SuccinateEdit

Succinate is a central metabolite in cellular energy production and a candidate signaling molecule whose activities extend beyond the mitochondrion. As a four-carbon dicarboxylic acid, it sits at a key crossroads of metabolism and communication, connecting the core biochemical machinery of the cell with systemic physiological responses. In the mitochondrion, succinate is produced in the Krebs cycle (also called the TCA cycle) from succinyl-CoA and is oxidized by the enzyme succinate dehydrogenase to fumarate, a step that also links metabolism to the electron transport chain. Beyond its intracellular role, succinate can accumulate outside the cell and activate signaling pathways through the receptor SUCNR1, influencing processes such as blood pressure regulation, inflammation, and adipose tissue metabolism. The dual character of succinate—as an indispensable metabolic intermediate and as a potential extracellular signal—makes it a focal point in discussions of metabolism, disease, and therapeutic innovation.

Biochemistry and metabolism

Chemical properties and structure - Succinate is a small, dicarboxylic acid with the chemical formula C4H6O4. Its two carboxyl groups confer strong polarity, enabling participation in both thiol-dependent reactions within the tricarboxylic acid machinery and signaling processes when present outside the cell.

Role in central metabolism - In the mitochondrial matrix, succinate is produced from succinyl-CoA by succinyl-CoA synthetase (transfer of a high-energy phosphate to coenzyme A) and then oxidized to fumarate by succinate dehydrogenase, a flavoprotein that doubles as Complex II of the electron transport chain. This arrangement places succinate at the interface between substrate-level phosphorylation and oxidative phosphorylation, helping to balance energy production with redox status. - The conversion of succinate to fumarate reduces the pool of reduced equivalents that feed the respiratory chain, while the subsequent steps in the cycle regenerate oxaloacetate for continued operation of the pathway. These dynamics matter in tissues with high energetic demands, such as heart and skeletal muscle, and in cells undergoing rapid metabolic remodeling.

Production, export, and catabolism - In addition to intracellular synthesis, succinate can be produced by gut microbiota through fermentation, notably by certain bacterial phyla such as Bacteroidetes. Microbial succinate can influence host metabolism and immunity in the gut and beyond. - Prokaryotic and eukaryotic cells can export succinate under specific conditions, creating a means for extracellular signaling that engages receptors on neighboring cells or distant tissues. - Catabolism of extracellular succinate typically involves uptake and reconversion to metabolic intermediates, feeding back into the Krebs cycle or other biosynthetic pathways.

Signaling and physiology

Extracellular signaling via SUCNR1 - Succinate can act as an extracellular signal by binding to the G protein-coupled receptor SUCNR1 (also known as GPR91). Activation of this receptor influences physiological processes such as renin release in the kidney, regulation of blood pressure, and inflammatory responses in various tissues. - The receptor-mediated effects of succinate illustrate a broader principle in which metabolic intermediates serve dual roles: they participate in intracellular energy production while also conveying tissue- and system-level information about metabolic state.

Hypoxia signaling and inflammation - Within cells, elevated succinate can inhibit prolyl hydroxylases that regulate the stability of hypoxia-inducible factor (HIF-1α). Stabilization of HIF-1α can promote angiogenesis and alter metabolic programming in ways that support tissue adaptation to low oxygen, with implications for development, wound healing, and cancer biology. - Extracellular succinate–SUCNR1 signaling has been linked to inflammatory pathways, including the activation of immune cells and the release of inflammatory mediators. The exact contribution of succinate signaling to human disease remains an active area of research.

Physiological and clinical significance

Ischemia, reperfusion injury, and redox biology - In ischemic tissues, succinate tends to accumulate as a consequence of altered metabolism and reduced oxidative flux. Upon reperfusion, rapid oxidation of accumulated succinate can drive reactive oxygen species production via the mitochondrial electron transport chain, contributing to tissue injury. This mechanistic link has informed strategies seeking to modulate succinate flux as a therapeutic approach to ischemia–reperfusion injury.

Cancer metabolism and hereditary tumor syndromes - Mutations in enzymes of the TCA cycle, including succinate dehydrogenase (SDH), can lead to succinate accumulation and contribute to tumorigenesis in hereditary cancer syndromes such as those involving SDHx genes. Accumulated succinate can promote epigenetic changes and alter cellular metabolism in ways that support tumor growth, making these pathways potential targets for therapy and diagnostic biomarkers. - In some cancers, altered succinate signaling may influence angiogenesis, immune microenvironment, and metabolic plasticity, underscoring the broader theme that metabolic intermediates can shape the behavior of malignant cells.

Metabolic disease and microbiome interactions - Variations in succinate levels have been observed in metabolic conditions such as obesity and type 2 diabetes in certain studies, where altered tissue metabolism and inflammatory tone coincide with changes in metabolite signaling. The gut microbiome contributes a further layer of complexity, with succinate produced by intestinal bacteria potentially affecting host energy balance and immune function. - The therapeutic potential of modulating succinate signaling—whether by receptor antagonists, enzyme inhibitors, or dietary interventions—remains an active area of translational research. The goal in this area is to achieve meaningful clinical benefits without unintended metabolic disturbance.

Controversies and debates

  • Extracellular signaling versus metabolic byproduct

    • A central debate centers on how much extracellular succinate signaling via SUCNR1 actually shapes physiology in humans, versus being a secondary consequence of metabolic flux. Proponents of signaling emphasize clear receptors and observed effects in multiple tissues; critics call for more rigorous demonstration of causality in humans and caution against overestimating the reach of a single metabolite.

  • Therapeutic targeting and side effects

    • The idea of targeting SUCNR1 or related metabolic nodes holds promise for metabolic and inflammatory diseases, but there are concerns about off-target effects given the receptor’s presence in multiple organ systems and the interconnected nature of metabolism. Skeptics urge careful risk–benefit analyses and robust trials to avoid unintended consequences in blood pressure regulation, renal function, or immune responses.

  • Translational reliability of model systems

    • As with many metabolic mediators, findings in cell culture or animal models do not always translate cleanly to humans. Critics caution against premature clinical enthusiasm and advocate for diverse, well-controlled studies that replicate results across species and tissues.

  • Biomarker versus mechanism

    • Elevated or reduced succinate levels in disease contexts can reflect an underlying disturbance rather than serve as a direct driver of pathology. The field continues to strive to distinguish correlative biomarkers from causative mediators, a distinction with implications for diagnostics and therapy.

See also