|Title||Mechanism of succinate efflux upon reperfusion of the ischemic heart.|
|Publication Type||Journal Article|
|Year of Publication||2020|
|Authors||Prag, HA, Gruszczyk, AV, Huang, MM, Beach, TE, Young, T, Tronci, L, Nikitopoulou, E, Mulvey, JF, Ascione, R, Hadjihambi, A, Shattock, MJ, Pellerin, L, Saeb-Parsy, K, Frezza, C, James, AM, Krieg, T, Murphy, MP, Aksentijević, D|
|Date Published||2020 Aug 07|
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 haploinsufficiency of the monocarboxylate transporter 1 (MCT1) significantly decreased succinate efflux from the reperfused heart.
CONCLUSION: 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.
TRANSLATIONAL PERSPECTIVES: In this study we demonstrate that succinate efflux upon reperfusion of the ischemic myocardium is mediated by the monocarboxylate transporter 1 (MCT1) and is enhanced by the ischemic acidification of the heart. These findings are an important advance in understanding how succinate is released upon reperfusion of ischemic organs. While this pathway is therapeutically tractable, greater understanding of the effects of succinate release is required before exploring this possibility.
|Alternate Journal||Cardiovasc. Res.|