Succinate function in metabolism
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Succinate in Cellular Energy Metabolism
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. It serves as a substrate for succinate dehydrogenase (SDH), which is crucial for the generation of adenosine triphosphate (ATP) in cells Zhang2023Mills2014Tretter2016. This fundamental role in energy metabolism is essential for maintaining cellular and organismal energy homeostasis Fernández-Veledo2021Fernández-Veledo2024.
Succinate as a Metabolic Signal and Hormone-Like Messenger
Beyond its metabolic function, succinate acts as a signaling molecule both inside and outside cells. It can activate the G protein-coupled receptor SUCNR1 (also known as GPR91), functioning similarly to hormones by reporting metabolic and stress states to the body Fernández-Veledo2021Fernández-Veledo2024Mills2014+1 MORE. This signaling capacity allows succinate to influence immune responses, inflammation, and tissue-specific metabolic processes Fernández-Veledo2021Zhang2023Mills2014+2 MORE.
Succinate in Inflammation and Disease
Elevated succinate levels are linked to various pathological conditions, including chronic inflammation, ischemia/reperfusion injury, cancer, and metabolic diseases like diabetes and obesity Zhang2023Fernández-Veledo2024Mills2014+3 MORE. Succinate can stabilize hypoxia-inducible factor-1α (HIF-1α), promoting inflammatory and angiogenic responses, especially in hypoxic environments such as tumors or inflamed tissues Mills2014Tretter2016Li2018. In rheumatoid arthritis, for example, succinate accumulation drives angiogenesis and inflammation through both intracellular and extracellular signaling pathways .
Microbiota-Derived Succinate and Host Metabolism
Succinate is also produced by gut microbiota during the fermentation of dietary fiber. This microbiota-derived succinate can improve glucose homeostasis by serving as a substrate for intestinal gluconeogenesis, which helps regulate blood sugar levels De Vadder2016Fernández-Veledo2019. The cross-talk between microbiota-produced succinate and host metabolism highlights its role as a mediator in the gut-liver axis and suggests potential for microbiota-based therapies in metabolic diseases De Vadder2016Fernández-Veledo2019.
Succinate as a Biomarker and Therapeutic Target
Circulating succinate levels are emerging as promising biomarkers for chronic metabolic diseases, including obesity and type 2 diabetes Fernández-Veledo2021Fernández-Veledo2024. Targeting the succinate-SUCNR1 axis, either by modulating succinate concentrations or by pharmacologically influencing SUCNR1, is being explored as a novel therapeutic strategy for managing metabolic and inflammatory diseases Fernández-Veledo2021Zhang2023Fernández-Veledo2024+1 MORE.
Context-Dependent Effects of Succinate
The effects of succinate are highly context-dependent, influenced by factors such as cellular metabolic state, tissue type, and the balance between its intra- and extracellular concentrations . For example, the metabolic substrate available (glucose or glutamine) can alter succinate production and SUCNR1 signaling, which in turn affects cellular energy homeostasis and immune responses .
Conclusion
Succinate is much more than a simple metabolic intermediate. It acts as a crucial link between energy metabolism, cellular signaling, immune regulation, and host-microbiota interactions. Its diverse roles in health and disease make it a key focus for understanding metabolic regulation and developing new therapeutic approaches for metabolic and inflammatory disorders.
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