Tricarboxylate transport protein, mitochondrial

File:Bovine mitochondrial ADP-ATP carrier 1.png]]

File:Bovine mitochondrial ADP-ATP carrier 2.png

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The structure of the tricarboxylate transport protein is consistent with the structures of other mitochondrial carriers. In particular, the tricarboxylate transport protein has a tripartite structure consisting of three repeated domains that are approximately 100 amino acids in length. Each repeat forms a transmembrane domain consisting of two hydrophobic α-helices.{{cite journal | vauthors = King MS, Kerr M, Crichton PG, Springett R, Kunji ER | title = Formation of a cytoplasmic salt bridge network in the matrix state is a fundamental step in the transport mechanism of the mitochondrial ADP/ATP carrier | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1857 | issue = 1 | pages = 14–22 | date = January 2016 | pmid = 26453935 | pmc = 4674015 | doi = 10.1016/j.bbabio.2015.09.013 }} The amino and carboxy termini are located on the cytosolic side of the inner mitochondrial membrane. Each domain is linked by two hydrophilic loops located on the cytosolic side of the membrane.{{cite journal | vauthors = Majd H, King MS, Smith AC, Kunji ER | title = Pathogenic mutations of the human mitochondrial citrate carrier SLC25A1 lead to impaired citrate export required for lipid, dolichol, ubiquinone and sterol synthesis | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1859 | issue = 1 | pages = 1–7 | date = January 2018 | pmid = 29031613 | doi = 10.1016/j.bbabio.2017.10.002 | doi-access = free }} The two α-helices of each repeated domain are connected by hydrophilic loops located on the matrix side of the membrane. A salt bridge network is present on both the matrix side and cytoplasmic side of the tricarboxylate transport protein.

The tricarboxylate transport protein exists in two states: a cytoplasmic state where it accepts malate from the cytoplasm and a matrix state where it accepts citrate from the mitochondrial matrix.{{cite journal | vauthors = Robinson AJ, Kunji ER | title = Mitochondrial carriers in the cytoplasmic state have a common substrate binding site | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 8 | pages = 2617–2622 | date = February 2006 | pmid = 16469842 | pmc = 1413793 | doi = 10.1073/pnas.0509994103 | bibcode = 2006PNAS..103.2617R | doi-access = free }} A single binding site is present near the center of the cavity of the tricarboxylate transport protein, which can be either exposed to the cytosol or the mitochondrial matrix depending on the state. A substrate induced conformational change occurs when citrate enters from the matrix side and binds to the central cavity of the tricarboxylate transport protein. This conformational change opens a gate on the cytosolic side and closes the gate on the matrix side. Likewise, when malate enters from the cytosolic side, the matrix gate opens and the cytosolic gate closes. Each side of the transporter is open and closed by the disruption and formation of the salt bridge networks, which allows access to the single binding site.{{cite journal | vauthors = Robinson AJ, Overy C, Kunji ER | title = The mechanism of transport by mitochondrial carriers based on analysis of symmetry | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 46 | pages = 17766–17771 | date = November 2008 | pmid = 19001266 | pmc = 2582046 | doi = 10.1073/pnas.0809580105 | bibcode = 2008PNAS..10517766R | doi-access = free }}{{cite journal | vauthors = Kunji ER, Robinson AJ | title = The conserved substrate binding site of mitochondrial carriers | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1757 | issue = 9–10 | pages = 1237–1248 | date = September 2006 | pmid = 16759636 | doi = 10.1016/j.bbabio.2006.03.021 | doi-access = free }}

Mutations in this gene have been associated with the inborn error of metabolism combined D-2- and L-2-hydroxyglutaric aciduria,{{cite journal | vauthors = Nota B, Struys EA, Pop A, Jansen EE, Fernandez Ojeda MR, Kanhai WA, Kranendijk M, van Dooren SJ, Bevova MR, Sistermans EA, Nieuwint AW, Barth M, Ben-Omran T, Hoffmann GF, de Lonlay P, McDonald MT, Meberg A, Muntau AC, Nuoffer JM, Parini R, Read MH, Renneberg A, Santer R, Strahleck T, van Schaftingen E, van der Knaap MS, Jakobs C, Salomons GS | title = Deficiency in SLC25A1, encoding the mitochondrial citrate carrier, causes combined D-2- and L-2-hydroxyglutaric aciduria | journal = American Journal of Human Genetics | volume = 92 | issue = 4 | pages = 627–631 | date = April 2013 | pmid = 23561848 | pmc = 3617390 | doi = 10.1016/j.ajhg.2013.03.009 }} which was the first reported case of a pathogenic mutation of the SLC25A1 gene.{{cite book | vauthors = Hoffmann GF, Köckler S | veditors = Saudubray JM, Baumgartner M, Walter J | chapter = Cerebral Organic Acid Disorders and Other Disorders of Lysine Catabolism | title = Inborn Metabolic Diseases | location = Germany | pages = 344 | year = 2016 | publisher = Springer | isbn = 978-3-662-49771-5 }} Patients with D-2/L-2-hydroxyglutaric aciduria display neonatal onset metabolic encephalopathy, infantile epilepsy, global developmental delay, muscular hypotonia and early death.{{cite journal | vauthors = Cohen I, Staretz-Chacham O, Wormser O, Perez Y, Saada A, Kadir R, Birk OS | title = A novel homozygous SLC25A1 mutation with impaired mitochondrial complex V: Possible phenotypic expansion | journal = American Journal of Medical Genetics. Part A | volume = 176 | issue = 2 | pages = 330–336 | date = February 2018 | pmid = 29226520 | doi = 10.1002/ajmg.a.38574 | s2cid = 6953669 }} It is believed low levels of citrate in the cytosol and high levels of citrate in the mitochondria caused by the impaired citrate transport plays a role in the disease. In addition, increased expression of the tricarboxylate transport protein has been linked to cancer{{cite journal | vauthors = Jiang L, Boufersaoui A, Yang C, Ko B, Rakheja D, Guevara G, Hu Z, DeBerardinis RJ | title = Quantitative metabolic flux analysis reveals an unconventional pathway of fatty acid synthesis in cancer cells deficient for the mitochondrial citrate transport protein | journal = Metabolic Engineering | volume = 43 | issue = Pt B | pages = 198–207 | date = September 2017 | pmid = 27856334 | pmc = 5429990 | doi = 10.1016/j.ymben.2016.11.004 }}{{Cite journal | vauthors = Poolsri WA, Phokrai P, Suwankulanan S, Phakdeeto N, Phunsomboon P, Pekthong D, Richert L, Pongcharoen S, Srisawang P | title = Combination of Mitochondrial and Plasma Membrane Citrate Transporter Inhibitors Inhibits De Novo Lipogenesis Pathway and Triggers Apoptosis in Hepatocellular Carcinoma Cells | journal = BioMed Research International | volume = 2018 | pages = 3683026 | date = 2018 | pmid = 29546056 | pmc = 5818947 | doi = 10.1155/2018/3683026 | doi-access = free }} and the production of inflammatory mediators.{{cite journal | vauthors = Infantino V, Convertini P, Cucci L, Panaro MA, Di Noia MA, Calvello R, Palmieri F, Iacobazzi V | title = The mitochondrial citrate carrier: a new player in inflammation | journal = The Biochemical Journal | volume = 438 | issue = 3 | pages = 433–436 | date = September 2011 | pmid = 21787310 | doi = 10.1042/BJ20111275 | url = https://hal.archives-ouvertes.fr/hal-00617325 | hdl = 11563/18487 | hdl-access = free }}{{cite journal | vauthors = Infantino V, Iacobazzi V, Menga A, Avantaggiati ML, Palmieri F | title = A key role of the mitochondrial citrate carrier (SLC25A1) in TNFα- and IFNγ-triggered inflammation | journal = Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms | volume = 1839 | issue = 11 | pages = 1217–1225 | date = November 2014 | pmid = 25072865 | pmc = 4346166 | doi = 10.1016/j.bbagrm.2014.07.013 }}{{cite journal | vauthors = Palmieri EM, Spera I, Menga A, Infantino V, Porcelli V, Iacobazzi V, Pierri CL, Hooper DC, Palmieri F, Castegna A | title = Acetylation of human mitochondrial citrate carrier modulates mitochondrial citrate/malate exchange activity to sustain NADPH production during macrophage activation | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1847 | issue = 8 | pages = 729–738 | date = August 2015 | pmid = 25917893 | doi = 10.1016/j.bbabio.2015.04.009 | doi-access = free }} Therefore, it has been suggested that inhibition of the tricarboxylate transport protein may have a therapeutic effect in chronic inflammation diseases and cancer.

• {{MeshName|SLC25A1+protein,+human}}

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Category:Solute carrier family