Succinate induces aberrant mitochondrial fission in cardiomyocytes through GPR91 signaling

Abstract

Altered mitochondrial metabolism acts as an initial cause for cardiovascular diseases and metabolic intermediate succinate emerges as a mediator of mitochondrial dysfunction. This work aims to investigate whether or not extracellular succinate accumulation and its targeted G protein-coupled receptor-91 (GPR91) activation induce cardiac injury through mitochondrial impairment. The results showed that extracellular succinate promoted the translocation of dynamin-related protein 1 (Drp1) to mitochondria via protein kinase Cδ (PKCδ) activation, and induced mitochondrial fission factor (MFF) phosphorylation via extracellular signal-regulated kinases-1/2 (ERK1/2) activation in a GPR91-dependent manner. As a result, enhanced localization of MFF and Drp1 in mitochondria promoted mitochondrial fission, leading to mitochondrial dysfunction and cardiomyocyte apoptosis. We further showed that inhibition of succinate release and GPR91 signaling ameliorated oxygen–glucose deprivation-induced injury in cardiomyocytes and isoproterenol-induced myocardial ischemia injury in mice. Taken together, these results showed that in response to cardiac ischemia, succinate release activated GPR91 and induced mitochondrial fission via regulation of PKCδ and ERK1/2 signaling branches. These findings suggest that inhibition of extracellular succinate-mediated GPR91 activation might be a potential therapeutic strategy for protecting cardiomyocytes from ischemic injury.

GPR91 Receptor Mediates Protection against Doxorubicin-Induced Cardiotoxicity without Altering Its Anticancer Efficacy. An In Vitro Study on H9C2 Cardiomyoblasts and Breast Cancer-Derived MCF-7 Cells

“…The expression of GPR91 was validated in H9C2 cells by immunofluorescence staining, in accordance to similar observations by other authors [ 36 ], suggesting that this receptor may be strongly implicated in the protective effects of cis -ES and SUC. However, to ensure and validate the crucial role of the GPR91 receptor in the observed protective effects, a receptor knockout should be performed, as already reported [ 40 , 41 ].…”

“…Indeed, some authors reported that GPR91 induces cardiac hypertrophy [ 15 , 35 ], while others observed that a prolonged incubation of cardiomyocytes with high concentrations of succinate (10 mM) promoted apoptosis [ 16 ]. Similar observations were made in the context of an ischemic injury, where the release of succinate and the triggering of the GPR91-associated signaling pathway were responsible for mitochondrial dysfunction and apoptosis in cardiomyocytes [ 36 ]. In the present study, although both agonists significantly reduced the DOX-induced overactivity of caspase 3, SUC alone induced an increased activity of caspase 3, while no such effect was found for cis -ES alone.…”

The cardiolipin-binding peptide elamipretide mitigates fragmentation of cristae networks following cardiac ischemia reperfusion in rats

“…The modest reduction in RET we observed was also associated with improved cristae ultrastructure. Accordingly, it might be hypothesized that succinate accumulation induces RET, which has been associated with mitochondrial fragmentation 89 .…”

Exercise immunology: Future directions

“…In particular, byproducts of glycolysis and the Kreb cycle, such as lactate and succinate, respectively, have been shown to alter the activities of multiple immune cell types. Succinate, in addition to its role as a Krebs cycle intermediate, acts as a chemical messenger to induce inflammatory responses, 69 and lactate promotes proinflammatory phenotypes in T cells 70 and promotes an anti-inflammatory phenotype in monocytes. 71 Exercise is well known to promote succinate and lactate accumulation; 72 thus, increases in these metabolites may play a role in regulating immunity.…”