ADP/ATP translocase 4
|, AAC4, ANT4, SFEC35kDa, ANT 4, solute carrier family 25 member 31|
ADP/ATP translocase 4 (ANT4) is an enzyme that in humans is encoded by the SLC25A31 gene on chromosome 4. This enzyme inhibits apoptosis by catalyzing ADP/ATP exchange across the mitochondrial membranes and regulating membrane potential. In particular, ANT4 is essential to spermatogenesis, as it imports ATP into sperm mitochondria to support their development and survival. Outside this role, the SLC25AC31 gene has not been implicated in any human disease.
The ANT4 protein contains six transmembrane helices, and a homodimer functional unit, which serves as an ADP/ATP channel protein. Unlike the other three ANT isoforms, ANT4 has additional amino acids at its N- and C-terminals. These amino acid sequences may interact with different factors for specialized functions such as localization to sperm flagella. The SLC25A31 gene is composed of 6 exons over a stretch of 44 kbp of DNA.
The ANT4 protein is a mitochondrial ADP/ATP carrier that catalyzes the exchange of ADP and ATP between the mitochondrial matrix and cytoplasm during ATP synthesis. In addition, ANT4 stabilizes the mitochondrial membrane potential and decreases the permeability transition pore complex (PTPC) opening in order to prevent nuclear chromatin fragmentation and resulting cell death. In humans, the protein localizes to the liver, brain and testis, though in adult males, it is expressed primarily in the testis. Studies on Ant4-deficient mice reveal increased apoptosis in the testis leading to infertility, thus indicating that Ant4 is required as for spermatogenesis. In this case, the anti-apoptotic function for ANT4 is attributed to its importing of cytosolic ATP into the mitochondria. In other cells, the isoform ANT2 carries out this role; however, since sperm lack the X chromosome on which the ANT2 gene resides, survival of the sperm is dependent on ANT4.
The SLC25A31 enzyme is an important constituent in apoptotic signaling and oxidative stress, most notably as part of the mitochondrial death pathway and cardiac myocyte apoptosis signaling. Programmed cell death is a distinct genetic and biochemical pathway essential to metazoans. An intact death pathway is required for successful embryonic development and the maintenance of normal tissue homeostasis. Apoptosis has proven to be tightly interwoven with other essential cell pathways. The identification of critical control points in the cell death pathway has yielded fundamental insights for basic biology, as well as provided rational targets for new therapeutics a normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response. It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells.
The SLC25A31 gene is important for the coding of the most abundant mitochondrial protein Ancp which represents 10% of the proteins of the inner membrane of bovine heart mitochondria. Ancp is encoded by four different genes: SLC25A4 (also known as ANC1 or ANT1), SLC25A5 (ANC3 or ANT2), SLC25A6 (ANC2 or ANT3) and SLC25A31 (ANC4 or ANT4). Their expression is tissue specific and highly regulated and adapted to particular cellular energetic demand. Indeed, human ANC expression patterns depend on the tissue and cell types, the developmental stage and the status of cell proliferation. Furthermore, expression of the genes is modulated by different transcriptional elements in the promoter regions. Therefore, Ancp emerges as a logical candidate to regulate the cellular dependence on oxidative energy metabolism.
To date, there is no evidence of SLC25A31 gene mutations associated with human disease, though they have been associated with male infertility in mice. In addition, ANT4 overexpression has been observed to protect cancer cells from induced apoptosis by anti-cancer drugs such as lonidamine and staurosporine.
- GRCh38: Ensembl release 89: ENSG00000151475 - Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000069041 - Ensembl, May 2017
- "Human PubMed Reference:".
- "Mouse PubMed Reference:".
- Dolce V, Scarcia P, Iacopetta D, Palmieri F (Jan 2005). "A fourth ADP/ATP carrier isoform in man: identification, bacterial expression, functional characterization and tissue distribution". FEBS Letters. 579 (3): 633–7. doi:10.1016/j.febslet.2004.12.034. PMID 15670820.
- "Entrez Gene: SLC25A31 solute carrier family 25 (mitochondrial carrier; adenine nucleotide translocator), member 31".
- Gallerne C, Touat Z, Chen ZX, Martel C, Mayola E, Sharaf el dein O, Buron N, Le Bras M, Jacotot E, Borgne-Sanchez A, Lemoine A, Lemaire C, Pervaiz S, Brenner C (May 2010). "The fourth isoform of the adenine nucleotide translocator inhibits mitochondrial apoptosis in cancer cells". The International Journal of Biochemistry & Cell Biology. 42 (5): 623–9. doi:10.1016/j.biocel.2009.12.024. PMID 20060930.
- Dupont PY, Stepien G (Nov 2011). "Computational analysis of the transcriptional regulation of the adenine nucleotide translocator isoform 4 gene and its role in spermatozoid glycolytic metabolism". Gene. 487 (1): 38–45. doi:10.1016/j.gene.2011.07.024. PMID 21827840.
- Hamazaki T, Leung WY, Cain BD, Ostrov DA, Thorsness PE, Terada N (21 April 2011). "Functional expression of human adenine nucleotide translocase 4 in Saccharomyces cerevisiae". PLOS ONE. 6 (4): e19250. doi:10.1371/journal.pone.0019250. PMC 3080916. PMID 21532989.
- Clémençon B, Babot M, Trézéguet V (2013). "The mitochondrial ADP/ATP carrier (SLC25 family): pathological implications of its dysfunction". Molecular Aspects of Medicine. 34 (2–3): 485–93. doi:10.1016/j.mam.2012.05.006. PMID 23506884.
- Chevrollier A, Loiseau D, Reynier P, Stepien G (Jun 2011). "Adenine nucleotide translocase 2 is a key mitochondrial protein in cancer metabolism". Biochimica et Biophysica Acta. 1807 (6): 562–7. doi:10.1016/j.bbabio.2010.10.008. PMID 20950584.
- Danial NN, Korsmeyer SJ (Jan 2004). "Cell death: critical control points". Cell. 116 (2): 205–19. doi:10.1016/S0092-8674(04)00046-7. PMID 14744432.
- Kerr JF, Wyllie AH, Currie AR (Aug 1972). "Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics". British Journal of Cancer. 26 (4): 239–57. doi:10.1038/bjc.1972.33. PMC 2008650. PMID 4561027.
- De Marcos Lousa C, Trézéguet V, Dianoux AC, Brandolin G, Lauquin GJ (Dec 2002). "The human mitochondrial ADP/ATP carriers: kinetic properties and biogenesis of wild-type and mutant proteins in the yeast S. cerevisiae". Biochemistry. 41 (48): 14412–20. doi:10.1021/bi0261490. PMID 12450408.
- Patten DA, Wong J, Khacho M, Soubannier V, Mailloux RJ, Pilon-Larose K, MacLaurin JG, Park DS, McBride HM, Trinkle-Mulcahy L, Harper ME, Germain M, Slack RS (Nov 2014). "OPA1-dependent cristae modulation is essential for cellular adaptation to metabolic demand". The EMBO Journal. 33 (22): 2676–91. doi:10.15252/embj.201488349. PMC 4282575. PMID 25298396.
- Kim YH, Haidl G, Schaefer M, Egner U, Mandal A, Herr JC (Feb 2007). "Compartmentalization of a unique ADP/ATP carrier protein SFEC (Sperm Flagellar Energy Carrier, AAC4) with glycolytic enzymes in the fibrous sheath of the human sperm flagellar principal piece". Developmental Biology. 302 (2): 463–76. doi:10.1016/j.ydbio.2006.10.004. PMC 1858657. PMID 17137571.
- Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A, Wiemann S (Jan 2006). "The LIFEdb database in 2006". Nucleic Acids Research. 34 (Database issue): D415–8. doi:10.1093/nar/gkj139. PMC 1347501. PMID 16381901.
- Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A (Oct 2004). "From ORFeome to biology: a functional genomics pipeline". Genome Research. 14 (10B): 2136–44. doi:10.1101/gr.2576704. PMC 528930. PMID 15489336.
- Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S (Sep 2000). "Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing". EMBO Reports. 1 (3): 287–92. doi:10.1093/embo-reports/kvd058. PMC 1083732. PMID 11256614.
- Wiemann S, Weil B, Wellenreuther R, Gassenhuber J, Glassl S, Ansorge W, Böcher M, Blöcker H, Bauersachs S, Blum H, Lauber J, Düsterhöft A, Beyer A, Köhrer K, Strack N, Mewes HW, Ottenwälder B, Obermaier B, Tampe J, Heubner D, Wambutt R, Korn B, Klein M, Poustka A (Mar 2001). "Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs". Genome Research. 11 (3): 422–35. doi:10.1101/gr.GR1547R. PMC 311072. PMID 11230166.
- Hartley JL, Temple GF, Brasch MA (Nov 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.