Succinate what does it do
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The Multifaceted Role of Succinate in Biological Processes
Succinate, a key intermediate in the tricarboxylic acid (TCA) cycle, has emerged as a significant player beyond its traditional metabolic role. Recent research highlights its involvement in various physiological and pathological processes, including inflammation, metabolism, and disease progression.
Succinate and Inflammation
Pro-Inflammatory Signaling
Succinate has been shown to communicate pro-inflammatory signals to the host. In a pig model, dietary succinate activated the expression of succinate receptor 1 (SUCNR1) and increased the concentrations of pro-inflammatory cytokines in the intestine. This activation disrupted bile acid metabolism by inhibiting the ileal Farnesol X receptor (FXR) and its target genes, promoting hepatic bile acid secretion, and altering the bile acid metabolic profile. Additionally, succinate stabilizes hypoxia-inducible factor-1α (HIF-1α) in activated macrophages, further contributing to inflammation.
Immune Cell Activation
Succinate produced by gut microbiota can regulate host homeostasis and treat diseases such as inflammation. It activates intestinal mucosal cells, including macrophages, dendritic cells, and intestinal epithelial cells, thereby playing a crucial role in the gut-immune tissue axis. This metabolite also influences macrophage polarization, promoting the formation of tumor-associated macrophages (TAMs) that support tumor progression and metastasis.
Succinate in Metabolic Regulation
Thermogenesis
Succinate plays a pivotal role in adipose tissue thermogenesis. It accumulates in brown adipose tissue upon exposure to cold, driving thermogenic respiration through succinate dehydrogenase-mediated oxidation. This process generates reactive oxygen species, which are essential for thermogenesis. Systemic administration of succinate in mice has been shown to protect against diet-induced obesity and improve glucose tolerance.
Liver Fibrogenesis
In the liver, succinate promotes fibrogenesis by activating hepatic stellate cells (HSCs). It induces HSC proliferation, migration, and inhibits apoptosis, leading to increased production of inflammatory cytokines and extracellular matrix components. This suggests that targeting succinate accumulation could be a potential therapeutic strategy for reversing liver fibrosis.
Succinate in Disease Contexts
Cancer Progression
Succinate's role extends into cancer biology, where it modulates the hypoxic response and protein succinylation. Mutations in succinate dehydrogenase (SDH) can lead to tumor formation and inflammatory processes. Succinate also promotes cancer cell migration, invasion, and metastasis by activating SUCNR1 and the PI3K-HIF-1α axis .
Angiogenesis
Succinate induces angiogenesis through metabolic remodeling and the HIF-1α/VEGF axis. In rheumatoid arthritis, succinate accumulation in the synovium promotes VEGF production and angiogenesis, exacerbating inflammation. Suppressing SDH activity can prevent succinate accumulation and inhibit angiogenesis, offering a potential therapeutic approach. Additionally, succinate injection has been shown to promote angiogenesis and improve functional recovery following acute peripheral ischemia in rodent models.
Conclusion
Succinate is a versatile metabolite with roles extending far beyond its traditional function in the TCA cycle. It acts as a signaling molecule in inflammation, metabolic regulation, and disease progression, influencing processes such as immune cell activation, thermogenesis, fibrogenesis, cancer progression, and angiogenesis. Understanding these diverse roles opens new avenues for therapeutic interventions targeting succinate pathways in various diseases.
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