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Succinic acid () is a
dicarboxylic acid In organic chemistry, a dicarboxylic acid is an organic compound containing two carboxyl groups (). The general molecular formula for dicarboxylic acids can be written as , where R can be aliphatic or aromatic.Boy Cornils, Peter Lappe "Dicarbox ...
with the
chemical formula A chemical formula is a way of presenting information about the chemical proportions of atoms that constitute a particular chemical compound or molecule, using chemical element symbols, numbers, and sometimes also other symbols, such as pare ...
(CH2)2(CO2H)2. In living organisms, succinic acid takes the form of an
anion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conven ...
, succinate, which has multiple biological roles as a
metabolic intermediate Metabolic intermediates are compounds produced during the conversion of substrates (starting molecules) into final products in biochemical reactions within cells. Although these intermediates are of relatively minor direct importance to cell ...
being converted into fumarate by the enzyme
succinate dehydrogenase Succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase (SQR) or respiratory complex II is an enzyme complex, found in many bacterial cells and in the inner mitochondrial membrane of eukaryotes. It is the only enzyme that participates ...
in complex 2 of the
electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules which transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...
which is involved in making ATP, and as a signaling molecule reflecting the cellular metabolic state. Succinate is generated in
mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...
via the tricarboxylic acid (TCA) cycle. Succinate can exit the mitochondrial matrix and function in the cytoplasm as well as the extracellular space, changing gene expression patterns, modulating
epigenetic In biology, epigenetics is the study of changes in gene expression that happen without changes to the DNA sequence. The Greek prefix ''epi-'' (ἐπι- "over, outside of, around") in ''epigenetics'' implies features that are "on top of" or "in ...
landscape or demonstrating
hormone A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physio ...
-like signaling. As such, succinate links cellular
metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...
, especially ATP formation, to the regulation of cellular function. Dysregulation of succinate synthesis, and therefore ATP synthesis, happens in some genetic mitochondrial diseases, such as
Leigh syndrome Leigh syndrome (also called Leigh disease and subacute necrotizing encephalomyelopathy) is an inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who fir ...
, and Melas syndrome, and degradation can lead to pathological conditions, such as
malignant Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous benign tumor, ''benign'' tumor in that a malig ...
transformation,
inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
and tissue injury. Succinic acid is marketed as food additive E363. The name derives from Latin ''succinum'', meaning
amber Amber is fossilized tree resin. Examples of it have been appreciated for its color and natural beauty since the Neolithic times, and worked as a gemstone since antiquity."Amber" (2004). In Maxine N. Lurie and Marc Mappen (eds.) ''Encyclopedia ...
.


Physical properties

Succinic acid is a white, odorless solid with a highly acidic taste. In an
aqueous solution An aqueous solution is a solution in which the solvent is water. It is mostly shown in chemical equations by appending (aq) to the relevant chemical formula. For example, a solution of table salt, also known as sodium chloride (NaCl), in water ...
, succinic acid readily ionizes to form its conjugate base, succinate (). As a
diprotic acid An acid is a molecule or ion capable of either donating a proton (i.e. hydrogen cation, H+), known as a Brønsted–Lowry acid, or forming a covalent bond with an electron pair, known as a Lewis acid. The first category of acids are the ...
, succinic acid undergoes two successive deprotonation reactions: :(CH2)2(CO2H)2 → (CH2)2(CO2H)(CO2) + H+ :(CH2)2(CO2H)(CO2) → (CH2)2(CO2)22− + H+ The pKa of these processes are 4.3 and 5.6, respectively. Both anions are colorless and can be isolated as the salts, e.g., Na(CH2)2(CO2H)(CO2) and Na2(CH2)2(CO2)2. In living organisms, primarily succinate, not succinic acid, is found. As a radical group it is called a succinyl () group. Like most simple mono- and dicarboxylic acids, it is not harmful but can be an irritant to skin and eyes.


Commercial production

Historically, succinic acid was obtained from
amber Amber is fossilized tree resin. Examples of it have been appreciated for its color and natural beauty since the Neolithic times, and worked as a gemstone since antiquity."Amber" (2004). In Maxine N. Lurie and Marc Mappen (eds.) ''Encyclopedia ...
by distillation and has thus been known as spirit of amber (). Common industrial routes include
hydrogenation Hydrogenation is a chemical reaction between molecular hydrogen (H2) and another compound or element, usually in the presence of a catalyst such as nickel, palladium or platinum. The process is commonly employed to redox, reduce or Saturated ...
of
maleic acid Maleic acid or ''cis''-butenedioic acid is an organic compound that is a dicarboxylic acid, a molecule with two carboxyl groups. Its chemical formula is HO2CCH=CHCO2H. Maleic acid is the ''cis'' Cis–trans isomerism, isomer of butenedioic acid, ...
, oxidation of 1,4-butanediol, and
carbonylation In chemistry, carbonylation refers to reactions that introduce carbon monoxide (CO) into organic and inorganic substrates. Carbon monoxide is abundantly available and conveniently reactive, so it is widely used as a reactant in industrial chemis ...
of
ethylene glycol Ethylene glycol ( IUPAC name: ethane-1,2-diol) is an organic compound (a vicinal diol) with the formula . It is mainly used for two purposes: as a raw material in the manufacture of polyester fibers and for antifreeze formulations. It is an odo ...
. Succinate is also produced from
butane Butane () is an alkane with the formula C4H10. Butane exists as two isomers, ''n''-butane with connectivity and iso-butane with the formula . Both isomers are highly flammable, colorless, easily liquefied gases that quickly vaporize at ro ...
via
maleic anhydride Maleic anhydride is an organic compound with the formula . It is the acid anhydride of maleic acid. It is a colorless or white solid with an acrid odor. It is produced industrially on a large scale for applications in coatings and polymers. Str ...
. Global production is estimated at 16,000 to 30,000 tons a year, with an annual growth rate of 10%. Genetically engineered ''
Escherichia coli ''Escherichia coli'' ( )Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. is a gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus '' Escherichia'' that is commonly fo ...
'' and ''
Saccharomyces cerevisiae ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungal microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have be ...
'' are proposed for the commercial production via fermentation of
glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...
.


Chemical reactions

Succinic acid can be dehydrogenated to
fumaric acid Fumaric acid or ''trans''-butenedioic acid is an organic compound with the formula HO2CCH=CHCO2H. A white solid, fumaric acid occurs widely in nature. It has a fruit-like taste and has been used as a food additive. Its E number is E297. The sa ...
or be converted to diesters, such as diethylsuccinate (CH2CO2CH2CH3)2. This diethyl ester is a substrate in the Stobbe condensation. Dehydration of succinic acid gives succinic anhydride. Succinate can be used to derive 1,4-butanediol, maleic anhydride, succinimide, 2-pyrrolidinone and
tetrahydrofuran Tetrahydrofuran (THF), or oxolane, is an organic compound with the formula (CH2)4O. The compound is classified as heterocyclic compound, specifically a cyclic ether. It is a colorless, water- miscible organic liquid with low viscosity. It is ...
.


Applications

In 2004, succinate was placed on the US Department of Energy's list of top 12 platform chemicals from biomass.


Precursor to polymers, resins, and solvents

Succinic acid is a precursor to some
polyester Polyester is a category of polymers that contain one or two ester linkages in every repeat unit of their main chain. As a specific material, it most commonly refers to a type called polyethylene terephthalate (PET). Polyesters include some natura ...
s and a component of some
alkyd resin An alkyd is a polyester resin modified by the addition of fatty acids and other components. Alkyds are derived from polyols and organic acids including dicarboxylic acids or carboxylic acid anhydride and triglyceride oils. The term ''alkyd'' is ...
s. 1,4-Butanediol (BDO) can be synthesized using succinic acid as a precursor. The automotive and electronics industries heavily rely on BDO to produce connectors, insulators, wheel covers, gearshift knobs and reinforcing beams. Succinic acid also serves as the bases of certain biodegradable polymers, which are of interest in tissue engineering applications. Acylation with succinic acid is called ''succination''. ''Oversuccination'' occurs when more than one succinate adds to a substrate.


Food and dietary supplement

As a
food additive Food additives are substances added to food to preserve flavor or enhance taste, appearance, or other sensory qualities. Some additives, such as vinegar ( pickling), salt ( salting), smoke ( smoking) and sugar ( crystallization), have been used f ...
and
dietary supplement A dietary supplement is a manufactured product intended to supplement a person's diet by taking a pill (pharmacy), pill, capsule (pharmacy), capsule, tablet (pharmacy), tablet, powder, or liquid. A supplement can provide nutrients eithe ...
, succinic acid is
generally recognized as safe Generally recognized as safe (GRAS) is a United States Food and Drug Administration (FDA) designation that a chemical or substance added to food is considered safe by experts under the conditions of its intended use. An ingredient with a GRAS d ...
by the U.S. Food and Drug Administration. Succinic acid is used primarily as an
acidity regulator Acidity regulators, or pH control agents, are food additives used to change or maintain pH ( acidity or basicity). They can be organic or mineral acids, bases, neutralizing agents, or buffering agents. Typical agents include the following ac ...
in the food and beverage industry. It is also available as a flavoring agent, contributing a somewhat sour and astringent component to umami taste. As an
excipient An excipient is a substance formulated alongside the active ingredient of a medication. They may be used to enhance the active ingredient’s therapeutic properties; to facilitate drug absorption; to reduce viscosity; to enhance solubility; to i ...
in pharmaceutical products, it is also used to control acidity or as a counter ion. Drugs involving succinate include metoprolol succinate, sumatriptan succinate, doxylamine succinate or solifenacin succinate.


Biosynthesis


Tricarboxylic acid (TCA) cycle

Succinate is a key intermediate in the tricarboxylic acid cycle, a primary metabolic pathway used to produce chemical energy in the presence of O2. Succinate is generated from
succinyl-CoA Succinyl-coenzyme A, abbreviated as succinyl-CoA () or SucCoA, is a thioester of succinic acid and coenzyme A. Sources It is an important intermediate in the citric acid cycle, where it is synthesized from Alpha-Ketoglutaric acid, α-ketoglutarate ...
by the enzyme succinyl-CoA synthetase in a GTP/ ATP-producing step: Succinyl-CoA + NDP + Pi → Succinate + CoA + NTP Catalyzed by the enzyme
succinate dehydrogenase Succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase (SQR) or respiratory complex II is an enzyme complex, found in many bacterial cells and in the inner mitochondrial membrane of eukaryotes. It is the only enzyme that participates ...
(SDH), succinate is subsequently oxidized to fumarate: Succinate + FAD → Fumarate + FADH2 SDH also participates in the mitochondrial
electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules which transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...
, where it is known as respiratory complex II. This enzyme complex is a 4 subunit membrane-bound lipoprotein which couples the oxidation of succinate to the reduction of
ubiquinone Coenzyme Q10 (CoQ10 ), also known as ubiquinone, is a naturally occurring Cofactor (biochemistry), biochemical cofactor (coenzyme) and an antioxidant produced by the human body. It can also be obtained from dietary sources, such as meat, fish, ...
via the intermediate electron carriers
FAD A fad, trend, or craze is any form of collective behavior that develops within a culture, a generation, or social group in which a group of people enthusiastically follow an impulse for a short time period. Fads are objects or behaviors tha ...
and three 2Fe-2S clusters. Succinate thus serves as a direct electron donor to the electron transport chain, and itself is converted into fumarate.


Reductive branch of the TCA cycle

Succinate can alternatively be formed by reverse activity of SDH. Under anaerobic conditions certain bacteria such as ''A. succinogenes'', ''A. succiniciproducens'' and ''M. succiniciproducens'', run the TCA cycle in reverse and convert glucose to succinate through the intermediates of
oxaloacetate Oxaloacetic acid (also known as oxalacetic acid or OAA) is a crystalline organic compound with the chemical formula HO2CC(O)CH2CO2H. Oxaloacetic acid, in the form of its conjugate base oxaloacetate, is a metabolic intermediate in many processes ...
,
malate Malic acid is an organic compound with the molecular formula . It is a dicarboxylic acid that is made by all living organisms, contributes to the sour taste of fruits, and is used as a food additive. Malic acid has two stereoisomeric forms ( ...
and fumarate. This pathway is exploited in metabolic engineering to net generate succinate for human use. Additionally, succinic acid produced during the fermentation of sugar provides a combination of saltiness, bitterness and acidity to fermented alcohols. Accumulation of fumarate can drive the reverse activity of SDH, thus enhancing succinate generation. Under pathological and physiological conditions, the malate-aspartate shuttle or the purine nucleotide shuttle can increase mitochondrial fumarate, which is then readily converted to succinate.


Glyoxylate cycle

Succinate is also a product of the glyoxylate cycle, which converts two two-carbon acetyl units into the four-carbon succinate. The glyoxylate cycle is utilized by many bacteria, plants and fungi and allows these organisms to subsist on acetate or acetyl CoA yielding compounds. The pathway avoids the
decarboxylation Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is ...
steps of the TCA cycle via the enzyme isocitrate lyase which cleaves isocitrate into succinate and glyoxylate. Generated succinate is then available for either energy production or biosynthesis.


GABA shunt

Succinate is the re-entry point for the
gamma-aminobutyric acid GABA (gamma-aminobutyric acid, γ-aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. GA ...
(GABA) shunt into the TCA cycle, a closed cycle which synthesizes and recycles GABA. The GABA shunt serves as an alternate route to convert alpha-ketoglutarate into succinate, bypassing the TCA cycle intermediate succinyl-CoA and instead producing the intermediate GABA. Transamination and subsequent decarboxylation of alpha-ketoglutarate leads to the formation of GABA. GABA is then metabolized by
GABA transaminase In enzymology, 4-aminobutyrate transaminase (), also called GABA transaminase or 4-aminobutyrate aminotransferase, or GABA-T, is an enzyme that catalysis, catalyzes the chemical reaction: :4-aminobutanoate + 2-oxoglutarate \rightleftharpoons suc ...
to succinic semialdehyde. Finally, succinic semialdehyde is oxidized by succinic semialdehyde dehydrogenase (SSADH) to form succinate, re-entering the TCA cycle and closing the loop. Enzymes required for the GABA shunt are expressed in neurons, glial cells, macrophages and pancreatic cells.


Cellular metabolism


Metabolic intermediate

Succinate is produced and concentrated in the
mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...
and its primary biological function is that of a metabolic intermediate. All metabolic pathways that are interlinked with the TCA cycle, including the metabolism of carbohydrates, amino acids, fatty acids, cholesterol, and heme, rely on the temporary formation of succinate. The intermediate is made available for biosynthetic processes through multiple pathways, including the reductive branch of the TCA cycle or the glyoxylate cycle, which are able to drive net production of succinate. In rodents, mitochondrial concentrations are approximately ~0.5 mM while plasma concentration are only 2–20 μM.


ROS production

The activity of succinate dehydrogenase (SDH), which interconverts succinate into fumarate participates in mitochondrial
reactive oxygen species In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...
(ROS) production by directing electron flow in the electron transport chain. Under conditions of succinate accumulation, rapid oxidation of succinate by SDH can drive reverse electron transport (RET). If mitochondrial respiratory complex III is unable to accommodate excess electrons supplied by succinate oxidation, it forces electrons to flow backwards along the electron transport chain. RET at mitochondrial respiratory complex 1, the complex normally preceding SDH in the electron transport chain, leads to ROS production and creates a pro-oxidant microenvironment.


Additional biologic functions

In addition to its metabolic roles, succinate serves as an intracellular and extracellular signaling molecule. Extra-mitochondrial succinate alters the epigenetic landscape by inhibiting the family of 2-oxogluterate-dependent dioxygenases. Alternative, succinate can be released into the extracellular milieu and the blood stream where it is recognized by target receptors. In general, leakage from the mitochondria requires succinate overproduction or underconsumption and occurs due to reduced, reverse or completely absent activity of SDH or alternative changes in metabolic state. Mutations in SDH, hypoxia or energetic misbalance are all linked to an alteration of flux through the TCA cycle and succinate accumulation. Upon exiting the mitochondria, succinate serves as a signal of metabolic state, communicating to neighboring cells how metabolically active the originating cell population is. As such, succinate links TCA cycle dysfunction or metabolic changes to cell-cell communication and to oxidative stress-related responses.


Transporters

Succinate requires specific transporters to move through both the mitochondrial and plasma membrane. Succinate exits the mitochondrial matrix and passes through the inner mitochondrial membrane via dicarboxylate transporters, primarily SLC25A10, a succinate-fumarate/malate transporter. In the second step of mitochondrial export, succinate readily crosses the outer mitochondrial membrane through porins, nonspecific protein channels that facilitate the diffusion of molecules less than 1.5 kDa. Transport across the plasma membrane is likely tissue specific. A key candidate transporter is INDY (I'm not dead yet), a sodium-independent anion exchanger, which moves both dicarboxylate and citrate into the bloodstream.


Extracellular signaling

Extracellular succinate can act as a signaling molecule with hormone-like functions in stimulating a variety of cells such as those in the blood, adipose tissues, immune tissues, liver, heart, retina and kidney. Extracellular succinate works by binding to and thereby activating the GPR91 (also termed SUCNR1)
receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...
on the cells that express this receptor. Most studies have reported that the GPR91 protein consists of 330
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
s although a few studies have detected a 334 amino acid product of ''GPR91'' gene. Arg99, His103, Arg252, and Arg281 near the center of the GPR91 protein generate a positively charged binding site for succinate. GPR91 resides on its target cells' surface membranes with its binding site facing the extracellular space. It is a
G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related ...
sub-type of receptor that, depending on the cell type bearing it, interacts with multiple G proteins subtypes including Gs, Gi and Gq. This enables GPR91 to regulate a multitude of signaling outcomes. Succinate has a high affinity for GPR91, with an EC50 (i.e., concentration that induces a half maximal response) for stimulating GPR91 in the 20–50 μM range. Succinate's activation of the GPR91 receptor simulates a wide range of cell types and
physiological Physiology (; ) is the science, scientific study of function (biology), functions and mechanism (biology), mechanisms in a life, living system. As a branches of science, subdiscipline of biology, physiology focuses on how organisms, organ syst ...
responses (see Functions regulated by SUCNR1).


Effect on adipocytes

In
adipocyte Adipocytes, also known as lipocytes and fat cells, are the cell (biology), cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through ...
s, the succinate-activated GPR91 signaling cascade inhibits
lipolysis Lipolysis is the metabolic pathway through which lipid triglycerides are hydrolysis, hydrolyzed into a glycerol and free fatty acids. It is used to mobilize stored energy during fasting or exercise, and usually occurs in Adipose tissue, fat adip ...
.


Effect on the liver and retina

Succinate signaling often occurs in response to hypoxic conditions. In the liver, succinate serves as a
paracrine In cellular biology, paracrine signaling is a form of cell signaling, a type of cellular communication (biology), cellular communication in which a Cell (biology), cell produces a signal to induce changes in nearby cells, altering the behaviour of ...
signal, released by anoxic
hepatocyte A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass. These cells are involved in: * Protein synthesis * Protein storage * Transformation of carbohydrates * Synthesis of cholesterol, bi ...
s, and targets
stellate cell Stellate cells are neurons in the central nervous system, named for their star-like shape formed by dendritic processes radiating from the cell body. These cells play significant roles in various brain functions, including inhibition in the ce ...
s via GPR91. This leads to stellate cell activation and fibrogenesis. Thus, succinate is thought to play a role in liver
homeostasis In biology, homeostasis (British English, British also homoeostasis; ) is the state of steady internal physics, physical and chemistry, chemical conditions maintained by organism, living systems. This is the condition of optimal functioning fo ...
. In the retina, succinate accumulates in
retinal ganglion cell A retinal ganglion cell (RGC) is a type of neuron located near the inner surface (the ganglion cell layer) of the retina of the eye. It receives visual information from photoreceptor cell, photoreceptors via two intermediate neuron types: Bipolar ...
s in response to ischemic conditions.
Autocrine Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with ...
succinate signaling promotes retinal
neovascularization Neovascularization is the natural formation of new blood vessels ('' neo-'' + ''vascular'' + '' -ization''), usually in the form of functional microvascular networks, capable of perfusion by red blood cells, that form to serve as collateral circu ...
, triggering the activation of angiogenic factors such as
endothelial growth factor Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors ...
(VEGF).


Effect on the heart

Extracellular succinate regulates
cardiomyocyte Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall of ...
viability through GPR91 activation; long-term succinate exposure leads to pathological cardiomyocyte
hypertrophy Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It is distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number. Although hypertro ...
. Stimulation of GPR91 triggers at least two signaling pathways in the heart: a MEK1/2 and ERK1/2 pathway that activates hypertrophic gene expression and a
phospholipase C Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role i ...
pathway which changes the pattern of Ca2+ uptake and distribution and triggers
CaM Cam or CAM may refer to: Science and technology * Cam (mechanism), a mechanical linkage which translates motion * Camshaft, a shaft with a cam * Camera or webcam, a device that records images or video In computing * Computer-aided manufacturin ...
-dependent hypertrophic gene activation.


Effect on immune cells

SUCNR1 is highly expressed on immature
dendritic cell A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...
s, where succinate binding stimulates
chemotaxis Chemotaxis (from ''chemical substance, chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell organism, single-cell or multicellular organisms direct thei ...
. Furthermore, SUCNR1 synergizes with
toll-like receptor Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-pass membrane protein, single-spanning receptor (biochemistry), receptors usually expressed on sentinel cells such as macrophages ...
s to increase the production of proinflammatory cytokines such as TNF alpha and interleukin-1beta. Succinate may enhance
adaptive immunity The adaptive immune system (AIS), also known as the acquired immune system, or specific immune system is a subsystem of the immune system that is composed of specialized cells, organs, and processes that eliminate pathogens specifically. The ac ...
by triggering the activity of antigen-presenting cells that, in turn, activate
T-cells T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell ...
.


Effect on platelets

SUCNR1 is one of the highest expressed G protein-coupled receptors on human platelets, present at levels similar to P2Y12, though the role of succinate signaling in
platelet aggregation Platelets or thrombocytes () are a part of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a blood clot. Platelets have no cell nucleus; they are fragments of cytop ...
is debated. Multiple studies have demonstrated succinate-induced aggregation, but the effect has high inter-individual variability.


Effect on the kidneys

Succinate serves as a modulator of blood pressure by stimulating renin release in
macula densa In the kidney, the macula densa is an area of closely packed specialized cells lining the wall of the distal tubule where it touches the glomerulus. Specifically, the macula densa is found in the terminal portion of the distal straight tubule ...
and juxtaglomerular apparatus cells via GPR91. Therapies targeting succinate to reduce cardiovascular risk and hypertension are currently under investigation.


Intracellular signaling

Accumulation of either fumarate or succinate reduces the activity of 2-oxoglutarate-dependent dioxygenases, including histone and DNA
demethylase Demethylases are enzymes that remove methyl (CH3) groups from nucleic acids, proteins (particularly histones), and other molecules. Demethylases are important epigenetics, epigenetic proteins, as they are responsible for transcriptional regulation ...
s, prolyl hydroxylases and collagen prolyl-4-hydroxylases, through
competitive inhibition Competitive inhibition is interruption of a chemistry, chemical pathway owing to one chemical substance inhibiting the effect of another by competing with it for molecular binding, binding or chemical bond, bonding. Any metabolism, metabolic or c ...
. 2-oxoglutarate-dependent dioxygenases require an iron cofactor to catalyze hydroxylations, desaturations and ring closures. Simultaneous to substrate oxidation, they convert 2-oxoglutarate, also known as alpha-ketoglutarate, into succinate and CO2. 2-oxoglutarate-dependent dioxygenases bind substrates in a sequential, ordered manner. First, 2-oxoglutarate coordinates with an Fe(II) ion bound to a conserved 2-histidinyl–1-aspartyl/glutamyl triad of residues present in the enzymatic center. Subsequently, the primary substrate enters the binding pocket and lastly dioxygen binds to the enzyme-substrate complex. Oxidative decarboxylation then generates a ferryl intermediate coordinated to succinate, which serves to oxidize the bound primary substrate. Succinate may interfere with the enzymatic process by attaching to the Fe(II) center first, prohibiting the binding of 2-oxoglutarate. Thus, via enzymatic inhibition, increased succinate load can lead to changes in transcription factor activity and genome-wide alterations in histone and DNA methylation.


Epigenetic effects

Succinate and fumarate inhibit the TET (ten-eleven translocation) family of
5-methylcytosine 5-Methylcytosine (5mC) is a methylation, methylated form of the DNA base cytosine (C) that regulates gene Transcription (genetics), transcription and takes several other biological roles. When cytosine is methylated, the DNA maintains the same s ...
DNA modifying enzymes and the JmjC domain-containing histone lysine demethylase (KDM). Pathologically elevated levels of succinate lead to hypermethylation, epigenetic silencing and changes in neuroendocrine differentiation, potentially driving cancer formation.


Gene regulation

Succinate inhibition of
prolyl hydroxylase Procollagen-proline dioxygenase, commonly known as prolyl hydroxylase, is a member of the class of enzymes known as alpha-ketoglutarate-dependent hydroxylases. These enzymes catalyze the incorporation of oxygen into organic substrates through a me ...
s (PHDs) stabilizes the transcription factor hypoxia inducible factor (HIF)1α. PHDs hydroxylate proline in parallel to oxidatively decarboxylating 2-oxyglutarate to succinate and CO2. In humans, three HIF prolyl 4-hydroxylases regulate the stability of HIFs. Hydroxylation of two prolyl residues in HIF1α facilitates ubiquitin ligation, thus marking it for proteolytic destruction by the ubiquitin/proteasome pathway. Since PHDs have an absolute requirement for molecular oxygen, this process is suppressed in hypoxia allowing HIF1α to escape destruction. High concentrations of succinate will mimic the hypoxia state by suppressing PHDs, therefore stabilizing HIF1α and inducing the transcription of HIF1-dependent genes even under normal oxygen conditions. HIF1 is known to induce transcription of more than 60 genes, including genes involved in vascularization and
angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...
, energy
metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...
, cell survival, and tumor invasion.


Role in human health


Inflammation

Metabolic signaling involving succinate can be involved in
inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
via stabilization of HIF1-alpha or GPR91 signaling in innate immune cells. Through these mechanisms, succinate accumulation has been shown to regulate production of inflammatory
cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
s. For dendritic cells, succinate functions as a chemoattractant and increases their antigen-presenting function via receptor stimulated cytokine production. In inflammatory
macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s, succinate-induced stability of HIF1 results in increased transcription of HIF1-dependent genes, including the pro-inflammatory cytokine interleukin-1β. Other inflammatory cytokines produced by activated macrophages such as
tumor necrosis factor Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...
or
interleukin 6 Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the ''IL6'' gene. In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation. Smoo ...
are not directly affected by succinate and HIF1. The mechanism by which succinate accumulates in immune cells is not fully understood. Activation of inflammatory macrophages through
toll-like receptor Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-pass membrane protein, single-spanning receptor (biochemistry), receptors usually expressed on sentinel cells such as macrophages ...
s induces a metabolic shift towards glycolysis. In spite of a general downregulation of the TCA cycle under these conditions, succinate concentration is increased. However,
lipopolysaccharide Lipopolysaccharide (LPS), now more commonly known as endotoxin, is a collective term for components of the outermost membrane of the cell envelope of gram-negative bacteria, such as '' E. coli'' and ''Salmonella'' with a common structural archit ...
s involved in the activation of macrophages increase
glutamine Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral ...
and GABA transporters. Succinate may thus be produced from enhanced glutamine metabolism via alpha-ketoglutarate or the GABA shunt.


Tumorigenesis

Succinate is one of three oncometabolites, metabolic intermediates whose accumulation causes metabolic and non-metabolic dysregulation implicated in
tumorigenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abn ...
. Loss-of-function mutations in the genes encoding
succinate dehydrogenase Succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase (SQR) or respiratory complex II is an enzyme complex, found in many bacterial cells and in the inner mitochondrial membrane of eukaryotes. It is the only enzyme that participates ...
, frequently found in hereditary
paraganglioma A paraganglioma is a rare neuroendocrine tumour, neuroendocrine neoplasm that may develop at various body sites (including the head, neck, thorax and abdomen). When the same type of tumor is found in the adrenal gland, they are referred to as a p ...
and
pheochromocytoma Pheochromocytoma is a rare tumor of the adrenal medulla composed of chromaffin cells and is part of the paraganglioma (PGL) family of tumors, being defined as an intra-adrenal PGL. These neuroendocrine tumors can be sympathetic, where they relea ...
, cause pathological increase in succinate. SDH mutations have also been identified in gastrointestinal stromal tumors, renal tumors, thyroid tumors, testicular seminomas and neuroblastomas. The oncogenic mechanism caused by mutated SHD is thought to relate to succinate's ability to inhibit 2-oxogluterate-dependent dioxygenases. Inhibition of KDMs and TET hydroxylases results in epigenetic dysregulation and hypermethylation affecting genes involved in
cell differentiation Cellular differentiation is the process in which a stem cell changes from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellular ...
. Additionally, succinate-promoted activation of HIF-1α generates a pseudo-hypoxic state that can promote tumorneogensis by transcriptional activation of genes involved in proliferation, metabolism and angiogenesis. The other two oncometabolites, fumarate and 2-hydroxyglutarate have similar structures to succinate and function through parallel HIF-inducing oncogenic mechanisms.


Ischemia reperfusion injury

Succinate accumulation under hypoxic conditions has been implicated in the
reperfusion injury Reperfusion injury, sometimes called ischemia-reperfusion injury (IRI) or reoxygenation injury, is the tissue damage caused when blood supply returns to tissue ('' re-'' + ''perfusion'') after a period of ischemia or lack of oxygen (anoxia or hy ...
through increased ROS production. During ischemia, succinate accumulates. Upon reperfusion, succinate is rapidly oxidized leading to abrupt and extensive production of ROS. ROS then trigger the cellular apoptotic machinery or induce oxidative damage to proteins, membranes, organelles etc. In animal models, pharmacological inhibition of ischemic succinate accumulation ameliorated ischemia-reperfusion injury. As of 2016 the inhibition of succinate-mediated ROS production was under investigation as a therapeutic
drug target A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets ...
.


See also

*
Flame retardant Flame retardants are a diverse group of chemicals that are added to manufactured materials, such as plastics and textiles, and surface finishes and coatings. Flame retardants are activated by the presence of an combustion, ignition source and pr ...
* Oil of amber, procured by heating succinic acid *
Citric acid cycle The citric acid cycle—also known as the Krebs cycle, Szent–Györgyi–Krebs cycle, or TCA cycle (tricarboxylic acid cycle)—is a series of chemical reaction, biochemical reactions that release the energy stored in nutrients through acetyl-Co ...
*
Metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
* Oncometabolism


References


External links


FDA



Calculator: Water and solute activities in aqueous succinic acid

PubChem: Compound Summary for Succinic Acid
{{DEFAULTSORT:Succinic Acid Citric acid cycle compounds Dicarboxylic acids Excipients Succinates E-number additives Metabolic intermediates