Mechanism of succinate efflux upon reperfusion of the ischaemic heart

Abstract

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.

Different Roles of Mitochondria in Cell Death and Inflammation: Focusing on Mitochondrial Quality Control in Ischemic Stroke and Reperfusion

“…Upon I/R, complex I has been assessed as the major source of ROS. Following I/R, oxidized succinate, markedly increased during ischemia, provides the initiating burst of ROS production at complex I via reverse electron transport (RET) [ 115 , 116 ] ( Figure 1 ). Under physiological conditions, ROS are important second messengers involved in several cellular pathways [ 117 ], and adequate antioxidant systems limit damage to cellular constituents.…”

DJ-1: A promising therapeutic candidate for ischemia-reperfusion injury

“…Following the acute phase of reperfusion injury, the release of damage-associated molecular patterns (DAMPs) from injured cells leads to activation of an innate immune response [ 71 , 75 ]. Interestingly, metabolites, such as lactate and succinate, effluxed into the circulation during reperfusion, have also recently been postulated to play a role in this immune activation [ 76 , 77 ]. The initial immune response induces the production of pro-inflammatory cytokines and chemokines, facilitating the infiltration of leukocytes and an inflammatory response [ 78 ].…”

Succinate metabolism uncouples retinal pigment epithelium mitochondria

“…The copyright holder for this preprint this version posted February 10, 2021. ; https://doi.org/10.1101/2021.02.10.430650 doi: bioRxiv preprint 10 al., 2000). The transporters for succinate have not been fully characterized, and in addition to plasma membrane dicarboxylate transporters (Kaufhold et al, 2011), MCT1 can also export succinate (Prag et al, 2020;Reddy et al, 2020). This may apply to other MCTs as well.…”

“…The current state of the literature suggests that exogenous succinate is not imported into most cells (Clerc & Polster, 2012;Ehinger et al, 2016;MacDonald et al, 1989;Protti, 2018), despite widespread expression of monocarboxylate and dicarboxylate transporters capable of carrying succinate across the plasma membrane (Andrienko et al, 2017;Nakai et al, 2006;Pajor, 2014;Prag et al, 2020;Reddy et al, 2020). Brown adipose tissue is thought to be the main sink for succinate, allowing it to fuel thermogenesis (Mills et al, 2018).…”

“…The current literature suggests that exogenous succinate is not imported into most cells (Ehinger et al, 2016), despite widespread expression of monocarboxylate and dicarboxylate transporters capable of carrying succinate across the plasma membrane (Andrienko et al, 2017;Nakai et al, 2006;Pajor, 2014;Prag et al, 2020). Succinate is believed to be produced primarily in muscle (Hochachka & Dressendorfer, 1976), pancreas (Jang et al, 2019), and possibly by gut microbiota (Serena et al, 2018).…”