The adenine nucleotide transporter 1 (Ant1) gene encodes an inner mitochondrial membrane protein that transports ADP into mitochondria and ATP from mitochondria to the cytosol. This condition was characterized more or less sequentially by optic atrophy with visual failure, sensorineural deafness, ataxia, myopathy, axonal sensory-motor polyneuropathy, and PEO. ATP and AMP are common ligands acting in the allosteric control of key metabolic enzymes (e.g., glycogen metabolism, gluconeogenesis, and more). (Recall that these adenine nucleotides are negatively charged: ADP3- and … The specific pathways are tissue specific. Alternative name(s): ADP,ATP carrier protein 1. Indeed, chemical modification of ANT has long been used to modulate MPTP opening (152). The relationship between this defect of mitochondrial dynamics and altered mitochondrial maintenance is intriguing. Atractylate, which inhibits the ANT and stabilizes it in the so-called ‘c’ conformation (nucleotide-binding sites facing the cytosolic side of the inner membrane), favors PTP opening, while bongkrekate, which also inhibits the ANT but stabilizes it in the ‘m’ conformation (nucleotide-binding sites facing the matrix side of the inner membrane), favors PTP closure. Description. [26] The negatively charged groups of the inhibitors bind strongly to the positively charged residues deep within the binding pocket. uncovered an inhibitory effect of atractyloside on the energy-transfer system (oxidative phosphorylation) and ADP binding sites of rat liver mitochondria. Int J Biochem Cell Biol. In 2001, autosomal dominant PEO with multiple mtDNA deletions was associated with mutations in the gene (PEO1), encoding a mitochondrial helicase called Twinkle, an essential factor for mtDNA maintenance and for the regulation of mtDNA copy number. We recently identified a novel member of the Ant family in mouse, Ant4, of which gene configuration as well as amino acid homology is well conserved among mammals. Experiments in mitochondria from Vdac1−/−, Vdac3−/−, and Vdac1−/− Vdac3−/− mice and in fibroblasts lacking all three VDAC isoforms indicate that the PT is identical to that observed in strain-matched wild-type mitochondria, demonstrating that VDACs are fully dispensable for PTP opening and regulation. The adenine nucleotide translocator (ANT) has long been considered to be the main component of the PTP, possibly in association with the outer membrane voltage-dependent anion channel (VDAC). Short name: ANT 1. Reduced activities of complex I and IV together with a significant decline in cardiac and skeletal muscle mtDNA levels and gene expression were reported. The relatively benign, long-term progression also was noted in another large family with autosomal dominant PEO. [33][34][35] cDNA of ADP/ATP translocase was sequenced for bovine in 1982[36] and a yeast species Saccharomyces cerevisiae in 1986[37] before finally Battini et al. These reactions hamper the use of the binding equations that convert free [Mg2 +] to ANT-dependent ADP–ATP exchange rate (Chinopoulos et al., 2009). [8] Further work has demonstrated that ANT is a monomer in detergents [9] and functions as a monomer in mitochondrial membranes. The ANT is an ADP/ATP exchanger and is the most abundant protein on the mitochondrial inner membrane. adenine nucleotide translocase-1 induces cardiomyocyte death through upregulation of the pro-apoptotic protein bax Christopher P. Baines a, b and Jeffery D. Molkentin a a Department of Pediatrics, University of Cincinnati, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, 45229, USA The homology in the coding sequences between human and yeast ADP/ATP translocase was 47% while bovine and human sequences extended remarkable to 266 out of 297 residues, or 89.6%. Adenine Nucleotide Translocase 4 Utilizing various approaches, we and others recently identified a novel member of the Ant family, Ant4 both in mouse and human (16,17,33). [4][13], ANT transports the free, i.e. sequenced a cDNA clone of the human transporter in 1989. adPEO shows Mendelian inheritance patterns but is characterized by large-scale mitochondrial DNA (mtDNA) deletions. The changes in free extramitochondrial [Mg2 +] exhibit complete sensitivity to submicromolar amounts of the ANT inhibitor, carboxyatractyloside (cATR; Chinopoulos et al., 2009; Metelkin, Demin, Kovacs, & Chinopoulos, 2009). 2015 Jul;64:34-44. doi: 10.1016/j.biocel.2015.03.015. Karch et al. Among other nucleotides tested, only dADP and dATP exchange with a noticeable activity. ADP/ATP translocase, the most abundant mitochondrial protein, is an integral component of the inner mitochondrial membrane. Figure 3. Epub 2015 Mar 25. These are multimeric protein complexes, and differential expression of isoforms of some subunits has been described in skeletal muscle and other tissues. Thus, in permeabilized cells, all competing adenine nucleotide interconverting reactions need to be inhibited. Sci Adv. Mutational inactivation of the mouse Ant1 gene encoding the heart/muscle isoform of the mitochondrial ANT results in mitochondrial abnormalities, including a partial deficit in ADP-stimulated respiration consistent with impaired translocation of ADP into mitochondria in both skeletal muscle and heart. Central nervous system involvement was infrequent and included visual impairment, migraine, lethargy, hearing loss, and epilepsy. Here, we describe the isolation of adenine nucleotide translocase-1 (ANT-1) in a screen for dominant, apoptosis-inducing genes. [13] There are structures available that show the translocator locked in a cytoplasmic state by the inhibitor carboxyatractyloside,[27][28] or in the matrix state by the inhibitor bongkrekic acid. [7] The atomic structure of the bovine ANT confirmed this notion, and provided the first structural fold of a mitochondrial carrier. The pore could still be detected in mouse liver mitochondria where both ANT1 and ANT2 isoforms had been eliminated (Kokoszka et al., 2004), but recent experiments have shown that these mice overexpress the ANT4 isoform (Karch et al., 2019), which might have provided a permeabilization pathway even if respiration of ANT1/2 null mitochondria could not be stimulated by ADP (Kokoszka et al., 2004). Copyright © 2021 Elsevier B.V. or its licensors or contributors. The main components of the contact sites are hexokinase on the cytosolic surface of the outer membrane, VDAC in the outer membrane, creatine kinase in the intermembrane space, and ANT in the inner membrane. Footnotes ↵ 3 The abbreviations used are: Ant, adenine nucleotide translocase; PBS, phosphate-buffered saline; ES, embryonic stem; RT, reverse transcription; TUNEL, deoxynucleotidyltransferase-mediated dUTP nick end labeling; X-gal, 5-bromo-4-chloro-3-indolyl-β-d-galactopyranoside; DAB, diaminobenzidine. The outer membrane (which contains the voltage-dependent anion channel, VDAC) was placed into the picture after the definition of ‘contact sites’ between the outer and inner membranes. Recently, we found that the extraocular muscle mitochondria have lower content or lower activity of some enzyme complexes of the electron transport system, causing them to respire at slower rates. Dinitrophenol (DNP) An uncoupler that destroys the proton gradient by making the inner mitrochondrial membrane leaky. Ant1 knockout (Ant1–/–) mice develop cardiomyopathy and severe exercise intolerance. An energy deficit (low [ATP], high [AMP]) may stimulate not only the flux through metabolic pathways (glycolysis), but an AMP activated protein kinase (AMPK) can initiate transcriptional activation of selected genes in combination with other activators, or it can directly phosphorylate and activate metabolic enzymes. This paper briefly overviews experimental results focusing on the role of ANT in the mitochondrial permeability transition and The Ca2+-modified adenine nucleotide translocase (ANT) and F 0F1 ATP synthase are the major contenders for the role of pore in the PTP. Mitochondrial electron transport chain and ATP synthase. José Marín-García M.D., in Post-Genomic Cardiology (Second Edition), 2014. The adenine nucleotide translocases (Ant) facilitate the transport of ADP and ATP by an antiport mechanism across the inner mitochondrial membrane, thus playing an essential role in cellular energy metabolism. ORF Names: XELAEV_18038881mg Imported. Many but not all such promoters contain short sequence motifs for binding nuclear respiratory factors NRF-1 and/or NRF-2. It transports H ions and phosphate H,PO, ions into the matrix. Mitochondrial myopathies (MM) refer to a group of clinically and biochemically heterogeneous disorders that share common features of major mitochondrial structural abnormalities in skeletal muscle. Dinitrophenol ( DNP ) an uncoupler that destroys the proton gradient by making the inner mitochondrial membrane and belongs mitochondrial. This method introduced variability in the mitochondrial permeability transition by deletion of the membrane transports the free, i.e,. 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