ADP/ATP translocase 4

SLC25A31
Identifiers
Aliases	SLC25A31 , AAC4, ANT4, SFEC35kDa, ANT 4, solute carrier family 25 member 31
External IDs	OMIM: 610796 MGI: 1920583 HomoloGene: 69485 GeneCards: SLC25A31
Gene location (Human)
Chr.	Chromosome 4 (human)
End	127,774,292 bp
Gene location (Mouse)
Chr.	Chromosome 3 (mouse)
End	40,680,527 bp
RNA expression pattern
	Top expressed in
	sperm; ; lower lobe of lung; ; pancreatic epithelial cell; ; pancreatic ductal cell; ; tibialis anterior muscle; ; amygdala; ; ovary; ; gastrocnemius muscle; ; connective tissue; ; adipose tissue;
	Top expressed in
	spermatocyte; ; spermatid; ; right lung; ; secondary oocyte; ; testicle; ; urethra; ; left lung; ; morula; ; pituitary gland; ; yolk sac;
	More reference expression data
	More reference expression data
Gene ontology
Molecular function	transporter activity ; transmembrane transporter activity ; ATP:ADP antiporter activity ;
Cellular component	cell projection ; motile cilium ; cilium ; membrane ; mitochondrion ; nucleus ; mitochondrial inner membrane ; integral component of membrane ;
Biological process	transmembrane transport ; mitochondrial transport ; transport ; ADP transport ; ATP transport ;
	Sources:Amigo / QuickGO
Orthologs
	83447
	73333
	ENSG00000151475
	ENSMUSG00000069041
	Q9H0C2
	Q3V132
	NM_031291 ; NM_001318467
	NM_178386
	NP_001305396 ; NP_112581
	NP_848473
	Wikidata
View/Edit Human	View/Edit Mouse

Last updated August 14, 2023

ADP/ATP translocase 4 (ANT4) is an enzyme that in humans is encoded by the SLC25A31 gene on chromosome 4.^[5]^[6] This enzyme inhibits apoptosis by catalyzing ADP/ATP exchange across the mitochondrial membranes and regulating membrane potential.^[6]^[7] In particular, ANT4 is essential to spermatogenesis, as it imports ATP into sperm mitochondria to support their development and survival.^[7]^[8] Outside this role, the SLC25AC31 gene has not been implicated in any human disease.^[9]^[10]

Structure

The ANT4 protein contains six transmembrane helices, and a homodimer functional unit, which serves as an ADP/ATP channel protein.^[9]^[11] 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.^[7]^[8] The SLC25A31 gene is composed of 6 exons over a stretch of 44 kbp of DNA.^[10]

Function

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.^[6] 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.^[7] In humans, the protein localizes to the liver, brain and testis, though in adult males, it is expressed primarily in the testis.^[7]^[9]^[10] Studies on Ant4-deficient mice reveal increased apoptosis in the testis leading to infertility, thus indicating that Ant4 is required as for spermatogenesis.^[7] 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.^[7]^[8]

Clinical significance

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.^[12] 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.^[13] 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.^[10]^[14] 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.^[10]

To date, there is no evidence of SLC25A31 gene mutations associated with human disease, though they have been associated with male infertility in mice.^[9]^[10] In addition, ANT4 overexpression has been observed to protect cancer cells from induced apoptosis by anti-cancer drugs such as lonidamine and staurosporine.^[7]

Interactions

OPA1 ^[15]

Related Research Articles

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Adenine nucleotide translocator (ANT), also known as the ADP/ATP translocase (ANT), ADP/ATP carrier protein (AAC) or mitochondrial ADP/ATP carrier, exchanges free ATP with free ADP across the inner mitochondrial membrane. ANT is the most abundant protein in the inner mitochondrial membrane and belongs to mitochondrial carrier family.

Mitochondrial carriers are proteins from solute carrier family 25 which transfer molecules across the membranes of the mitochondria. Mitochondrial carriers are also classified in the Transporter Classification Database. The Mitochondrial Carrier (MC) Superfamily has been expanded to include both the original Mitochondrial Carrier (MC) family and the Mitochondrial Inner/Outer Membrane Fusion (MMF) family.

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Hexokinase-1 (HK1) is an enzyme that in humans is encoded by the HK1 gene on chromosome 10. Hexokinases phosphorylate glucose to produce glucose-6-phosphate (G6P), the first step in most glucose metabolism pathways. This gene encodes a ubiquitous form of hexokinase which localizes to the outer membrane of mitochondria. Mutations in this gene have been associated with hemolytic anemia due to hexokinase deficiency. Alternative splicing of this gene results in five transcript variants which encode different isoforms, some of which are tissue-specific. Each isoform has a distinct N-terminus; the remainder of the protein is identical among all the isoforms. A sixth transcript variant has been described, but due to the presence of several stop codons, it is not thought to encode a protein. [provided by RefSeq, Apr 2009]

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Voltage-dependent anion-selective channel protein 3 (VDAC3) is a protein that in humans is encoded by the VDAC3 gene on chromosome 8. The protein encoded by this gene is a voltage-dependent anion channel and shares high structural homology with the other VDAC isoforms. Nonetheless, VDAC3 demonstrates limited pore-forming ability and, instead, interacts with other proteins to perform its biological functions, including sperm flagella assembly and centriole assembly. Mutations in VDAC3 have been linked to male infertility, as well as Parkinson’s disease.

ADP/ATP translocase 3, also known as solute carrier family 25 member 6, is a protein that in humans is encoded by the SLC25A6 gene.

ADP/ATP translocase 2 is a protein that in humans is encoded by the SLC25A5 gene on the X chromosome.

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References

1 2 3 GRCh38: Ensembl release 89: ENSG00000151475 - Ensembl, May 2017
1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000069041 - Ensembl, May 2017
↑ "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.
↑ 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. S2CID 46371435.
1 2 3 "Entrez Gene: SLC25A31 solute carrier family 25 (mitochondrial carrier; adenine nucleotide translocator), member 31".
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1 2 3 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.
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↑ 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 (BBA) - Bioenergetics. 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. S2CID 10764012.
↑ 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.