Mechanism of succinate efflux upon reperfusion of the ischemic heart

Hiran A. Prag, Anja V. Gruszczyk, Margaret M. Huang, Timothy E. Beach, Timothy Young, Laura Tronci, Efterpi Nikitopoulou, John F. Mulvey, Raimondo Ascione, Anna Hadjihambi, Michael J. Shattock, Luc Pellerin, Kourosh Saeb-Parsy, Christian Frezza, Andrew M. James, Thomas Krieg, Michael P. Murphy, Dunja Aksentijević*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Aims Succinate accumulates several-fold in the ischemic heart and is then rapidly oxidised upon reperfusion, contributing to reactive oxygen species (ROS) 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 ischemic 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 haploin sufficiency of the monocarboxylate transporter 1 (MCT1) significantly decreased succinate efflux from the reperfused heart.

Succinate release upon reperfusion of the ischemic heart is mediated by MCT1
and is facilitated by the acidification of the myocardium during ischemia. These findings will allow the signalling interaction between succinate released from reperfused ischemic myocardium and SUCNR1 to be explored.
Original languageEnglish
Article numbercvaa148
Number of pages14
JournalCardiovascular Research
Early online date7 Aug 2020
Publication statusE-pub ahead of print - 7 Aug 2020


  • ischemia/reperfusion injury
  • succinate
  • MCT1 transporter
  • mitochondria
  • SUCNR1


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