ADP/ATP translocase 4 (ANT4) is an enzyme that in humans is encoded by the SLC25A31gene 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 of 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.
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.
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