The SLC25A3 gene is located on the q arm of chromosome 12 in position 23.1 and spans 8,376 base pairs.[6] The gene has 9 exons and produces a 40.1 kDa protein composed of 362 amino acids.[10][11][9] 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.[7][8][12] 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 carrierfamily.[6] There exist two transcript variants of this protein, PHC-A and PHC-B, which differ by 13 amino acids.[12] Isoform A contains 42 amino acids while Isoform B contains 41. In vitro, the isoforms differ in their substrate affinities and transport rates.[13][9]
The encoded protein (PHC) catalyzes the transport of phosphate from the cytosol into the mitochondrial matrix, either by proton cotransportorin exchange forhydroxylions.[6] In the final steps of oxidative phosphorylation, this protein catalyzes the uptake of a phosphate ion with a proton across the mitochondrial inner membrane.[9] The availability of inorganic phosphate for oxidative phosphorylation is mainly dependent on PHC activity.[13] To substantially affect oxidative phosphorylation, PHC depletion must be severe, exceeding 85%.[14] This protein may be involved in regulation of the mitochondrial permeability transition pore (mPTP).[7][8]
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.[7][8]
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.[13][9]
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.[15][9]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^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. PMID8168843. S2CID39597611.
^ abcHuizing 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. PMID9733094. S2CID45811751.
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. PMID1777677.
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. PMID8125298.
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. PMID8575787.
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. PMID9373149.
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. PMID9733094. S2CID45811751.
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. PMID14743216. S2CID11683986.
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