermore, pharmacological inhibition, or haploinsufficiency of the monocarboxylate transporter 1 (MCT1) significantly decreased succinate efflux from the reperfused heart. CONCLUSION: Succinate release upon reperfusion of the ischaemic heart is mediated by MCT1 and is facilitated by the acidification of the myocardium during ischaemia. These findings will allow the signalling interaction between succinate released from reperfused ischaemic myocardium and SUCNR1 to be explored.
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