A number of mitochondrial diseases are associated with defects in the human gene SLC25A4 (often designated ANT1); (MIM:103220). SLC25A4 is a nuclear gene that encodes a component of a gated pore through which ADP is moved across the inner membrane into the mitochondrial matrix and ATP is moved from the matrix into the cytoplasm. SLC25A4 is one of four related genes in humans (SLC25A4, SLC25A31, SLC25A5, and SLC25A6); there are two similar genes in flies (sesB and Ant2). Loss-of-function alleles, RNAi-targeting constructs and alleles caused by insertional mutagenesis have been generated for both the fly genes.
The human Hsap\SLC25A4 gene has been introduced into flies, but has not been characterized. Specific diseases associated with SLC25A4 include two forms mitochondrial DNA depletion syndrome 12 (cardiomyopathic type) (MIM:615418, FBhh0000373; MIM:617184, FBhh0000579) and progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2 (MIM:609283, FBhh0000374).
Dmel\sesB is ubiquitously expressed at relatively high levels; Ant2 is expressed predominantly in testis. Animals homozygous for loss-of-function alleles of Dmel\sesB frequently die at or prior to the pupal stage; those that reach adulthood exhibit reduced lifespan, developmental retardation, seizures upon mechanical stress (bang sensitivity), and reduced activity levels. Sleep deprivation has been found to increase the seizure susceptibility.
Hemideficiency of Dmel\sesB affects synapse morphology, neurotransmission, plasticity, and sleep patterns. Similar phenotypes are observed for animals hemizygous for a second Drosophila mitochondrial solute transporter (sea; see FBhh0000951). It is postulated that this may extend more generally -- that synapse development is exquisitely sensitive to impairment of mitochondrial function, including reduced levels of mitochondrial solute transporters.
Genetic and physical interactions of Dmel\sesB have been described; see below and in the sesB gene report.
Several other fly genes characterized as models of mitochondrial disease also exhibit bang-sensitive phenotypes, including mt:ATPase6 (see mitochondrial complex V disorders, MT-ATP6-related, FBhh0000376), mt:ND2 (see mitochondrial complex I deficiency, MT-ND2-related, FBhh0000382), and Ttc19 (see mitochondrial complex III deficiency, nuclear type 2, FBhh0000369).
[updated Feb. 2020 by FlyBase; FBrf0222196]
For many diseases of the mitochondria, when muscle is stained with Gomori Trichrome, characteristic ragged-red fibers are visible under the microscope. This appearance is due to the accumulation of abnormal mitochondria below the plasma membrane of the muscle fiber. These may extend throughout the muscle fiber as the disease severity increases. The mitochondrial aggregates cause the contour of the muscle fiber to become irregular, causing the "ragged" appearance. [http://medcell.med.yale.edu/histology/cell_lab/red_ragged_fibers.php]
Although the mechanism is unclear, mutations in several nuclear genes, including SLC25A4, lead to the deletion of large segments of mtDNA in muscle cells. The size of the deleted region can range from 2kb to 10kb. [from Genetics Home Reference, progressive external ophthalmoplegia; 2016.08.25]
The SLC25A4 gene encodes a mitochondrial ADP/ATP translocator (also known as adenine nucleotide translocator 1, ANT1), which is a homodimer of 30-kD subunits embedded in the mitochondrial inner membrane. The dimer forms a gated pore through which ADP is moved across the inner membrane into the mitochondrial matrix and ATP is moved from the matrix into the cytoplasm (summary by Neckelmann et al., 1987; pubmed:2823266). [from MIM:103220; 2016.08.25]
Many to many (4 human to 2 Drosophila); the additional orthologous human genes are SLC25A31, SLC25A5, and SLC25A6.
High-scoring ortholog of human SLC25A4; moderate-scoring ortholog of SLC25A31, SLC25A5, and SLC25A6 (2 Drosophila to 4 human). Dmel\sesB shares 73-82% identity and 84-89% similarity with the human genes.
