Succinate function in cellular metabolism
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Succinate in Cellular Metabolism: TCA Cycle and Energy Production
Succinate is a key intermediate in the tricarboxylic acid (TCA) cycle, also known as the Krebs cycle, where it plays a central role in mitochondrial energy production. As a substrate for succinate dehydrogenase (SDH), succinate contributes to the generation of adenosine triphosphate (ATP) by facilitating electron transfer within the mitochondrial respiratory chain, which is essential for cellular energy homeostasis Zhang2023Mills2014Murphy2022. When mitochondrial function is impaired, such as during injury or metabolic stress, succinate supplementation can help restore oxidative metabolism and improve cellular energy states, as shown in glial cell models .
Succinate as a Metabolic Signal: Beyond Energy Production
Recent research has revealed that succinate is not just a metabolic intermediate but also acts as a signaling molecule both inside and outside the cell. Succinate can accumulate in the cytosol and extracellular space under certain conditions, such as inflammation or hypoxia, and acts as a signal to modulate cellular responses Mills2014Huang2024Fernández-Veledo2021. It stabilizes hypoxia-inducible factor-1α (HIF-1α) by inhibiting prolyl hydroxylases, thereby enhancing inflammatory responses and cellular adaptation to low oxygen environments Mills2014Huang2024Zhang2023.
Succinate Receptor 1 (SUCNR1/GPR91) and Cellular Signaling
Succinate exerts many of its signaling effects through the G-protein-coupled receptor SUCNR1 (also known as GPR91), which is expressed in various tissues including the kidney, liver, heart, and immune cells Liebing2025Fernández-Veledo2021Fernández-Veledo2024+1 MORE. Activation of SUCNR1 by succinate can lead to diverse physiological and pathological effects, such as regulation of blood pressure, inhibition of fat breakdown, immune cell activation, and tissue remodeling De Castro Fonseca2016Fernández-Veledo2021Fernández-Veledo2024. The specific outcomes of SUCNR1 signaling depend on the cell type, subcellular localization of the receptor, and the metabolic state of the cell, with different energy substrates (like glucose or glutamine) influencing succinate production and receptor activity .
Succinate in Immune Regulation and Inflammation
Succinate has emerged as a crucial regulator of immune cell function, particularly in macrophages. It can promote or suppress inflammation depending on the context, the form of succinate, and the presence or absence of SUCNR1 Mills2014Huang2024Harber2020. Elevated succinate levels are linked to exaggerated immune responses in diseases such as rheumatoid arthritis, inflammatory bowel disease, obesity, and atherosclerosis Huang2024Zhang2023. In macrophages, succinate can either enhance or inhibit the production of inflammatory mediators, highlighting its context-dependent immunoregulatory role .
Succinate as a Biomarker and Therapeutic Target in Metabolic Diseases
Circulating succinate levels are increasingly recognized as biomarkers for metabolic diseases, including diabetes and obesity Fernández-Veledo2021Fernández-Veledo2024. The succinate–SUCNR1 axis is being explored as a potential therapeutic target, with strategies aimed at modulating succinate concentrations or SUCNR1 activity to manage disease complications Fernández-Veledo2024Zhang2023. Manipulating succinate metabolism or signaling may offer new avenues for treating inflammation, ischemia/reperfusion injury, cancer, and metabolic disorders Zhang2023Fernández-Veledo2024.
Succinate as a Reporter of Mitochondrial Redox State
Succinate levels reflect the redox state of the mitochondrial coenzyme Q (CoQ) pool, integrating information about mitochondrial electron supply, oxygen availability, and ATP demand. This allows succinate to act as a messenger, communicating mitochondrial status to the rest of the cell and even to other cells via the circulation . This regulatory function explains many of the emerging roles of succinate in cellular adaptation and stress responses .
Conclusion
Succinate is a central metabolite in cellular metabolism, bridging energy production, metabolic signaling, and immune regulation. Its functions extend beyond the TCA cycle, acting as a key messenger in cellular adaptation, inflammation, and disease. Understanding the diverse roles of succinate and its receptor SUCNR1 opens new possibilities for diagnostics and therapeutic interventions in metabolic and inflammatory diseases.
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