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<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{Infobox_gene}}
{{PBB_Controls
'''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 | pmc =  | doi = 10.1007/bf00202832 }}</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| access-date = }}{{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 | vauthors =  | 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 | url = https://doi.org/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|Mutations]] 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" />
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
}}


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
== Structure ==
{{GNF_Protein_box
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|exons]] 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 | pmid = 8144629 }}</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 }}</ref><ref name=":1" />
| image =
| image_source = 
| PDB =
| Name = Solute carrier family 25 (mitochondrial carrier; phosphate carrier), member 3
| HGNCid = 10989
| Symbol = SLC25A3
| AltSymbols =; OK/SW-cl.48; PHC
| OMIM = 600370
| ECnumber =
| Homologene = 37649
| MGIid = 1353498
| Function = {{GNF_GO|id=GO:0005215 |text = transporter activity}} {{GNF_GO|id=GO:0005488 |text = binding}} {{GNF_GO|id=GO:0015293 |text = symporter activity}} {{GNF_GO|id=GO:0015320 |text = phosphate carrier activity}}  
| Component = {{GNF_GO|id=GO:0005739 |text = mitochondrion}} {{GNF_GO|id=GO:0005743 |text = mitochondrial inner membrane}} {{GNF_GO|id=GO:0005887 |text = integral to plasma membrane}} {{GNF_GO|id=GO:0016020 |text = membrane}} {{GNF_GO|id=GO:0016021 |text = integral to membrane}}
| Process = {{GNF_GO|id=GO:0006091 |text = generation of precursor metabolites and energy}} {{GNF_GO|id=GO:0006810 |text = transport}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 5250
    | Hs_Ensembl = ENSG00000075415
    | Hs_RefseqProtein = NP_998777
    | Hs_RefseqmRNA = NM_213612
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 12
    | Hs_GenLoc_start = 97511534
    | Hs_GenLoc_end = 97519906
    | Hs_Uniprot = Q00325
    | Mm_EntrezGene = 18674
    | Mm_Ensembl = ENSMUSG00000061904
    | Mm_RefseqmRNA = NM_133668
    | Mm_RefseqProtein = NP_598429
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 10
    | Mm_GenLoc_start = 90546377
    | Mm_GenLoc_end = 90553762
    | Mm_Uniprot = Q3THU8
  }}
}}
'''Solute carrier family 25 (mitochondrial carrier; phosphate carrier), member 3''', also known as '''SLC25A3''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: SLC25A3 solute carrier family 25 (mitochondrial carrier; phosphate carrier), member 3| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5250| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{PBB_Summary
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|ions]].<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 }}</ref> This protein may be involved in regulation of the [[mitochondrial permeability transition pore]] (mPTP).<ref name=":0" /><ref name=":3" />
| section_title =  
| summary_text = The protein encoded by this gene catalyzes the transport of phosphate into the mitochondrial matrix, either by proton cotransport or in exchange for hydroxyl ions. The protein contains three related segments arranged in tandem which are related to those found in other characterized members of the mitochondrial carrier family. Both the N-terminal and C-terminal regions of this protein protrude toward the cytosol. Multiple alternatively spliced transcript variants have been isolated.<ref name="entrez">{{cite web | title = Entrez Gene: SLC25A3 solute carrier family 25 (mitochondrial carrier; phosphate carrier), member 3| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5250| accessdate = }}</ref>
}}


==See also==
== 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|fibroblasts]], 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]]
* [[Solute carrier family]]


==References==
== References ==
{{reflist|2}}
{{reflist}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
* {{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 }}
| citations =
* {{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 | author=Dolce V, Fiermonte G, Messina A, Palmieri F |title=Nucleotide sequence of a human heart cDNA encoding the mitochondrial phosphate carrier. |journal=DNA Seq. |volume=2 |issue= 2 |pages= 133-5 |year= 1992 |pmid= 1777677 |doi= }}
* {{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 | pmid = 8144629 | doi =  }}
*{{cite journal | author=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 |year= 1994 |pmid= 8125298 |doi= }}
* {{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 | author=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=J. Biol. Chem. |volume=269 |issue= 14 |pages= 10451-60 |year= 1994 |pmid= 8144629 |doi=  }}
* {{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 | author=Jabs EW, Thomas PJ, Bernstein M, ''et al.'' |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=Hum. Genet. |volume=93 |issue= 5 |pages= 600-2 |year= 1994 |pmid= 8168843 |doi=  }}
* {{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 }}
*{{cite journal  | author=Marsh S, Carter NP, Dolce V, ''et al.'' |title=Chromosomal localization of the mitochondrial phosphate carrier gene PHC to 12q23. |journal=Genomics |volume=29 |issue= 3 |pages= 814-5 |year= 1996 |pmid= 8575787 |doi= 10.1006/geno.1995.9924 }}
* {{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 }}
*{{cite journal | author=Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, ''et al.'' |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 |year= 1997 |pmid= 9373149 |doi= }}
* {{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 }}
*{{cite journal | author=Huizing M, Ruitenbeek W, van den Heuvel LP, ''et al.'' |title=Human mitochondrial transmembrane metabolite carriers: tissue distribution and its implication for mitochondrial disorders. |journal=J. Bioenerg. Biomembr. |volume=30 |issue= 3 |pages= 277-84 |year= 1999 |pmid= 9733094 |doi= }}
* {{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 | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
* {{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 }}
*{{cite journal  | author=Ota T, Suzuki Y, Nishikawa T, ''et al.'' |title=Complete sequencing and characterization of 21,243 full-length human cDNAs. |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40-5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 }}
* {{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 }}
*{{cite journal  | author=Bouwmeester T, Bauch A, Ruffner H, ''et al.'' |title=A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. |journal=Nat. Cell Biol. |volume=6 |issue= 2 |pages= 97-105 |year= 2004 |pmid= 14743216 |doi= 10.1038/ncb1086 }}
*{{cite journal | author=Jin J, Smith FD, Stark C, ''et al.'' |title=Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization. |journal=Curr. Biol. |volume=14 |issue= 16 |pages= 1436-50 |year= 2004 |pmid= 15324660 |doi= 10.1016/j.cub.2004.07.051 }}
*{{cite journal | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
*{{cite journal  | author=Iacobazzi V, Infantino V, Costanzo P, ''et al.'' |title=Functional analysis of the promoter of the mitochondrial phosphate carrier human gene: identification of activator and repressor elements and their transcription factors. |journal=Biochem. J. |volume=391 |issue= Pt 3 |pages= 613-21 |year= 2006 |pmid= 15984930 |doi= 10.1042/BJ20050776 }}
*{{cite journal | author=Otsuki T, Ota T, Nishikawa T, ''et al.'' |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 Res. |volume=12 |issue= 2 |pages= 117-26 |year= 2007 |pmid= 16303743 |doi= 10.1093/dnares/12.2.117 }}
*{{cite journal | author=Mayr JA, Merkel O, Kohlwein SD, ''et al.'' |title=Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation. |journal=Am. J. Hum. Genet. |volume=80 |issue= 3 |pages= 478-84 |year= 2007 |pmid= 17273968 |doi= 10.1086/511788 }}
}}
{{refend}}
{{refend}}


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{{NLM content}}
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[[Category:Solute carrier family]]
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Latest revision as of 05:05, 24 December 2018

VALUE_ERROR (nil)
Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

n/a

n/a

Ensembl

n/a

n/a

UniProt

n/a

n/a

RefSeq (mRNA)

n/a

n/a

RefSeq (protein)

n/a

n/a

Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

Phosphate carrier protein, mitochondrial is a protein that in humans is encoded by the SLC25A3 gene.[1][2] The encoded protein is a transmembrane protein located in the mitochondrial inner membrane and catalyzes the transport of phosphate ions across it for the purpose of oxidative phosphorylation.[3][4] There are two significant isoforms of this gene expressed in human cells, which differ slightly in structure and function.[5] Mutations in this gene can cause mitochondrial phosphate carrier deficiency (MPCD), a fatal disorder of oxidative phosphorylation symptomized by lactic acidosis, neonatal hypotonia, hypertrophic cardiomyopathy, and death within the first year of life.[3][4]

Structure

The SLC25A3 gene is located on the q arm of chromosome 12 in position 23.1 and spans 8,376 base pairs.[2] The gene has 9 exons and produces a 40.1 kDa protein composed of 362 amino acids.[6][7][5] The encoded protein (PHC) is a multi-pass transmembrane protein located in the mitochondrial inner membrane; it contains six transmembrane segments, emerging into a large extramembranous loop.[3][4][8] Both the N-terminal and 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 family.[2] There exist two transcript variants of this protein, PHC-A and PHC-B, which differ by 13 amino acids.[8] Isoform A contains 42 amino acids while Isoform B contains 41. In vitro, the isoforms differ in their substrate affinities and transport rates.[9][5]

Function

The encoded protein (PHC) catalyzes the transport of phosphate from the cytosol into the mitochondrial matrix, either by proton cotransport or in exchange for hydroxyl ions.[2] In the final steps of oxidative phosphorylation, this protein catalyzes the uptake of a phosphate ion with a proton across the mitochondrial inner membrane.[5] The availability of inorganic phosphate for oxidative phosphorylation is mainly dependent on PHC activity.[9] To substantially affect oxidative phosphorylation, PHC depletion must be severe, exceeding 85%.[10] This protein may be involved in regulation of the mitochondrial permeability transition pore (mPTP).[3][4]

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.[3][4]

Isoform A of this gene is expressed at high levels in heart, pancreatic, and skeletal muscle cells while Isoform B is expressed in all tissues, albeit poorly.[9][5]

In the sole recorded case of a mutation in this gene, a homozygous mutation (c.215G>A) in the alternatively spliced exon 3A of this gene caused an amino acid replacement (G72E) in Isoform A. This leads to ATP synthase deficiency in muscle cells, which express Isoform A, but not in fibroblasts, which express Isoform B, causing MPCD and the aforementioned standard symptoms.[11][5]

Interactions

The encoded protein interacts with PPIF; this interaction is impaired by CsA.[3][4]

See also

References

  1. ↑ Jabs EW, Thomas PJ, Bernstein M, Coss C, Ferreira GC, Pedersen PL (May 1994). "Chromosomal localization of genes required for the terminal steps of oxidative metabolism: alpha and gamma subunits of ATP synthase and the phosphate carrier". Human Genetics. 93 (5): 600–2. doi:10.1007/bf00202832. PMID 8168843.
  2. ↑ 2.0 2.1 2.2 2.3 "Entrez Gene: SLC25A3 solute carrier family 25 (mitochondrial carrier; phosphate carrier), member 3". This article incorporates text from this source, which is in the public domain.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 "SLC25A3 - Phosphate carrier protein, mitochondrial precursor - Homo sapiens (Human) - SLC25A46 gene & protein". www.uniprot.org. Retrieved 2018-08-20.File:CC-BY-icon-80x15.png This article incorporates text available under the CC BY 4.0 license.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 "UniProt: the universal protein knowledgebase". Nucleic Acids Research. 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMC 5210571. PMID 27899622.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Online Mendelian Inheritance in Man (OMIM) SLC25A3 -600370
  6. ↑ 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 (October 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.
  7. ↑ "SLC25A3 - Phosphate carrier protein, mitochondrial". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
  8. ↑ 8.0 8.1 Dolce V, Iacobazzi V, Palmieri F, Walker JE (April 1994). "The sequences of human and bovine genes of the phosphate carrier from mitochondria contain evidence of alternatively spliced forms". The Journal of Biological Chemistry. 269 (14): 10451–60. PMID 8144629.
  9. ↑ 9.0 9.1 9.2 Huizing M, Ruitenbeek W, van den Heuvel LP, Dolce V, Iacobazzi V, Smeitink JA, Palmieri F, Trijbels JM (June 1998). "Human mitochondrial transmembrane metabolite carriers: tissue distribution and its implication for mitochondrial disorders". Journal of Bioenergetics and Biomembranes. 30 (3): 277–84. PMID 9733094.
  10. ↑ Seifert EL, Gál A, Acoba MG, Li Q, Anderson-Pullinger L, Golenár T, Moffat C, Sondheimer N, Claypool SM, Hajnóczky G (December 2016). "Natural and Induced Mitochondrial Phosphate Carrier Loss: DIFFERENTIAL DEPENDENCE OF MITOCHONDRIAL METABOLISM AND DYNAMICS AND CELL SURVIVAL ON THE EXTENT OF DEPLETION". The Journal of Biological Chemistry. 291 (50): 26126–26137. doi:10.1074/jbc.M116.744714. PMC 5207081. PMID 27780865.
  11. ↑ Mayr JA, Merkel O, Kohlwein SD, Gebhardt BR, Böhles H, Fötschl U, Koch J, Jaksch M, Lochmüller H, Horváth R, Freisinger P, Sperl W (March 2007). "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation". American Journal of Human Genetics. 80 (3): 478–84. doi:10.1086/511788. PMC 1821108. PMID 17273968.

Further reading

  • Dolce V, Fiermonte G, Messina A, Palmieri F (1992). "Nucleotide sequence of a human heart cDNA encoding the mitochondrial phosphate carrier". DNA Sequence. 2 (2): 133–5. doi:10.3109/10425179109039683. PMID 1777677.
  • Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
  • Dolce V, Iacobazzi V, Palmieri F, Walker JE (April 1994). "The sequences of human and bovine genes of the phosphate carrier from mitochondria contain evidence of alternatively spliced forms". The Journal of Biological Chemistry. 269 (14): 10451–60. PMID 8144629.
  • Marsh S, Carter NP, Dolce V, Iacobazzi V, Palmieri F (October 1995). "Chromosomal localization of the mitochondrial phosphate carrier gene PHC to 12q23". Genomics. 29 (3): 814–5. doi:10.1006/geno.1995.9924. PMID 8575787.
  • Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
  • Huizing M, Ruitenbeek W, van den Heuvel LP, Dolce V, Iacobazzi V, Smeitink JA, Palmieri F, Trijbels JM (June 1998). "Human mitochondrial transmembrane metabolite carriers: tissue distribution and its implication for mitochondrial disorders". Journal of Bioenergetics and Biomembranes. 30 (3): 277–84. doi:10.1023/A:1020501021222. PMID 9733094.
  • 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 (February 2004). "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nature Cell Biology. 6 (2): 97–105. doi:10.1038/ncb1086. PMID 14743216.
  • 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 (August 2004). "Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization". Current Biology. 14 (16): 1436–50. doi:10.1016/j.cub.2004.07.051. PMID 15324660.
  • Iacobazzi V, Infantino V, Costanzo P, Izzo P, Palmieri F (November 2005). "Functional analysis of the promoter of the mitochondrial phosphate carrier human gene: identification of activator and repressor elements and their transcription factors". The Biochemical Journal. 391 (Pt 3): 613–21. doi:10.1042/BJ20050776. PMC 1276962. PMID 15984930.
  • 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 (2007). "Signal sequence and keyword trap in silico for selection of full-length human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA libraries". DNA Research. 12 (2): 117–26. doi:10.1093/dnares/12.2.117. PMID 16303743.
  • Mayr JA, Merkel O, Kohlwein SD, Gebhardt BR, Böhles H, Fötschl U, Koch J, Jaksch M, Lochmüller H, Horváth R, Freisinger P, Sperl W (March 2007). "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation". American Journal of Human Genetics. 80 (3): 478–84. doi:10.1086/511788. PMC 1821108. PMID 17273968.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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