Disease relevance of Slc25a4

• Therefore, Ant1 mutant mice have the biochemical, histological, metabolic and physiological characteristics of mitochondrial myopathy and cardiomyopathy [1].
• A mouse model for mitochondrial myopathy and cardiomyopathy resulting from a deficiency in the heart/muscle isoform of the adenine nucleotide translocator [1].
• In an attempt to create an animal model of tissue-specific mitochondrial disease, we generated 'knockout' mice deficient in the heart/muscle isoform of the adenine nucleotide translocator (Ant1) [1].
• Ant1 mutant adults also had a resting serum lactate level fourfold higher than that of controls, indicative of metabolic acidosis [1].
• Histological and ultrastructural examination of skeletal muscle from Ant1 null mutants revealed ragged-red muscle fibers and a dramatic proliferation of mitochondria, while examination of the heart revealed cardiac hypertrophy with mitochondrial proliferation [1].

High impact information on Slc25a4

• This change in membrane potential results from the failure of the adenine nucleotide translocator (ANT)/voltage-dependent anion channel (VDAC) complex to maintain ATP/ADP exchange [2].
• The PT pore complex is regulated by thiol-reactive agents, calcium, cyclophilin D ligands (cyclosporin A and a nonimmunosuppressive cyclosporin A derivative), ligands of the adenine nucleotide translocator, apoptosis-related endoproteases (caspases), and Bcl-2-like proteins [3].
• A specific ligand of the mitochondrial adenine nucleotide translocator (ANT), bongkreik acid, inhibits PT and reduces apoptosis induction by mitochondria in a cell-free system [4].
• We tested the effect of a specific inhibitor of PT, bongkrekic acid (BA), a ligand of the mitochondrial adenine nucleotide translocator, on a prototypic model of apoptosis glucocorticoid-induced thymocyte death [5].
• Inhibition of adenine nucleotide translocator pore function and protection against apoptosis in vivo by an HIV protease inhibitor [6].

Biological context of Slc25a4

• The mouse and human ANT1 and ANT2 genes showed substantial homology starting about 300 base pairs (bp) 5' to the coding region and continuing through the 3' untranslated region (UTR) [7].
• The mouse Ant1 and Ant2 genes are very similar in sequence to their human homologs, and we have mapped them to mouse Chromosomes (Chrs) (8 and X respectively) that exhibit conserved synteny with the chromosomes on which the human genes are located [8].
• Adenine nucleotide translocase-1, a component of the permeability transition pore, can dominantly induce apoptosis [9].
• BACKGROUND: The adenine nucleotide translocator 1 (Ant1) is an inner mitochondrial membrane protein involved with energy mobilization during oxidative phosphorylation [10].
• The first report of expression of Smads 2, 3 and 4 in astrocytes provided here is consistent with a regulation of Ant1 gene expression by these transcription factors in reactive astrocytes [10].

Anatomical context of Slc25a4

• Mouse Ant1 is expressed at high levels in skeletal muscle and heart, similar to human ANT1 [7].
• To test this hypothesis, we examined the mitochondria from mice lacking the heart/muscle isoform of the adenine nucleotide translocator (Ant1), designated Ant1(tm2Mgr) (-/-) mice [11].
• Consistent with Ant1 expression, mitochondria isolated from skeletal muscle, heart, and brain of the Ant1-deficient mice produced markedly increased amounts of the ROS hydrogen peroxide, whereas liver mitochondria, which express a different Ant isoform, produced normally low levels of hydrogen peroxide [11].
• Ant1 expression in reactive astrocytes is regulated by transforming growth factor-beta1, a pluripotent CNS injury-induced cytokine [12].
• Using DD-PCR analysis, adenine nucleotide translocase (ANT) 3, an enzyme which exchanges ATP and ADP through mitochondrial membrane, has been identified as a novel target counter-regulated by IL-4 and IFN-gamma [13].

Associations of Slc25a4 with chemical compounds

• The influence of chromatin on the human adenine nucleotide translocase isoform 2 (ANT2) promoter was investigated in transfected cells treated with the deacetylase inhibitors butyrate and trichostatin A (TSA) [14].
• Thus, the astrocytic response to CNS injury includes an apparent increase in energy mobilization capacity by Ant1 that contributes to neuroprotective, energy-dependent glutamate uptake [12].
• The amounts of ATP attained with glutamine were decreased in some instances by the addition of atractyloside, an inhibitor of adenine nucleotide translocase in mitochondria, and were decreased consistently and to a greater extent by 2,4-dinitrophenol [15].
• The synthetic tripeptide arsenical 4-(N-(S-glutathionylacetyl)amino)p-phenylarsenoxide (p-GSAO) is an angiogenesis inhibitor that inactivates mitochondrial adenine nucleotide translocase (ANT) by cross-linking a pair of matrix-facing cysteine residues [16].
• All these findings indicate that mitochondrial creatine kinase activity located within the intermembrane and intercristae space, in conjunction with its tight functional coupling to oxidative phosphorylation, via the adenine nucleotide translocase, can modulate mitochondrial permeability transition in the presence of creatine [17].

Regulatory relationships of Slc25a4

• In the present study, we describe the molecular mechanisms by which TGF-beta1 regulates Ant1 gene expression in cultured primary rodent astrocytes [10].

Other interactions of Slc25a4

• Repeats constituted 32% of 15kb of Ant1 sequence and 36% of the 27kb of Ant2 sequence and included SINEs, LINEs and LTR elements [7].
• A 69 basepair TGF-beta1 responsive element of the Ant1 promoter was also identified [10].
• The Ant1 gene maps near Klk3 on proximal mouse chromosome 8 [18].
• Consistent with the lower antioxidant defenses in heart, the heart mtDNAs of the Ant1-deficient mice showed a striking increase in the accumulation of mtDNA rearrangements, whereas skeletal muscle, with higher antioxidant defenses, had fewer mtDNA rearrangements [11].
• Con sequently, superoxide was generated at a higher rate, and several mitochondrial proteins, including adenine nucleotide translocase 1 (ANT1), were more oxidized by HSF1 deficiency in vivo [19].

Analytical, diagnostic and therapeutic context of Slc25a4

• Expression and sequence analysis of the mouse adenine nucleotide translocase 1 and 2 genes [7].
• To identify genes expressed by reactive astrocytes, we employed an in vivo model of the glial scar and differential display PCR and found an increase in the level of Ant1, a mitochondrial ATP/ADP exchanger that facilitates the flux of ATP out of the mitochondria [12].
• Heart eluates and serum were tested for IgG antibodies to myosin and to adenine nucleotide translocator and branched chain ketoacid dehydrogenase molecules by ELISA [20].
• Surface plasmon resonance experiments demonstrated that some of these antibodies prevented the interaction between Vpr and one of its cellular partners, the adenine nucleotide translocator [21].
• Two major types of experimental models are discussed: adjuvant-induced myocarditis, in which animals are given multiple immunizations of heart proteins (myosin, adenine nucleotide translocator); and virus-induced myocarditis, in which animals are infected with the viruses predominantly associated with the human disease [22].

References