Editing Succinic acid (section)

== Role in human health ==

=== Inflammation ===
Metabolic signaling involving succinate can be involved in [[inflammation]] via stabilization of [[HIF1A|HIF1-alpha]] or GPR91 signaling in innate immune cells. Through these mechanisms, succinate accumulation has been shown to regulate production of inflammatory [[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 [[macrophage]]s, succinate-induced stability of HIF1 results in increased transcription of HIF1-dependent genes, including the pro-inflammatory cytokine [[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 [[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 [[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, [[lipopolysaccharide]]s involved in the activation of macrophages increase [[glutamine]] and [[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 [[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 [[succinate dehydrogenase]], frequently found in hereditary [[paraganglioma]] and [[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 tumor]]s, [[Kidney tumour|renal tumors]], [[Thyroid neoplasm|thyroid tumors]], testicular seminomas and [[neuroblastoma]]s.<ref name=Yang2013rev/> The oncogenic mechanism caused by mutated SHD is thought to relate to succinate's ability to inhibit [[2-oxoglutarate (2OG)-dependent dioxygenases|2-oxogluterate-dependent dioxygenases]]. Inhibition of KDMs and TET hydroxylases results in epigenetic dysregulation and hypermethylation affecting genes involved in [[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=|s2cid=26263513 }}</ref> The other two oncometabolites, [[Fumaric acid|fumarate]] and [[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 [[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 [[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/>