Editing Pyruvate dehydrogenase complex (section)

==Clinical relevance==
[[Pyruvate dehydrogenase deficiency]] (PDCD) can result from mutations in any of the enzymes or cofactors used to build the complex. Its primary clinical finding is [[lactic acidosis]].<ref>{{cite web|title=Pyruvate dehydrogenase deficiency|url=http://ghr.nlm.nih.gov/condition/pyruvate-dehydrogenase-deficiency|work=Genetics Home Reference|access-date=March 17, 2013}}</ref> Such PDCD mutations, leading to subsequent deficiencies in NAD and FAD production, hinder oxidative phosphorylation processes that are key in aerobic respiration. Thus, acetyl-CoA is instead reduced via anaerobic mechanisms into other molecules like lactate, leading to an excess of bodily lactate and associated neurological pathologies.<ref>{{cite journal |last1=Gupta |first1=N. |last2=Rutledge |first2=C. |title=Pyruvate Dehydrogenase Complex Deficiency: An Unusual Cause of Recurrent Lactic Acidosis in a Paediatric Critical Care Unit |journal=The Journal of Critical Care Medicine |year=2019 |volume=5 |issue=2 |pages=71–75 |doi=10.2478/jccm-2019-0012|pmid=31161145 |pmc=6534940 |doi-access=free }}</ref>

While pyruvate dehydrogenase deficiency is rare, there are a variety of different genes when mutated or nonfunctional that can induce this deficiency. First, the E1 subunit of pyruvate dehydrogenase contains four different subunits: two alpha subunits designated as E1-alpha and two beta subunits designated as E1-beta. The PDHA1 gene found in the E1-alpha subunits, when mutated, causes 80% of the cases of pyruvate dehydrogenase deficiency because this mutation abridges the E1-alpha protein. Decreased functional E1 alpha prevents pyruvate dehydrogenase from sufficiently binding to pyruvate, thus reducing the activity of the overall complex.<ref>{{Cite journal|last1=Lissens|first1=Willy|last2=De Meirleir|first2=Linda|last3=Seneca|first3=Sara|last4=Liebaers|first4=Inge|last5=Brown|first5=Garry K.|last6=Brown|first6=Ruth M.|last7=Ito|first7=Michinori|last8=Naito|first8=Etsuo|last9=Kuroda|first9=Yasuhiro|last10=Kerr|first10=Douglas S.|last11=Wexler|first11=Isaiah D.|date=March 2000|title=Mutations in the X-linked pyruvate dehydrogenase (E1) ? subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency|journal=Human Mutation|volume=15|issue=3|pages=209–219|doi=10.1002/(sici)1098-1004(200003)15:3<209::aid-humu1>3.0.co;2-k|pmid=10679936 |s2cid=29926332 |issn=1059-7794|doi-access=free}}</ref> When the PDHB gene found in the E1 beta subunit of the complex is mutated, this also leads to pyruvate dehydrogenase deficiency.<ref>{{Cite journal|last1=Okajima|first1=K.|last2=Korotchkina|first2=L.G.|last3=Prasad|first3=C.|last4=Rupar|first4=T.|last5=Phillips III|first5=J.A.|last6=Ficicioglu|first6=C.|last7=Hertecant|first7=J.|last8=Patel|first8=M.S.|last9=Kerr|first9=D.S.|date=April 2008|title=Mutations of the E1β subunit gene (PDHB) in four families with pyruvate dehydrogenase deficiency|url=http://dx.doi.org/10.1016/j.ymgme.2007.10.135|journal=Molecular Genetics and Metabolism|volume=93|issue=4|pages=371–380|doi=10.1016/j.ymgme.2007.10.135|pmid=18164639|issn=1096-7192|url-access=subscription}}</ref> Likewise, mutations found on other subunits of the complex, like the DLAT gene found on the E2 subunit, the PDHX gene found on the E3 subunit, as well as a mutation on a pyruvate dehydrogenase phosphatase gene, known as PDP1, have all been traced back to pyruvate dehydrogenase deficiency, while their specific contribution to the disease state is unknown.<ref>{{Cite journal|last1=Head|first1=Rosemary A.|last2=Brown|first2=Ruth M.|last3=Zolkipli|first3=Zarazuela|last4=Shahdadpuri|first4=Raveen|last5=King|first5=Mary D.|last6=Clayton|first6=Peter T.|last7=Brown|first7=Garry K.|date=2005-07-27|title=Clinical and genetic spectrum of pyruvate dehydrogenase deficiency: Dihydrolipoamide acetyltransferase (E2) deficiency|url=http://dx.doi.org/10.1002/ana.20550|journal=Annals of Neurology|volume=58|issue=2|pages=234–241|doi=10.1002/ana.20550|pmid=16049940|s2cid=38264402|issn=0364-5134|url-access=subscription}}</ref><ref>{{cite journal |last1=Pavlu-Pereira |first1=Hana |last2=Silva |first2=Maria João |last3=Florindo |first3=Cristina |last4=Sequeira |first4=Sílvia |last5=Ferreira |first5=Ana Cristina |last6=Duarte |first6=Sofia |last7=Rodrigues |first7=Ana Luísa |last8=Janeiro |first8=Patrícia |last9=Oliveira |first9=Anabela |last10=Gomes |first10=Daniel |last11=Bandeira |first11=Anabela |last12=Martins |first12=Esmeralda |last13=Gomes |first13=Roseli |last14=Soares |first14=Sérgia |last15=Tavares de Almeida |first15=Isabel |last16=Vicente |first16=João B. |last17=Rivera |first17=Isabel |title=Pyruvate dehydrogenase complex deficiency: updating the clinical, metabolic and mutational landscapes in a cohort of Portuguese patients |journal=Orphanet Journal of Rare Diseases |date=December 2020 |volume=15 |issue=1 |pages=298 |doi=10.1186/s13023-020-01586-3 |pmid=33092611 |pmc=7579914 |doi-access=free}}</ref><ref>{{Cite journal|last1=Heo|first1=Hye Jin|last2=Kim|first2=Hyoung Kyu|last3=Youm|first3=Jae Boum|last4=Cho|first4=Sung Woo|last5=Song|first5=In-Sung|last6=Lee|first6=Sun Young|last7=Ko|first7=Tae Hee|last8=Kim|first8=Nari|last9=Ko|first9=Kyung Soo|last10=Rhee|first10=Byoung Doo|last11=Han|first11=Jin|date=August 2016|title=Mitochondrial pyruvate dehydrogenase phosphatase 1 regulates the early differentiation of cardiomyocytes from mouse embryonic stem cells|url= |journal=Experimental & Molecular Medicine|volume=48|issue=8|pages=e254|doi=10.1038/emm.2016.70|pmid=27538372|pmc=5007642|issn=2092-6413}}</ref>