Succinic acid and its applications

Succinic acid is a dicarboxylic acid with the formula (CH2)2(CO2H)2.The name is derived from the Latin succinum,meaning amber. In living organisms,succinate exists as an anion, succinate,which has various biological roles, as a metabolic intermediate, dehydrogenated by succinate in complex 2 of the electron transport chain involved in the production of ATP The enzyme converts to fumarate and acts as a signaling molecule for metabolites reflecting the state of the cell.Marketed as food additive E363.Succinate is produced in mitochondria via the tricarboxylic acid cycle (TCA).Succinate can leave the mitochondrial matrix and act in the cytoplasm and extracellular space,altering an epigenetic pattern of gene expression and modulating class signaling.Thus,succinate links cellular metabolism,especially ATP formation,with the regulation of cellular function.In some inherited mitochondrial disorders,such as Leigh syndrome and Melas syndrome,succinate synthesis is dysregulated,which in turn leads to dysregulation of ATP synthesis,and degradation can lead to pathological conditions such as malignancy,inflammation, and tissue damage.

Applications 

Precursors to polymers,resins,and solvents:

Succinic acid is a precursor to some polyesters and a component of some alkyd resins.1,4-Butanediol (BDO) can be synthesized using succinic acid as a precursor.The automotive and electronics industries rely heavily on BDO for the production of connectors, insulators,wheel housings, gear levers and reinforcement beams.Succinic acid is also used as the basis for certain biodegradable polymers that are of interest for tissue engineering applications.Acylation with succinic acid is called succinylation.Hypersuccination occurs when more than one succinate is added to the substrate.

Food and dietary supplements:

As a food additive and dietary supplement,succinic acid is generally recognized as safe by the U.S. Food and Drug Administration. Succinic acid is mainly used as an acidity regulator in the food and beverage industry.It is also used as a flavoring agent,adding a touch of sourness and astringency to umami.As an excipient for pharmaceutical products,it is also used to control acidity or as a counterion.Drugs involving succinates include metoprolol succinate,sumatriptan succinate,doxylamine succinate,or solifenacin succinate.

Role in human health:

Inflammation

Metabolic signaling involving succinate may be involved in inflammation by stabilizing HIF1-α or GPR91 signaling in innate immune cells.Through these mechanisms,accumulation of succinate has been shown to regulate inflammatory cytokine production.For dendritic cells,succinate acts as a chemoattractant and increases their antigen-presenting function through receptor-stimulated cytokine production.In inflammatory macrophages,succinate-induced stabilization of HIF1 resulted in increased transcription of HIF1-dependent genes,including the proinflammatory cytokine interleukin-1β.Other inflammatory cytokines produced by activated macrophages,such as tumor necrosis factor or interleukin 6,were not directly affected by succinate and HIF1.The mechanism by which succinate accumulates in immune cells is not fully understood.Activation of inflammatory macrophages via toll-like receptors induces a metabolic shift towards glycolysis.Despite the general downregulation of the TCA cycle under these conditions,succinate concentrations increased.However,lipopolysaccharides involved in macrophage activation increase glutamine and GABA transporters. Thus, succinate may be produced by enhanced glutamine metabolism through alpha-ketoglutarate or GABA shunting.

Tumor occurrence:

Succinate is one of three oncogenic metabolites, and the accumulation of metabolic intermediates leads to metabolic and non-metabolic dysregulation associated with tumorigenesis.Loss-of-function mutations in the gene encoding succinate dehydrogenase frequently found in hereditary paragangliomas and pheochromocytomas lead to pathological increases in succinate.SDH mutations have also been found in gastrointestinal stromal tumors,renal tumors,thyroid tumors,testicular seminoma,and neuroblastoma.The mechanism of carcinogenesis caused by mutated SHD is thought to be related to the ability of succinate to inhibit 2-oxoglutarate-dependent dioxygenase.Inhibition of KDM and TET hydroxylases leads to epigenetic dysregulation and hypermethylation affecting genes involved in cell differentiation.Furthermore, succinate-promoted activation of HIF-1α produces a pseudo-hypoxic state that can promote tumorigenesis through transcriptional activation of genes involved in proliferation,metabolism, and angiogenesis.Two other oncogenic metabolites,fumarate and 2-hydroxyglutarate,have similar structures to succinate and act through a parallel HIF-induced oncogenic mechanism.

Ischemia-reperfusion injury:

Accumulation of succinate under hypoxic conditions is associated with reperfusion injury by increasing ROS production.During ischemia,succinate accumulates.After reperfusion,succinate is rapidly oxidized,resulting in a sudden and massive production of reactive oxygen species.ROS then trigger apoptotic mechanisms or induce oxidative damage to proteins,cell membranes,organelles, etc.Pharmacological inhibition of ischemic succinate accumulation ameliorated ischemia-reperfusion injury in animal models.As of 2016,inhibition of succinate-mediated ROS production is being investigated as a therapeutic drug target.