View source for Chemistry:Succinic acid

{{short description|Dicarboxylic acid}}
{{chembox
| Watchedfields = changed
| verifiedrevid = 470471892
| Name = Succinic acid
| ImageFile_Ref = {{chemboximage|correct|??}}
| ImageFile = Bernsteinsäure2.svg
| ImageFile1 = Succinic acid molecule ball from xtal.png
| ImageFile2 = Sample of succinic acid.jpg
| ImageSize2 = 200px
| PIN = Butanedioic acid<ref name=iupac2013>{{cite book | title =  Nomenclature of Organic Chemistry : IUPAC Recommendations and Preferred Names 2013 (Blue Book) | publisher = [[Organization:Royal Society of Chemistry|The Royal Society of Chemistry]] | date = 2014 | location = Cambridge | page = 747 | doi = 10.1039/9781849733069-00648 | isbn = 978-0-85404-182-4| chapter = CHAPTER P-6. Applications to Specific Classes of Compounds }}</ref>
| OtherNames = Succinic acid<ref name=iupac2013 /><br />1,4-Butanedioic acid
|Section1={{Chembox Identifiers
| IUPHAR_ligand = 3637
| PubChem = 1110
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = AB6MNQ6J6L
| InChI = 1/C4H6O4/c5-3(6)1-2-4(7)8/h1-2H2,(H,5,6)(H,7,8)
| InChIKey = KDYFGRWQOYBRFD-UHFFFAOYAC
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 576
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C4H6O4/c5-3(6)1-2-4(7)8/h1-2H2,(H,5,6)(H,7,8)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = KDYFGRWQOYBRFD-UHFFFAOYSA-N
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo = 110-15-6
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 1078
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00139
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 15741
| SMILES = C(CC(=O)O)C(=O)O
}}
|Section2={{Chembox Properties
| C=4 | H=6 | O=4
| Density = 1.56 g/cm<sup>3</sup><ref name=GESTIS/>
| MeltingPtC = 184 - 190
| MeltingPt_ref = <ref name=GESTIS>{{GESTIS|ZVG=37700}}</ref><ref>{{Cite journal|last1=Chikhalia|first1=V.|last2=Forbes|first2=R.T.|last3=Storey|first3=R.A.|last4=Ticehurst|first4=M.|date=January 2006|title=The effect of crystal morphology and mill type on milling induced crystal disorder |journal=European Journal of Pharmaceutical Sciences|volume=27|issue=1|pages=19–26|doi=10.1016/j.ejps.2005.08.013|pmid=16246535|issn=0928-0987}}</ref>
| BoilingPtC = 235
| BoilingPt_ref = <ref name=GESTIS/>
| Solubility = 58 g/L (20 °C)<ref name=GESTIS/> or 100 mg/mL<ref name="SigmaAl">{{cite web | url=https://www.sigmaaldrich.com/content/dam/sigma-aldrich/docs/Sigma-Aldrich/Product_Information_Sheet/398055pis.pdf | title=Product Information Sheet: Succinic Acid | publisher=Sigma Aldrich | access-date=7 November 2015 | archive-date=7 November 2017 | archive-url=https://web.archive.org/web/20171107151056/https://www.sigmaaldrich.com/content/dam/sigma-aldrich/docs/Sigma-Aldrich/Product_Information_Sheet/398055pis.pdf | url-status=dead }}</ref>
| Solubility1 = 158 mg/mL<ref name="SigmaAl"/>
| Solvent1 = Methanol
| Solubility2 = 54 mg/mL<ref name="SigmaAl"/>
| Solvent2 = Ethanol
| Solubility3 = 27 mg/mL<ref name="SigmaAl"/>
| Solvent3 = Acetone
| Solubility4 = 50 mg/mL<ref name="SigmaAl"/>
| Solvent4 = Glycerol
| Solubility5 = 8.8 mg/mL<ref name="SigmaAl"/>
| Solvent5 = Ether
| pKa = p''K''<sub>a1</sub> = 4.2<br />p''K''<sub>a2</sub> = 5.6
| MagSus = -57.9·10<sup>−6</sup> cm<sup>3</sup>/mol
  }}
|Section3={{Chembox Hazards
| MainHazards =
| FlashPtC = 206
| FlashPt_ref = <ref name=GESTIS/>
| AutoignitionPt = }}
|Section4={{Chembox Related
| OtherAnions = sodium succinate
| OtherFunction_label = [[Chemistry:Carboxylic acid|carboxylic acid]]s
| OtherFunction = [[Chemistry:Propionic acid|propionic acid]]<br />[[Chemistry:Malonic acid|malonic acid]]<br />[[Chemistry:Butyric acid|butyric acid]]<br />[[Chemistry:Malic acid|malic acid]]<br />[[Chemistry:Tartaric acid|tartaric acid]]<br />[[Chemistry:Fumaric acid|fumaric acid]]<br />[[Chemistry:Valeric acid|valeric acid]]<br />[[Chemistry:Glutaric acid|glutaric acid]]
  }}
}}

'''Succinic acid''' ({{IPAc-en|s|ə|k|ˈ|s|ɪ|n|ᵻ|k}})  is a [[Chemistry:Dicarboxylic acid|dicarboxylic acid]] with the [[Chemistry:Chemical formula|chemical formula]] (CH<sub>2</sub>)<sub>2</sub>(CO<sub>2</sub>H)<sub>2</sub>.<ref name=Toxnet/>  In living organisms, succinic acid takes the form of an anion, '''succinate''', which has multiple biological roles as a [[Biology:Metabolic intermediate|metabolic intermediate]] being converted into [[Chemistry:Fumaric acid|fumarate]] by the enzyme [[Biology:Succinate dehydrogenase|succinate dehydrogenase]] in complex 2 of the [[Biology:Electron transport chain|electron transport chain]] which is involved in making [[Chemistry:Adenosine triphosphate|ATP]], and as a signaling molecule reflecting the cellular metabolic state.<ref name=Tretter2016rev/>

Succinate is generated in [[Biology:Mitochondria|mitochondria]] via the [[Biology:Citric acid cycle|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 landscape or demonstrating hormone-like signaling.<ref name="Tretter2016rev" /> As such, succinate links cellular [[Biology:Metabolism|metabolism]], 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 [[Medicine:Leigh syndrome|Leigh syndrome]], and Melas syndrome, and degradation can lead to pathological conditions, such as [[Medicine:Malignancy|malignant]] transformation, [[Medicine:Inflammation|inflammation]] and tissue injury.<ref name="Tretter2016rev" /><ref name="Mills2014rev">{{Cite journal|last1=Mills|first1=Evanna|last2=O'Neill|first2=Luke A.J.|title=Succinate: a metabolic signal in inflammation|journal=Trends in Cell Biology|volume=24|issue=5|pages=313–320|doi=10.1016/j.tcb.2013.11.008|pmid=24361092|date=May 2014|hdl=2262/67833|hdl-access=free}}</ref><ref name="Chouchani|2014primary" />

Succinic acid is marketed as food additive E363. The name derives from Latin ''succinum'', meaning [[Earth:Amber|amber]].

==Physical properties==
Succinic acid is a white, odorless solid with a highly acidic taste.<ref name=Toxnet/>  In an [[Chemistry:Aqueous solution|aqueous solution]], succinic acid readily [[Physics:Ion|ion]]izes to form its conjugate base, succinate ({{IPAc-en|ˈ|s|ʌ|k|s|ᵻ|n|eɪ|t}}). As a diprotic acid, succinic acid undergoes two successive deprotonation reactions:
:(CH<sub>2</sub>)<sub>2</sub>(CO<sub>2</sub>H)<sub>2</sub>  →   (CH<sub>2</sub>)<sub>2</sub>(CO<sub>2</sub>H)(CO<sub>2</sub>)<sup>−</sup>  +  H<sup>+</sup>
:(CH<sub>2</sub>)<sub>2</sub>(CO<sub>2</sub>H)(CO<sub>2</sub>)<sup>−</sup> →   (CH<sub>2</sub>)<sub>2</sub>(CO<sub>2</sub>)<sub>2</sub><sup>2−</sup>  +  H<sup>+</sup>
The [[Chemistry:Acid dissociation constant|pK<sub>a</sub>]] of these processes are 4.3 and 5.6, respectively.  Both anions are colorless and can be isolated as the salts, e.g., Na(CH<sub>2</sub>)<sub>2</sub>(CO<sub>2</sub>H)(CO<sub>2</sub>) and Na<sub>2</sub>(CH<sub>2</sub>)<sub>2</sub>(CO<sub>2</sub>)<sub>2</sub>.  In living organisms, primarily succinate, not succinic acid, is found.<ref name=Toxnet>{{cite web|title=Succinic Acid|url=https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+791|publisher=Toxnet National Library of Medicine HSDB Database|access-date=28 May 2017|date=2005-01-31}}</ref>

As a [[Biology:Radical|radical]] group it is called a succinyl ({{IPAc-en|ˈ|s|ʌ|k|s|ᵻ|n|əl}}) group.<ref>{{Cite web|url=https://www.merriam-webster.com/dictionary/succinyl|title=Definition of SUCCINYL|website=www.merriam-webster.com|access-date=2017-03-09}}</ref>

Like most simple mono- and dicarboxylic acids, it is not harmful but can be an irritant to skin and eyes.<ref name=Toxnet/>

== Commercial production ==
Historically, succinic acid was obtained from [[Earth:Amber|amber]] by distillation and has thus been known as spirit of amber. Common industrial routes include [[Chemistry:Hydrogenation|hydrogenation]] of [[Chemistry:Maleic acid|maleic acid]], oxidation of 1,4-butanediol, and [[Chemistry:Carbonylation|carbonylation]] of [[Chemistry:Ethylene glycol|ethylene glycol]]. Succinate is also produced from [[Chemistry:Butane|butane]] via [[Chemistry:Maleic anhydride|maleic anhydride]].<ref name="Ullmann">{{Ullmann |author=Boy Cornils|author2=Peter Lappe|title=Dicarboxylic Acids, Aliphatic|doi=10.1002/14356007.a08_523}}</ref> Global production is estimated at 16,000 to 30,000 tons a year, with an annual growth rate of 10%.<ref>{{cite web|url = http://www.nnfcc.co.uk/publications/nnfcc-renewable-chemicals-factsheet-succinic-acid |title = NNFCC Renewable Chemicals Factsheet: Succinic Acid|date= 3 February 2010|archive-url =https://web.archive.org/web/20110720182449/http://www.nnfcc.co.uk/publications/nnfcc-renewable-chemicals-factsheet-succinic-acid|archive-date = 20 July 2011}}</ref>

Genetically engineered ''[[Biology:Escherichia coli|Escherichia coli]]'' and ''[[Biology:Saccharomyces cerevisiae|Saccharomyces cerevisiae]]'' are proposed for the commercial production via fermentation of [[Chemistry:Glucose|glucose]].<ref name=Thakker2012rev/><ref>{{Cite journal|last1=Otero|first1=José Manuel|last2=Cimini|first2=Donatella|last3=Patil|first3=Kiran R.|last4=Poulsen|first4=Simon G.|last5=Olsson|first5=Lisbeth|last6=Nielsen|first6=Jens|date=2013-01-21|title=Industrial Systems Biology of Saccharomyces cerevisiae Enables Novel Succinic Acid Cell Factory|journal=PLOS ONE|volume=8|issue=1|pages=e54144|doi=10.1371/journal.pone.0054144|issn=1932-6203|pmc=3549990|pmid=23349810|bibcode=2013PLoSO...854144O|doi-access=free}}</ref>

==Chemical reactions==
Succinic acid can be dehydrogenated to [[Chemistry:Fumaric acid|fumaric acid]] or be converted to diesters, such as diethylsuccinate (CH<sub>2</sub>CO<sub>2</sub>CH<sub>2</sub>CH<sub>3</sub>)<sub>2</sub>. This diethyl ester is a substrate in the [[Chemistry:Stobbe condensation|Stobbe condensation]].  Dehydration of succinic acid gives [[Chemistry:Succinic anhydride|succinic anhydride]].<ref>{{cite journal|first1=Louis F.|last1=Fieser|first2=E. L.|last2=Martin|year=1932|title=Succinic Anhydride|journal=Organic Syntheses|volume=12|pages=66|doi=10.15227/orgsyn.012.0066}}</ref> Succinate can be used to derive 1,4-butanediol, maleic anhydride, succinimide, 2-pyrrolidinone and [[Chemistry:Tetrahydrofuran|tetrahydrofuran]].<ref name=Thakker2012rev>{{Cite journal|last1=Thakker|first1=Chandresh|last2=Martínez|first2=Irene|last3=San|first3=Ka-Yiu|last4=Bennett|first4=George N.|date=2017-03-07|title=Succinate production in Escherichia coli|journal=Biotechnology Journal|volume=7|issue=2|pages=213–224|doi=10.1002/biot.201100061|pmc=3517001|pmid=21932253}}</ref>

==Applications==
In 2004, succinate was placed on the US Department of Energy's list of top 12 platform chemicals from biomass.<ref>{{cite web|url=https://www1.eere.energy.gov/bioenergy/pdfs/35523.pdf |archive-url=https://web.archive.org/web/20131021015804/http://www1.eere.energy.gov/bioenergy/pdfs/35523.pdf |archive-date=2013-10-21 |url-status=live|title=Top Value Added Chemicals from Biomass, Volume 1: Results of Screening for Potential Candidates from Sugars and Synthesis Gas|date=November 1, 2004|publisher=U.S. Department of Energy|access-date=2013-11-12}}</ref>

===Precursor to polymers, resins, and solvents===
Succinic acid is a [[Biology:Precursor|precursor]] to some [[Chemistry:Polyester|polyester]]s and a component of some alkyd resins.<ref name=Ullmann/> [[Chemistry:1,4-Butanediol|1,4-Butanediol]] (BDO) can be synthesized using succinic acid as a precursor.<ref>{{Citation | title = Ashford's Dictionary of Industrial Chemicals | edition = 3rd | year = 2011 | isbn = 978-0-9522674-3-0 | page = 1517| last1 = Ashford | first1 = Robert D. | publisher = Wavelength }}</ref> The automotive and electronics industries heavily rely on BDO to produce connectors, insulators, wheel covers, gearshift knobs and reinforcing beams.<ref>{{cite web|url=http://www.grandviewresearch.com/industry-analysis/1-4-butanediol-market  |work=Grand View Research |title=1,4-Butanediol (BDO) Market Analysis By Application (Tetrahydrofuran, Polybutylene Teraphthalate, Gamma-Butyrolactone & Polyurethanes), And Segment Forecasts To 2020 |date=September 2015 |access-date=2015-11-18}}</ref> Succinic acid also serves as the bases of certain biodegradable polymers, which are of interest in tissue engineering applications.<ref>{{Cite journal|last1=Barrett|first1=Devin G.|last2=Yousaf|first2=Muhammad N.|date=2009-10-12|title=Design and Applications of Biodegradable Polyester Tissue Scaffolds Based on Endogenous Monomers Found in Human Metabolism|journal=Molecules|volume=14|issue=10|pages=4022–4050|doi=10.3390/molecules14104022|pmid=19924045|pmc=6255442|doi-access=free}}</ref>

[[Chemistry:Acylation|Acylation]] with succinic acid is called ''succination''. ''Oversuccination'' occurs when more than one succinate adds to a substrate.{{Citation needed|date=January 2021}}

===Food and dietary supplement===
As a [[Chemistry:Food additive|food additive]] and dietary supplement, succinic acid is [[Chemistry:Generally recognized as safe|generally recognized as safe]] by the U.S. Food and Drug Administration.<ref>{{cite web|website = FDA GRAS Database|url = https://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/SCOGS/ucm261458.htm|title = Succinic acid in the FDA SCOGS Database|date = 31 October 2015|access-date = 9 March 2020|archive-date = 31 October 2017|archive-url = https://wayback.archive-it.org/7993/20171031060940/https://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/SCOGS/ucm261458.htm|url-status = bot: unknown}}</ref> Succinic acid is used primarily as an acidity regulator<ref>{{cite journal | doi = 10.1007/s002530051431 | title = Biotechnology of succinic acid production and markets for derived industrial products | year = 1999 | last1 = Zeikus | first1 = J. G. | last2 = Jain | first2 = M. K. | last3 = Elankovan | first3 = P. | journal = Applied Microbiology and Biotechnology | volume = 51 | issue = 5 | pages = 545| s2cid = 38868987 }}</ref> in the food and beverage industry. It is also available as a flavoring agent, contributing a somewhat sour and astringent component to umami taste.<ref name= Thakker2012rev/>  As an [[Chemistry:Excipient|excipient]] in pharmaceutical products, it is also used to control acidity<ref>{{cite web |url=http://drugtopics.modernmedicine.com/drugtopics/Drugtopics.com+Exclusives/Overview-of-pharmaceutical-excipients-used-in-tabl/ArticleStandard/Article/detail/561047|title=Overview of pharmaceutical excipients used in tablets and capsules |date=24 October 2008|publisher=Modern Medicine Network|access-date=7 November 2015|url-status=dead|archive-url= https://web.archive.org/web/20120219203453/http://drugtopics.modernmedicine.com/drugtopics/Drugtopics.com+Exclusives/Overview-of-pharmaceutical-excipients-used-in-tabl/ArticleStandard/Article/detail/561047|archive-date=19 February 2012}}</ref> or as a counter ion.<ref name=Thakker2012rev/> Drugs involving succinate include [[Chemistry:Metoprolol|metoprolol succinate]], [[Chemistry:Sumatriptan|sumatriptan succinate]], Doxylamine succinate or [[Chemistry:Solifenacin|solifenacin succinate]].{{Citation needed|date=January 2021}}

== Biosynthesis ==

=== Tricarboxylic acid (TCA) cycle ===
Succinate is a key intermediate in the [[Biology:Citric acid cycle|tricarboxylic acid cycle]], a primary metabolic pathway used to produce chemical energy in the presence of O<sub>2</sub>. Succinate is generated from [[Chemistry:Succinyl-CoA|succinyl-CoA]] by the enzyme [[Biology:Succinyl coenzyme A synthetase|succinyl-CoA synthetase]] in a [[Chemistry:Guanosine triphosphate|GTP]]/[[Chemistry:Adenosine triphosphate|ATP]]-producing step:<ref name=BiochemText5th/>{{rp|Section 17.1}}

Succinyl-CoA + NDP + Pi → Succinate + CoA + NTP

Catalyzed by the enzyme [[Biology:Succinate dehydrogenase|succinate dehydrogenase]] (SDH), succinate is subsequently oxidized to [[Chemistry:Fumaric acid|fumarate]]:<ref name=BiochemText5th/>{{rp|Section 17.1}}

Succinate + FAD → Fumarate + FADH<sub>2</sub>

SDH also participates in the mitochondrial [[Biology:Electron transport chain|electron transport chain]], 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 [[Chemistry:Coenzyme Q10|ubiquinone]] via the intermediate electron carriers [[Chemistry:Flavin adenine dinucleotide|FAD]] and three 2Fe-2S clusters. Succinate thus serves as a direct electron donor to the electron transport chain, and itself is converted into fumarate.<ref name=Drose2013rev>{{Cite journal|last=Dröse|first=Stefan|date=2013-05-01|title=Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning|journal=Biochimica et Biophysica Acta (BBA) - Bioenergetics|series=Respiratory complex II: Role in cellular physiology and disease|volume=1827|issue=5|pages=578–587|doi=10.1016/j.bbabio.2013.01.004|pmid=23333272 |doi-access=}}</ref>


=== 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 [[Chemistry:Oxaloacetic acid|oxaloacetate]], [[Chemistry:Malic acid|malate]] and [[Chemistry:Fumaric acid|fumarate]].<ref name=Cheng2013rev>{{Cite journal|last1=Cheng|first1=Ke-Ke|last2=Wang|first2=Gen-Yu|last3=Zeng|first3=Jing|last4=Zhang|first4=Jian-An|date=2013-04-18|title=Improved Succinate Production by Metabolic Engineering|journal=BioMed Research International|volume=2013|pages=538790|doi=10.1155/2013/538790|issn=2314-6133|pmc=3652112|pmid=23691505|doi-access=free}}</ref> This pathway is exploited in metabolic engineering to net generate succinate for human use.<ref name=Cheng2013rev/> Additionally, succinic acid produced during the fermentation of sugar provides a combination of saltiness, bitterness and acidity to fermented alcohols.<ref>{{Cite book|title=Knowing and Making Wine|last=Peynaud|first=Emile|date=1984}}</ref>

Accumulation of fumarate can drive the reverse activity of SDH, thus enhancing succinate generation. Under pathological and physiological conditions, the [[Biology:Malate-aspartate shuttle|malate-aspartate shuttle]] or the [[Biology:Purine nucleotide cycle|purine nucleotide shuttle]] can increase mitochondrial fumarate, which is then readily converted to succinate.<ref name=Haas2016rev/>

=== Glyoxylate cycle ===
Succinate is also a product of the [[Biology:Glyoxylate cycle|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 [[Chemistry:Decarboxylation|decarboxylation]] steps of the TCA cycle via the enzyme [[Biology:Isocitrate lyase|isocitrate lyase]] which cleaves [[Chemistry:Isocitric acid|isocitrate]] into succinate and [[Chemistry:Glyoxylic acid|glyoxylate]]. Generated succinate is then available for either energy production or biosynthesis.<ref name=BiochemText5th>{{cite book|last1=Berg|first1=JM|last2=Tymoczko|first2=JL|last3=Stryer|first3=L|title=Biochemistry|date=2002|publisher=W H Freeman|location=New York|edition=5th|url=https://www.ncbi.nlm.nih.gov/books/NBK22383/}}</ref>{{rp|Section 17.4}}

=== GABA shunt ===
Succinate is the re-entry point for the [[Chemistry:Gamma-Aminobutyric acid|gamma-aminobutyric acid]] (GABA) shunt into the TCA cycle, a closed cycle which synthesizes and recycles GABA.<ref name=BasicNeurochemTextChapter>{{cite book|last1=Olsen|first1=Richard W|last2=DeLorey|first2=Timothy M|editor1-last=Siegel|editor1-first=GJ|editor2-last=Agranoff|editor2-first=BW|editor3-last=Albers|editor3-first=RW |display-editors=etal |title=Basic Neurochemistry: Molecular, Cellular and Medical Aspects|date=1999|publisher=Lippincott-Raven|location=Philadelphia|edition=6th|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK27979/|chapter=GABA Synthesis, Uptake and Release}}</ref> The GABA shunt serves as an alternate route to convert [[Chemistry:Alpha-Ketoglutaric acid|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 to [[Chemistry:Succinic semialdehyde|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.<ref name=BasicNeurochemTextChapter/>
[[File:Integrated Diagram of Succinate Biofunctionality .png|thumb|540x540px|Biological roles of succinate. Inside the mitochondria, succinate serves as an intermediate in multiple metabolic pathways and contributes to the generation of ROS. Outside the mitochondria, succinate functions as both an intracellular and extracellular signaling molecule. OOA=oxaloacetate; a-KG=alpha ketoglutarate; GLUT= Glutamate; GABA = gamma-aminobutyric acid; SSA=Succinic semialdehyde; PHD= prolyl hydroxylase; HIF-1a=hypoxia inducible factor 1a; TET= Ten-eleven Translocation Enzymes; JMJD3= Histone demethylase Jumonji D3]]

== Cellular metabolism ==

=== Metabolic intermediate ===
Succinate is produced and concentrated in the [[Biology:Mitochondrion|mitochondria]] and its primary biological function is that of a metabolic [[Biology:Metabolite|intermediate]].<ref name=Tretter2016rev/><ref name=BiochemText5th/>{{rp|Section 17.1}} 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.<ref name=Tretter2016rev/> 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.<ref name=Cheng2013rev/><ref name=BasicNeurochemTextChapter/> In rodents, mitochondrial concentrations are approximately ~0.5 mM<ref name=Tretter2016rev>{{Cite journal|last1=Tretter|first1=Laszlo|last2=Patocs|first2=Attila|last3=Chinopoulos|first3=Christos|date=2016-08-01|title=Succinate, an intermediate in metabolism, signal transduction, ROS, hypoxia, and tumorigenesis|journal=Biochimica et Biophysica Acta (BBA) - Bioenergetics|series=EBEC 2016: 19th European Bioenergetics Conference|volume=1857|issue=8|pages=1086–1101|doi=10.1016/j.bbabio.2016.03.012|pmid=26971832 |doi-access=free}}</ref> while plasma concentration are only 2–20 μM.<ref name=Ariza2012rev>{{Cite journal|last1=Ariza|first1=Ana Carolina|last2=Deen|first2=Peter M. T.|last3=Robben|first3=Joris Hubertus|date=2012-01-01|title=The succinate receptor as a novel therapeutic target for oxidative and metabolic stress-related conditions|journal= Frontiers in Endocrinology|volume=3|pages=22|doi=10.3389/fendo.2012.00022|pmc=3355999|pmid=22649411|doi-access=free}}</ref>

=== ROS production ===
The activity of succinate dehydrogenase (SDH), which interconverts succinate into fumarate participates in mitochondrial [[Biology:Reactive oxygen species|reactive oxygen species]] (ROS) production by directing electron flow in the electron transport chain.<ref name=Tretter2016rev/><ref name=Drose2013rev/> Under conditions of succinate accumulation, rapid oxidation of succinate by SDH can drive reverse electron transport (RET).<ref name=Pell2016rev/> If [[Biology:Coenzyme Q – cytochrome c reductase|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.<ref name=Pell2016rev/>

== Additional biologic functions ==
In addition to its metabolic roles, succinate serves as an intracellular and extracellular signaling molecule.<ref name=Tretter2016rev/><ref name=Haas2016rev>{{Cite journal|last1=Haas|first1=Robert|last2=Cucchi|first2=Danilo|last3=Smith|first3=Joanne|last4=Pucino|first4=Valentina|last5=Macdougall|first5=Claire Elizabeth|last6=Mauro|first6=Claudio|title=Intermediates of Metabolism: From Bystanders to Signalling Molecules|journal=Trends in Biochemical Sciences|volume=41|issue=5|pages=460–471|doi=10.1016/j.tibs.2016.02.003|pmid=26935843|year=2016|url=http://qmro.qmul.ac.uk/xmlui/handle/123456789/18257}}</ref> Extra-mitochondrial succinate alters the epigenetic landscape by inhibiting the family of [[Biology:Dioxygenase|2-oxogluterate-dependent dioxygenases]].<ref name=Haas2016rev/> Alternative, succinate can be released into the [[Biology:Extracellular fluid|extracellular milieu]] and the blood stream where it is recognized by target receptors.<ref name=Fonseca2016rev /> 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, [[Medicine:Hypoxia (medical)|hypoxia]] or energetic misbalance are all linked to an alteration of flux through the TCA cycle and succinate accumulation.<ref name=Tretter2016rev /><ref name=Haas2016rev/><ref name=Bardella2011rev/> Upon exiting the mitochondria, succinate serves as a signal of metabolic state, communicating to neighboring cells how metabolically active the originating cell population is.<ref name=Haas2016rev/> 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 [[Biology:SLC25A10|dicarboxylate transporters]], primarily SLC25A10, a succinate-fumarate/malate transporter.<ref name=Fonseca2016rev>{{Cite journal|last1=de Castro Fonseca|first1=Matheus|last2=Aguiar|first2=Carla J.|last3=da Rocha Franco|first3=Joao Antônio|last4=Gingold|first4=Rafael N.|last5=Leite|first5=M. Fatima|date=2016-01-01|title=GPR91: expanding the frontiers of Krebs cycle intermediates|journal=Cell Communication and Signaling|volume=14|pages=3|doi=10.1186/s12964-016-0126-1|pmc=4709936|pmid=26759054 |doi-access=free }}</ref> In the second step of mitochondrial export, succinate readily crosses the outer mitochondrial membrane through [[Biology:Porin (protein)|porins]], nonspecific protein channels that facilitate the diffusion of molecules less than 1.5 kDa.<ref name=Fonseca2016rev/> Transport across the plasma membrane is likely tissue specific. A key candidate transporter is [[Biology:Indy (gene)|INDY]] (I'm not dead yet), a sodium-independent anion exchanger, which moves both dicarboxylate and citrate into the bloodstream.<ref name=Fonseca2016rev/>
[[File:Snake diagram of GPR91.png|thumb|546x546px|Amino acid sequence of GPR91. Succinate binds to GPR91, a 7-transmembrane G-protein coupled receptor, located on a variety of cell types. Red amino acids represent those involved in binding succinate. All other amino acids are colored according to their chemical properties (grey=nonpolar, cyan=negative charge, dark blue = positive charge, green=aromatic, dark purple=polar and noncharged, orange/light purple = special cases).]]

=== Extracellular signaling ===
Extracellular succinate can act as a signaling molecule with hormone-like function, targeting a variety of tissues such as blood cells, adipose tissue, immune cells, the liver, the heart, the retina and primarily the kidney.<ref name=Fonseca2016rev/> The G-protein coupled receptor, GPR91 also known as [[Biology:SUCNR1|SUCNR1]], serves as the detector of extracellular succinate.<ref name=Gilissen2016rev>{{Cite journal|last1=Gilissen|first1=Julie|last2=Jouret|first2=François|last3=Pirotte|first3=Bernard|last4=Hanson|first4=Julien|date=2016-03-01|title=Insight into SUCNR1 (GPR91) structure and function|journal=Pharmacology & Therapeutics|volume=159|pages=56–65|doi=10.1016/j.pharmthera.2016.01.008|pmid=26808164|hdl=2268/194560|s2cid=24982373 |url=http://orbi.ulg.ac.be/handle/2268/194560|hdl-access=free}}</ref> Arg<sup>99</sup>, His<sup>103</sup>, Arg<sup>252</sup>, and Arg<sup>281</sup> near the center of the receptor generate a positively charged binding site for succinate.<ref name=Gilissen2016rev/> The ligand specificity of GPR91 was rigorously tested using 800 pharmacologically active compounds and 200 carboxylic acid and succinate-like compounds, all of which demonstrated significantly lower binding affinity.<ref name=Gilissen2016rev/> Overall, the [[Chemistry:EC50|EC<sub>50</sub>]] for succinate-GPR91 is in the 20–50 uM range.<ref name=Fonseca2016rev/> Depending on the cell type, GPR91 can interact with multiple G proteins, including [[Biology:Gs alpha subunit|G<sub>s</sub>]], [[Biology:Gi alpha subunit|G<sub>i</sub>]] and [[Biology:Gq alpha subunit|G<sub>q</sub>]], and enabling a multitude of signaling outcomes.<ref name=Fonseca2016rev/>

==== Effect on adipocytes ====
In [[Biology:Adipocyte|adipocyte]]s, the succinate-activated GPR91 signaling cascade inhibits [[Biology:Lipolysis|lipolysis]].<ref name=Fonseca2016rev/>

==== Effect on the liver and retina ====
Succinate signaling often occurs in response to hypoxic conditions. In the liver, succinate serves as a paracrine signal, released by anoxic [[Biology:Hepatocyte|hepatocyte]]s, and targets [[Biology:Stellate cell|stellate cell]]s via GPR91.<ref name=Fonseca2016rev /> This leads to stellate cell activation and fibrogenesis. Thus, succinate is thought to play a role in liver [[Homeostasis|homeostasis]]. In the retina, succinate accumulates in [[Biology:Retinal ganglion cell|retinal ganglion cell]]s in response to ischemic conditions. Autocrine succinate signaling promotes retinal [[Biology:Neovascularization|neovascularization]], triggering the activation of angiogenic factors such as [[Biology:Vascular endothelial growth factor|endothelial growth factor]] (VEGF).<ref name=Fonseca2016rev/><ref name=Gilissen2016rev/>

==== Effect on the heart ====
Extracellular succinate regulates [[Biology:Cardiac muscle cell|cardiomyocyte]] viability through GPR91 activation; long-term succinate exposure leads to pathological cardiomyocyte [[Medicine:Hypertrophy|hypertrophy]].<ref name=Fonseca2016rev/> Stimulation of GPR91 triggers at least two signaling pathways in the heart: a [[Biology:MAP2K1|MEK1/2]] and [[Biology:MAPK3|ERK1/2]] pathway that activates hypertrophic gene expression and a [[Biology:Phospholipase C|phospholipase C]] pathway which changes the pattern of Ca<sup>2+</sup> uptake and distribution and triggers [[Biology:Calmodulin|CaM]]-dependent hypertrophic gene activation.<ref name="Fonseca2016rev" />

==== Effect on immune cells ====
SUCNR1 is highly expressed on immature [[Biology:Dendritic cell|dendritic cell]]s, where succinate binding stimulates [[Physics:Chemotaxis|chemotaxis]].<ref name=Gilissen2016rev/> Furthermore, SUCNR1 synergizes with [[Biology:Toll-like receptor|toll-like receptor]]s to increase the production of [[Biology:Proinflammatory cytokine|proinflammatory cytokine]]s such as [[Biology:Tumor necrosis factor alpha|TNF alpha]] and interleukin-1beta.<ref name=Mills2014rev/><ref name=Gilissen2016rev/> Succinate may enhance [[Biology:Adaptive immune system|adaptive immunity]] by triggering the activity of antigen-presenting cells that, in turn, activate [[Biology:T cell|T-cells]].<ref name=Mills2014rev/>

==== Effect on platelets ====
SUCNR1 is one of the highest expressed G protein-coupled receptors on human platelets, present at levels similar to [[Biology:P2Y12|P2Y<sub>12</sub>]], though the role of succinate signaling in [[Biology:Platelet|platelet aggregation]] is debated. Multiple studies have demonstrated succinate-induced aggregation, but the effect has high inter-individual variability.<ref name=Ariza2012rev/>

==== Effect on the kidneys ====
Succinate serves as a modulator of blood pressure by stimulating renin release in macula densa and [[Biology:Juxtaglomerular cell|juxtaglomerular apparatus cells]] via GPR91.<ref>{{Cite journal|last1=Peti-Peterdi|first1=János|last2=Gevorgyan|first2=Haykanush|last3=Lam|first3=Lisa|last4=Riquier-Brison|first4=Anne|date=2012-06-23|title=Metabolic control of renin secretion|journal=Pflügers Archiv: European Journal of Physiology|volume=465|issue=1|pages=53–58|doi=10.1007/s00424-012-1130-y|issn=0031-6768|pmc=4574624|pmid=22729752}}</ref> Therapies targeting succinate to reduce cardiovascular risk and hypertension are currently under investigation.<ref name=Ariza2012rev/>

=== Intracellular signaling ===
[[File:Enzymatic inhibition by succinate accumulation.png|thumb|544x544px|Accumulated succinate inhibits dioxygenases, such as histone and DNA demethylases or prolyl hydroxylases, by competitive inhibition. Thus, succinate modifies the epigenic landscape and regulates gene expression.]]
Accumulation of either fumarate or succinate reduces the activity of 2-oxoglutarate-dependent dioxygenases, including histone and DNA [[Biology:Demethylase|demethylase]]s, [[Biology:Procollagen-proline dioxygenase|prolyl hydroxylases]] and collagen prolyl-4-hydroxylases, through [[Chemistry:Competitive inhibition|competitive inhibition]].<ref>{{Cite journal|last1=Xiao|first1=Mengtao|last2=Yang|first2=Hui|last3=Xu|first3=Wei|last4=Ma|first4=Shenghong|last5=Lin|first5=Huaipeng|last6=Zhu|first6=Honguang|last7=Liu|first7=Lixia|last8=Liu|first8=Ying|last9=Yang|first9=Chen|date=2012-06-15|title=Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors|journal=Genes & Development|volume=26|issue=12|pages=1326–1338|doi=10.1101/gad.191056.112|issn=0890-9369|pmc=3387660|pmid=22677546}}</ref> 2-oxoglutarate-dependent dioxygenases require an iron cofactor to catalyze hydroxylations, desaturations and ring closures.<ref name=Hewitson2005rev>{{Cite journal|last1=Hewitson|first1=K. S.|last2=Granatino|first2=N.|last3=Welford|first3=R. W. D.|last4=McDonough|first4=M. A.|last5=Schofield|first5=C. J.|date=2005-04-15|title=Oxidation by 2-oxoglutarate oxygenases: non-haem iron systems in catalysis and signalling|journal=Philosophical Transactions of the Royal Society of London A: Mathematical, Physical and Engineering Sciences|volume=363|issue=1829|pages=807–828|doi=10.1098/rsta.2004.1540|pmid=15901537|bibcode=2005RSPTA.363..807H|s2cid=8568103}}</ref> Simultaneous to substrate oxidation, they convert [[Chemistry:Alpha-Ketoglutaric acid|2-oxoglutarate]], also known as alpha-ketoglutarate, into succinate and CO<sub>2</sub>. 2-oxoglutarate-dependent dioxygenases bind substrates in a sequential, ordered manner.<ref name=Hewitson2005rev/> 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. [[Chemistry:Oxidative decarboxylation|Oxidative decarboxylation]] then generates a ferryl intermediate coordinated to succinate, which serves to oxidize the bound primary substrate.<ref name=Hewitson2005rev/> 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 [[Biology:Tet methylcytosine dioxygenase 2|TET]] (ten-eleven translocation) family of 5-methylcytosine DNA modifying enzymes and the [[Biology:(Histone-H3)-lysine-36 demethylase|JmjC domain-containing histone lysine demethylase]] (KDM).<ref name=Yang2013comment>{{Cite journal|last1=Yang|first1=Ming|last2=Pollard|first2=Patrick J.|title=Succinate: A New Epigenetic Hacker|journal=Cancer Cell|volume=23|issue=6|pages=709–711|doi=10.1016/j.ccr.2013.05.015|pmid=23763995|date=10 June 2013|doi-access=free}}</ref> Pathologically elevated levels of succinate lead to hypermethylation, epigenetic silencing and changes in neuroendocrine differentiation, potentially driving cancer formation.<ref name=Yang2013comment/><ref name=Yang2013rev/>

==== Gene regulation ====
Succinate inhibition of prolyl hydroxylases (PHDs) stabilizes the transcription factor [[Biology:Hypoxia-inducible factors|hypoxia inducible factor (HIF)1α]].<ref name=Tretter2016rev/><ref name=Haas2016rev/><ref name=Koivunen2007rev>{{cite journal|last1=Koivunen|first1=P|last2=Hirsilä|first2=M|last3=Remes|first3=AM|last4=Hassinen|first4=IE|last5=Kivirikko|first5=KI|last6=Myllyharju|first6=J|title=Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF.|journal=The Journal of Biological Chemistry|date=16 February 2007|volume=282|issue=7|pages=4524–32|doi=10.1074/jbc.M610415200|pmid=17182618|doi-access=free}}</ref> PHDs hydroxylate proline in parallel to oxidatively decarboxylating 2-oxyglutarate to succinate and CO<sub>2</sub>. In humans, three HIF prolyl 4-hydroxylases regulate the stability of HIFs.<ref name=Koivunen2007rev/> Hydroxylation of two prolyl residues in HIF1α facilitates ubiquitin ligation, thus marking it for proteolytic destruction by the [[Biology:Proteasome|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,<ref name=Yang2013rev/> 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 [[Biology:Angiogenesis|angiogenesis]], energy [[Biology:Metabolism|metabolism]], cell survival, and tumor invasion.<ref name=Tretter2016rev/><ref name=Koivunen2007rev/>

== Role in human health ==

=== Inflammation ===
Metabolic signaling involving succinate can be involved in [[Medicine:Inflammation|inflammation]] via stabilization of [[Biology:HIF1A|HIF1-alpha]] or GPR91 signaling in innate immune cells. Through these mechanisms, succinate accumulation has been shown to regulate production of inflammatory [[Biology:Cytokine|cytokine]]s.<ref name=Mills2014rev/> For dendritic cells, succinate functions as a chemoattractant and increases their antigen-presenting function via receptor stimulated cytokine production.<ref name=Gilissen2016rev/> In inflammatory [[Biology:Macrophage|macrophage]]s, succinate-induced stability of HIF1 results in increased transcription of HIF1-dependent genes, including the pro-inflammatory cytokine [[Biology:Interleukin|interleukin-1β]].<ref>{{Cite journal|last1=Tannahill|first1=GM|last2=Curtis|first2=AM|last3=Adamik|first3=J|last4=Palsson-McDermott|first4=EM|last5=McGettrick|first5=AF|last6=Goel|first6=G|last7=Frezza|first7=C|last8=Bernard|first8=NJ|last9=Kelly|first9=B|date=2013-04-11|title=Succinate is a danger signal that induces IL-1β via HIF-1α|journal=Nature|volume=496|issue=7444|pages=238–242|doi=10.1038/nature11986|issn=0028-0836|pmc=4031686|pmid=23535595}}</ref> Other inflammatory cytokines produced by activated macrophages such as [[Biology:Tumor necrosis factor superfamily|tumor necrosis factor]] or interleukin 6 are not directly affected by succinate and HIF1.<ref name=Mills2014rev /> The mechanism by which succinate accumulates in immune cells is not fully understood.<ref name=Mills2014rev/> Activation of inflammatory macrophages through [[Biology:Toll-like receptor|toll-like receptor]]s induces a metabolic shift towards glycolysis.<ref>{{Cite journal|last1=Kelly|first1=Beth|last2=O'Neill|first2=Luke AJ|date=2015-07-01|title=Metabolic reprogramming in macrophages and dendritic cells in innate immunity|journal=Cell Research|volume=25|issue=7|pages=771–784|doi=10.1038/cr.2015.68|issn=1001-0602|pmc=4493277|pmid=26045163}}</ref> In spite of a general downregulation of the TCA cycle under these conditions, succinate concentration is increased. However, [[Biology:Lipopolysaccharide|lipopolysaccharide]]s involved in the activation of macrophages increase [[Chemistry:Glutamine|glutamine]] and [[Biology:GABA transporter|GABA transporter]]s.<ref name=Mills2014rev/> Succinate may thus be produced from enhanced glutamine metabolism via alpha-ketoglutarate or the GABA shunt.{{Citation needed|date=January 2021}}

=== Tumorigenesis ===
Succinate is one of three oncometabolites, metabolic intermediates whose accumulation causes metabolic and non-metabolic dysregulation implicated in [[Biology:Carcinogenesis|tumorigenesis]].<ref name=Yang2013rev>{{Cite journal|last1=Yang|first1=Ming|last2=Soga|first2=Tomoyoshi|last3=Pollard|first3=Patrick J.|date=2013-09-03|title=Oncometabolites: linking altered metabolism with cancer|journal=The Journal of Clinical Investigation|volume=123|issue=9|pages=3652–8|doi=10.1172/JCI67228|issn=0021-9738|pmc=3754247|pmid=23999438}}</ref><ref name=Sciacovelli2017rev>{{Cite journal|last1=Sciacovelli|first1=Marco|last2=Frezza|first2=Christian|date=2017-03-06|title=Oncometabolites: Unconventional triggers of oncogenic signalling cascades|journal=Free Radical Biology & Medicine|volume=100|pages=175–181|doi=10.1016/j.freeradbiomed.2016.04.025|issn=0891-5849|pmc=5145802|pmid=27117029}}</ref> Loss-of-function mutations in the genes encoding [[Biology:Succinate dehydrogenase|succinate dehydrogenase]], frequently found in hereditary paraganglioma and [[Medicine:Pheochromocytoma|pheochromocytoma]], cause pathological increase in succinate.<ref name=Bardella2011rev>{{Cite journal|last1=Bardella|first1=Chiara|last2=Pollard|first2=Patrick J.|last3=Tomlinson|first3=Ian|date=2011-11-01|title=SDH mutations in cancer|journal=Biochimica et Biophysica Acta (BBA) - Bioenergetics|volume=1807|issue=11|pages=1432–1443|doi=10.1016/j.bbabio.2011.07.003|pmid=21771581|doi-access=free}}</ref> SDH mutations have also been identified in gastrointestinal stromal tumors, renal tumors, thyroid tumors, testicular seminomas and [[Medicine:Neuroblastoma|neuroblastoma]]s.<ref name=Yang2013rev/> 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 [[Biology:Cellular differentiation|cell differentiation]].<ref name=Yang2013comment/> 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.<ref>{{Cite journal|last1=King|first1=A.|last2=Selak|first2=M. A.|last3=Gottlieb|first3=E.|date=2006-01-01|title=Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer|journal=Oncogene|volume=25|issue=34|pages=4675–4682|doi=10.1038/sj.onc.1209594|pmid=16892081|issn=0950-9232|doi-access=}}</ref> The other two oncometabolites, [[Chemistry:Fumaric acid|fumarate]] and [[Chemistry:Alpha-Hydroxyglutaric acid|2-hydroxyglutarate]] have similar structures to succinate and function through parallel HIF-inducing oncogenic mechanisms.<ref name=Sciacovelli2017rev/>

=== Ischemia reperfusion injury ===
Succinate accumulation under hypoxic conditions has been implicated in the [[Medicine:Reperfusion injury|reperfusion injury]] through increased ROS production.<ref name=Chouchani|2014primary>{{cite journal|last1=Chouchani|first1=ET|last2=Pell|first2=VR|last3=Gaude|first3=E|last4=Aksentijević|first4=D|last5=Sundier|first5=SY|last6=Robb|first6=EL|last7=Logan|first7=A|last8=Nadtochiy|first8=SM|last9=Ord|first9=EN|last10=Smith|first10=AC|last11=Eyassu|first11=F|last12=Shirley|first12=R|last13=Hu|first13=CH|last14=Dare|first14=AJ|last15=James|first15=AM|last16=Rogatti|first16=S|last17=Hartley|first17=RC|last18=Eaton|first18=S|last19=Costa|first19=AS|last20=Brookes|first20=PS|last21=Davidson|first21=SM|last22=Duchen|first22=MR|last23=Saeb-Parsy|first23=K|last24=Shattock|first24=MJ|last25=Robinson|first25=AJ|last26=Work|first26=LM|last27=Frezza|first27=C|last28=Krieg|first28=T|last29=Murphy|first29=MP|title=Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS.|journal=Nature|date=20 November 2014|volume=515|issue=7527|pages=431–5|doi=10.1038/nature13909|pmid=25383517|pmc=4255242|bibcode=2014Natur.515..431C}}</ref><ref name=Pell2016rev/> During ischemia, succinate accumulates. Upon reperfusion, succinate is rapidly oxidized leading to abrupt and extensive production of ROS.<ref name=Chouchani|2014primary/> ROS then trigger the cellular [[Biology:Apoptosis|apoptotic]] machinery or induce oxidative damage to proteins, membranes, organelles etc. In animal models, pharmacological inhibition of ischemic succinate accumulation ameliorated ischemia-reperfusion injury.<ref name=Pell2016rev>{{Cite journal|last1=Pell|first1=Victoria R.|last2=Chouchani|first2=Edward T.|last3=Frezza|first3=Christian|last4=Murphy|first4=Michael P.|last5=Krieg|first5=Thomas|date=2016-07-15|title=Succinate metabolism: a new therapeutic target for myocardial reperfusion injury|journal=Cardiovascular Research|volume=111|issue=2|pages=134–141|doi=10.1093/cvr/cvw100|pmid= 27194563|url=https://www.repository.cam.ac.uk/handle/1810/284972|doi-access=free}}</ref> As of 2016 the inhibition of succinate-mediated ROS production was under investigation as a therapeutic drug target.<ref name=Pell2016rev/>

==See also==
* Flame retardant<ref>[https://journals.sagepub.com/doi/10.1177/0734904109105511 Flame Retardant Finishing of Cotton Fleece Fabric: Part IV-Bifunctional Carboxylic Acids]</ref>
* Oil of amber, procured by heating succinic acid
* [[Biology:Citric acid cycle|Citric acid cycle]]
* [[Biology:Metabolite|Metabolite]]
* [[Biology:Oncometabolism|Oncometabolism]]

==References==
{{Reflist|30em}}

==External links==
* [https://www.fda.gov/Food/IngredientsPackagingLabeling/FoodAdditivesIngredients/ucm115326.htm FDA]
* [http://chemicalland21.com/industrialchem/organic/SUCCINIC%20ACID.htm Succinic Acid]
* [http://www.aim.env.uea.ac.uk/aim/accent2/inputpage.php Calculator: Water and solute activities in aqueous succinic acid]
* [https://pubchem.ncbi.nlm.nih.gov/compound/1110 PubChem: Compound Summary for Succinic Acid]

{{citric acid cycle}}
{{Navbox linear saturated dicarboxylic acids}}


{{DEFAULTSORT:Succinic Acid}}
[[Category:Citric acid cycle compounds]]
[[Category:Dicarboxylic acids]]
[[Category:Excipients]]
[[Category:Succinates]]
[[Category:E-number additives]]

{{Sourceattribution|Succinic acid}}