Phosphate carrier protein, mitochondrial

Structure

The SLC25A3 gene is located on the q arm of chromosome 12 in position 23.1 and spans 8,376 base pairs. The gene has 9 exons and produces a 40.1 kDa protein composed of 362 amino acids. 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. 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. There exist two transcript variants of this protein, PHC-A and PHC-B, which differ by 13 amino acids. Isoform A contains 42 amino acids while Isoform B contains 41. In vitro, the isoforms differ in their substrate affinities and transport rates.

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. In the final steps of oxidative phosphorylation, this protein catalyzes the uptake of a phosphate ion with a proton across the mitochondrial inner membrane. The availability of inorganic phosphate for oxidative phosphorylation is mainly dependent on PHC activity. To substantially affect oxidative phosphorylation, PHC depletion must be severe, exceeding 85%. This protein may be involved in regulation of the mitochondrial permeability transition pore (mPTP).

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.

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.

In the sole recorded case of a mutation in this gene, a homozygous mutation (c.215GA) 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.

Interactions

The encoded protein interacts with PPIF; this interaction is impaired by CsA.

References

References

1. (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.
2. "Entrez Gene: SLC25A3 solute carrier family 25 (mitochondrial carrier; phosphate carrier), member 3".
3. "SLC25A3 - Phosphate carrier protein, mitochondrial precursor - Homo sapiens (Human) - SLC25A46 gene & protein".
4. (January 2017). "UniProt: the universal protein knowledgebase". Nucleic Acids Research.
5. {{OMIM. 600370. SLC25A3
6. (October 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research.
7. "SLC25A3 - Phosphate carrier protein, mitochondrial". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
8. (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.
9. (June 1998). "Human mitochondrial transmembrane metabolite carriers: tissue distribution and its implication for mitochondrial disorders". Journal of Bioenergetics and Biomembranes.
10. (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.
11. (March 2007). "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation". American Journal of Human Genetics.