View source for Phosphate carrier protein, mitochondrial

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{{Infobox_gene}}
'''Phosphate carrier protein, mitochondrial''' is a [[protein]] that in humans is encoded by the ''SLC25A3'' [[gene]].<ref name="pmid8168843">{{cite journal | vauthors = Jabs EW, Thomas PJ, Bernstein M, Coss C, Ferreira GC, Pedersen PL | title = Chromosomal localization of genes required for the terminal steps of oxidative metabolism: alpha and gamma subunits of ATP synthase and the phosphate carrier | journal = Human Genetics | volume = 93 | issue = 5 | pages = 600–2 | date = May 1994 | pmid = 8168843 | doi = 10.1007/bf00202832 | s2cid = 39597611 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: SLC25A3 solute carrier family 25 (mitochondrial carrier; phosphate carrier), member 3| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5250}}{{PD-notice}}</ref> The encoded protein is a [[transmembrane protein]] located in the [[Inner mitochondrial membrane|mitochondrial inner membrane]] and [[Catalysis|catalyzes]] the [[Membrane transport|transport]] of [[Phosphate#Biochemistry of phosphates|phosphate ions]] across it for the purpose of [[Oxidative phosphorylation#Eukaryotic electron transport chains|oxidative phosphorylation]].<ref name=":0">{{Cite web|url=https://www.uniprot.org/uniprot/Q00325|title=SLC25A3 - Phosphate carrier protein, mitochondrial precursor - Homo sapiens (Human) - SLC25A46 gene & protein|website=www.uniprot.org|language=en|access-date=2018-08-20}}{{CC-notice|cc=by4}}</ref><ref name=":3">{{cite journal | title = UniProt: the universal protein knowledgebase | journal = Nucleic Acids Research | volume = 45 | issue = D1 | pages = D158–D169 | date = January 2017 | pmid = 27899622 | pmc = 5210571 | doi = 10.1093/nar/gkw1099 }}</ref> There are two significant [[Protein isoform|isoforms]] of this gene [[Gene expression|expressed]] in human cells, which differ slightly in [[Protein structure|structure]] and function.<ref name=":1">{{OMIM|600370|SLC25A3}}</ref> [[Mutation]]s in this gene can cause [[Mitochondrial carrier|mitochondrial phosphate carrier]] deficiency (MPCD), a fatal disorder of oxidative phosphorylation symptomized by [[lactic acidosis]], [[Neonatal nursing|neonatal]] [[hypotonia]], [[hypertrophic cardiomyopathy]], and death within the first year of life.<ref name=":0" /><ref name=":3" />

== Structure ==
The ''SLC25A3'' gene is located on the q arm of [[chromosome 12]] in position 23.1 and spans 8,376 base pairs.<ref name = "entrez"/> The gene has 9 [[exon]]s and produces a 40.1 kDa protein composed of 362 [[amino acids]].<ref name=COPaKB>{{cite journal | vauthors = Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P | title = Integration of cardiac proteome biology and medicine by a specialized knowledgebase | journal = Circulation Research | volume = 113 | issue = 9 | pages = 1043–53 | date = October 2013 | pmid = 23965338 | pmc = 4076475 | doi = 10.1161/CIRCRESAHA.113.301151 }}</ref><ref name="url_COPaKB">{{cite web | url = https://amino.heartproteome.org/web/protein/Q00325 | work = Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) | title = SLC25A3 - Phosphate carrier protein, mitochondrial }}</ref><ref name=":1" /> The encoded protein (PHC) is a [[Integral membrane protein#Integral polytopic protein|multi-pass]] transmembrane protein located in the mitochondrial inner membrane; it contains six transmembrane segments, emerging into a large extramembranous loop.<ref name=":0" /><ref name=":3" /><ref name=":2">{{cite journal | vauthors = Dolce V, Iacobazzi V, Palmieri F, Walker JE | title = The sequences of human and bovine genes of the phosphate carrier from mitochondria contain evidence of alternatively spliced forms | journal = The Journal of Biological Chemistry | volume = 269 | issue = 14 | pages = 10451–60 | date = April 1994 | doi = 10.1016/S0021-9258(17)34081-4 | pmid = 8144629 | doi-access = free }}</ref> Both the [[N-terminus|N-terminal]] and [[C-terminus|C-terminal]] regions of this protein protrude toward the [[cytosol]]. PHC contains three related segments arranged in tandem which are related to those found in other characterized members of the [[mitochondrial carrier]] [[protein family|family]].<ref name="entrez" /> There exist two transcript variants of this protein, PHC-A and PHC-B, which differ by 13 amino acids.<ref name=":2" /> Isoform A contains 42 amino acids while Isoform B contains 41. [[In vitro]], the isoforms differ in their substrate affinities and transport rates.<ref name=":4">{{cite journal | vauthors = Huizing M, Ruitenbeek W, van den Heuvel LP, Dolce V, Iacobazzi V, Smeitink JA, Palmieri F, Trijbels JM | title = Human mitochondrial transmembrane metabolite carriers: tissue distribution and its implication for mitochondrial disorders | journal = Journal of Bioenergetics and Biomembranes | volume = 30 | issue = 3 | pages = 277–84 | date = June 1998 | pmid = 9733094 | doi = 10.1023/A:1020501021222 | s2cid = 45811751 }}</ref><ref name=":1" />

== Function ==
The encoded protein (PHC) catalyzes the transport of phosphate from the cytosol into the [[mitochondrial matrix]], either by proton [[Cotransporter|cotransport]] or [[Antiporter|in exchange for]] [[Hydroxide|hydroxyl]] [[ion]]s.<ref name="entrez" /> In the final steps of oxidative phosphorylation, this protein catalyzes the uptake of a phosphate ion with a proton across the mitochondrial inner membrane.<ref name=":1" /> The availability of inorganic phosphate for oxidative phosphorylation is mainly dependent on PHC activity.<ref name=":4" /> To substantially affect oxidative phosphorylation, PHC depletion must be severe, exceeding 85%.<ref>{{cite journal | vauthors = Seifert EL, Gál A, Acoba MG, Li Q, Anderson-Pullinger L, Golenár T, Moffat C, Sondheimer N, Claypool SM, Hajnóczky G | title = Natural and Induced Mitochondrial Phosphate Carrier Loss: DIFFERENTIAL DEPENDENCE OF MITOCHONDRIAL METABOLISM AND DYNAMICS AND CELL SURVIVAL ON THE EXTENT OF DEPLETION | journal = The Journal of Biological Chemistry | volume = 291 | issue = 50 | pages = 26126–26137 | date = December 2016 | pmid = 27780865 | pmc = 5207081 | doi = 10.1074/jbc.M116.744714 | doi-access = free }}</ref> This protein may be involved in regulation of the [[mitochondrial permeability transition pore]] (mPTP).<ref name=":0" /><ref name=":3" />

== Clinical significance ==
Mutations in this gene can cause mitochondrial phosphate carrier deficiency (MPCD), a fatal disorder of oxidative phosphorylation. Symptoms include lactic acidosis, hypertrophic cardiomyopathy, and neonatal hypotonia; afflicted patients die within the first year of life.<ref name=":0" /><ref name=":3" />

Isoform A of this gene is expressed at high levels in [[Cardiac muscle cell|heart]], [[pancrease|pancreatic]], and [[skeletal muscle]] cells while Isoform B is expressed in all tissues, albeit poorly.<ref name=":4" /><ref name=":1" />

In the sole recorded case of a mutation in this gene, a [[Zygosity#Homozygous|homozygous]] mutation (c.215G>A) in the [[Alternative splicing|alternatively spliced]] exon 3A of this gene caused an [[amino acid replacement]] (G72E) in Isoform A. This leads to [[ATP synthase]] deficiency in [[Myocyte|muscle cells]], which express Isoform A, but not in [[fibroblast]]s, which express Isoform B, causing MPCD and the aforementioned standard symptoms.<ref>{{cite journal | vauthors = Mayr JA, Merkel O, Kohlwein SD, Gebhardt BR, Böhles H, Fötschl U, Koch J, Jaksch M, Lochmüller H, Horváth R, Freisinger P, Sperl W | title = Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation | journal = American Journal of Human Genetics | volume = 80 | issue = 3 | pages = 478–84 | date = March 2007 | pmid = 17273968 | pmc = 1821108 | doi = 10.1086/511788 }}</ref><ref name=":1" />

== Interactions ==
The encoded protein [[protein-protein interactions|interacts]] with [[PPIF]]; this interaction is impaired by [[ERCC8 (gene)|CsA]].<ref name=":0" /><ref name=":3" />

== See also ==
* [[Solute carrier family]]

== References ==
{{reflist}}

== Further reading ==
{{refbegin | 2}}
* {{cite journal | vauthors = Dolce V, Fiermonte G, Messina A, Palmieri F | title = Nucleotide sequence of a human heart cDNA encoding the mitochondrial phosphate carrier | journal = DNA Sequence | volume = 2 | issue = 2 | pages = 133–5 | year = 1992 | pmid = 1777677 | doi = 10.3109/10425179109039683 }}
* {{cite journal | vauthors = Maruyama K, Sugano S | title = Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides | journal = Gene | volume = 138 | issue = 1–2 | pages = 171–4 | date = January 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }}
* {{cite journal | vauthors = Dolce V, Iacobazzi V, Palmieri F, Walker JE | title = The sequences of human and bovine genes of the phosphate carrier from mitochondria contain evidence of alternatively spliced forms | journal = The Journal of Biological Chemistry | volume = 269 | issue = 14 | pages = 10451–60 | date = April 1994 | doi = 10.1016/S0021-9258(17)34081-4 | pmid = 8144629 | doi-access = free }}
* {{cite journal | vauthors = Marsh S, Carter NP, Dolce V, Iacobazzi V, Palmieri F | title = Chromosomal localization of the mitochondrial phosphate carrier gene PHC to 12q23 | journal = Genomics | volume = 29 | issue = 3 | pages = 814–5 | date = October 1995 | pmid = 8575787 | doi = 10.1006/geno.1995.9924 }}
* {{cite journal | vauthors = Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | title = Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library | journal = Gene | volume = 200 | issue = 1–2 | pages = 149–56 | date = October 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }}
* {{cite journal | vauthors = Huizing M, Ruitenbeek W, van den Heuvel LP, Dolce V, Iacobazzi V, Smeitink JA, Palmieri F, Trijbels JM | title = Human mitochondrial transmembrane metabolite carriers: tissue distribution and its implication for mitochondrial disorders | journal = Journal of Bioenergetics and Biomembranes | volume = 30 | issue = 3 | pages = 277–84 | date = June 1998 | pmid = 9733094 | doi = 10.1023/A:1020501021222 | s2cid = 45811751 }}
* {{cite journal | vauthors = Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, Superti-Furga G | title = A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway | journal = Nature Cell Biology | volume = 6 | issue = 2 | pages = 97–105 | date = February 2004 | pmid = 14743216 | doi = 10.1038/ncb1086 | s2cid = 11683986 }}
* {{cite journal | vauthors = Jin J, Smith FD, Stark C, Wells CD, Fawcett JP, Kulkarni S, Metalnikov P, O'Donnell P, Taylor P, Taylor L, Zougman A, Woodgett JR, Langeberg LK, Scott JD, Pawson T | title = Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization | journal = Current Biology | volume = 14 | issue = 16 | pages = 1436–50 | date = August 2004 | pmid = 15324660 | doi = 10.1016/j.cub.2004.07.051 | doi-access = free | bibcode = 2004CBio...14.1436J }}
* {{cite journal | vauthors = Iacobazzi V, Infantino V, Costanzo P, Izzo P, Palmieri F | title = Functional analysis of the promoter of the mitochondrial phosphate carrier human gene: identification of activator and repressor elements and their transcription factors | journal = The Biochemical Journal | volume = 391 | issue = Pt 3 | pages = 613–21 | date = November 2005 | pmid = 15984930 | pmc = 1276962 | doi = 10.1042/BJ20050776 }}
* {{cite journal | vauthors = Otsuki T, Ota T, Nishikawa T, Hayashi K, Suzuki Y, Yamamoto J, Wakamatsu A, Kimura K, Sakamoto K, Hatano N, Kawai Y, Ishii S, Saito K, Kojima S, Sugiyama T, Ono T, Okano K, Yoshikawa Y, Aotsuka S, Sasaki N, Hattori A, Okumura K, Nagai K, Sugano S, Isogai T | title = Signal sequence and keyword trap in silico for selection of full-length human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA libraries | journal = DNA Research | volume = 12 | issue = 2 | pages = 117–26 | year = 2007 | pmid = 16303743 | doi = 10.1093/dnares/12.2.117 | doi-access = free }}
* {{cite journal | vauthors = Mayr JA, Merkel O, Kohlwein SD, Gebhardt BR, Böhles H, Fötschl U, Koch J, Jaksch M, Lochmüller H, Horváth R, Freisinger P, Sperl W | title = Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation | journal = American Journal of Human Genetics | volume = 80 | issue = 3 | pages = 478–84 | date = March 2007 | pmid = 17273968 | pmc = 1821108 | doi = 10.1086/511788 }}
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{{NLM content}}
{{Membrane transport proteins}}

[[Category:Solute carrier family]]