Mechanism of succinate efflux upon reperfusion of the ischaemic heart

Cardiovasc Res. 2021 Mar 21;117(4):1188-1201. doi: 10.1093/cvr/cvaa148.


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.

Keywords: Ischaemia/reperfusion injury; MCT1 transporter; Mitochondria; SUCNR1; Succinate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Disease Models, Animal
  • Female
  • Isolated Heart Preparation
  • Male
  • Metabolome
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria, Heart / metabolism*
  • Monocarboxylic Acid Transporters / genetics
  • Monocarboxylic Acid Transporters / metabolism*
  • Myocardial Infarction / genetics
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / therapy*
  • Myocardial Reperfusion / adverse effects*
  • Myocardial Reperfusion Injury / genetics
  • Myocardial Reperfusion Injury / metabolism*
  • Myocytes, Cardiac / metabolism*
  • Oxidation-Reduction
  • Rats
  • Reactive Oxygen Species / metabolism
  • Receptors, G-Protein-Coupled / metabolism
  • Succinic Acid / metabolism*
  • Sus scrofa
  • Symporters / genetics
  • Symporters / metabolism*
  • Time Factors


  • GPR91 protein, mouse
  • Monocarboxylic Acid Transporters
  • Reactive Oxygen Species
  • Receptors, G-Protein-Coupled
  • Symporters
  • monocarboxylate transport protein 1
  • Succinic Acid