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(2018) reported that the FAM173A gene encodes a … [6] These proteins are classified under the mitochondrial carrier superfamily. Experimentally induced affinity-purified anti-ANT antibodies cross-reacted with calcium channel complex proteins of rat cardiac myocytes, induced enhancement of transmembrane calcium current, and produced calcium-dependent cell lysis in the absence of complement [133]. 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. [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. The rate of change in free [Mg2 +] is converted to rate of ATP exported from mitochondria using standard binding equations (Chinopoulos et al., 2009).The ATP–ADP exchange rate mediated by the ANT from isolated mitochondria has been validated in Chinopoulos et al. 2019;5(8):eaaw4597. (2009), especially in view of the contribution of the ATP-Mg2 +/Pi carrier (Aprille, 1993) and a homolog of the Mrs2 protein originally described in yeast that mediates an electrophoretic uptake of Mg2 + in mitochondria (Kolisek et al., 2003). ANT-1 is a component of the mitochondrial permeability transition complex, a protein aggregate connecting the inner with the outer mitochondrial membrane that has recently been implicated in apoptosis. The PTP is modulated by ligands of the adenine nucleotide translocator (ANT). 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%. Although mitochondrial antigens have generally been classified as nonorgan-specific, the heart specificity of the M7 AABs was shown by absorption studies. This paper briefly overviews experimental results focusing on the role of ANT in the mitochondrial permeability transition and [29], In 1955, Siekevitz and Potter demonstrated that adenine nucleotides were distributed in cells in two pools located in the mitochondrial and cytosolic compartments. Contact sites are specialized structures where the two membranes get together through protein–protein interactions; this arrangement facilitates channeling of adenine nucleotides to and from the matrix into the cytosol. The Ca2+-modified adenine nucleotide translocase (ANT) and F 0F1 ATP synthase are the major contenders for the role of pore in the PTP. In permeabilized cells, however, numerous additional enzymes that interconvert adenine nucleotides exist. Because ANT transports adenine nucleotides only in the Mg2 +-free state (Klingenberg, 1980; Kramer, 1980), and Mg2 + has differential affinity for ADP and ATP, we are able to measure ANT activity using the membrane-impermeable Mg2 +-sensitive fluorescent indicator “Magnesium Green (MgGr).” In this assay, the rate of change in free extramitochondrial [Mg2 +] in the experimental medium is measured following the addition of ADP to mitochondria. (Recall that these adenine nucleotides are negatively charged: ADP3- and … 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. 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. Many but not all such promoters contain short sequence motifs for binding nuclear respiratory factors NRF-1 and/or NRF-2. 2 In the controlled state ADP exchanges 2–4 times faster than ATP. ADP in the intermembrane space, coming from the cytoplasm, binds the translocase and induces its eversion, resulting in the release of ADP 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. Mice that express a proofreading-deficient mitochondrial DNA polymerase γ targeted to the heart generated cardiac mtDNA mutations (average of two per mitochondrial genome) and eventually (over several weeks) developed DCM and interstitial fibrosis, often leading to HF.186 Surprisingly, the mechanism of the pathogenesis in these strains does not appear to involve increased OS levels.202 Measurements of enzyme function or the oxidative defense systems in the transgenic heart fail to detect increased levels of oxidative adducts in DNA or protein and signs of increased OS. Phosphate translocase is also located in the inner mitochondrial membrane. 997-1004,1993 Printed in U.S.A. On the Regulation of K+ Uniport in Intact Mitochondria by Adenine Nucleotides and Nucleotide Analogs* (Received for publication, August 14, 1992) Andrew D. BeavisS, Yun Lu, and Keith D. Garlid This condition was characterized more or less sequentially by optic atrophy with visual failure, sensorineural deafness, ataxia, myopathy, axonal sensory-motor polyneuropathy, and PEO. adPEO shows Mendelian inheritance patterns but is characterized by large-scale mitochondrial DNA (mtDNA) deletions. Antibody-dependent cell lysis has not been reported using the AABs from patients’ sera. It transports H ions and phosphate H,PO, ions into the matrix. Forlani et al. 2, Issue of January 15, pp. Cloning and Expression. Nuclear genes encoding subunits of complexes of the electron transport chain might be expected to be expressed coordinately, and a search for common promoter elements in these genes started long before whole mammalian genomes were sequenced [34–36]. The depression in ADP/ATP translocase alternatively faces the matrix and the cytoplasmic sides of the membrane. [7] The atomic structure of the bovine ANT confirmed this notion, and provided the first structural fold of a mitochondrial carrier. The adenine nucleotide translocase (ADP-ATP translocase), a transporter located in the inner mitochondrial membrane, transports ADP and ATP across the membrane. 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). In contrast, the second family, which includes bongkrekic acid (BA) and isobongkrekic acid (isoBA), binds the translocase from the matrix, locking it in a matrix side open conformation. ANT partially purified from bovine heart as well as the N. crassa species purified after heterologous expression in E. coli formed Ca2+-activated channels with conductances of 300–600 (Brustovetsky and Klingenberg, 1996) and 500–700 pS (Brustovetsky et al., 2002), respectively. On the basis of these findings, it was inferred that the observed switch in metabolism appeared unlikely to benefit energy homeostasis in the respiratory chain-deficient hearts and may actually promote further cardiac dysfunction. [13] Indeed, arginine residues 96, 204, 252, 253, and 294, as well as lysine 38, have been shown to be essential for transporter activity. However, because MgGr is a fluorimetric dye with single excitation and emission, it is subjected to the potential pitfalls of nonratiometric dyes related to variations in dye concentration and/or bleaching. Here, we describe the isolation of adenine nucleotide translocase-1 (ANT-1) in a screen for dominant, apoptosis-inducing genes. 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. Adenine nucleotide translocase (ANT) exchanges ATP for ADP across the inner mitochondrial membrane (Klingenberg, 1980; Pebay-Peyroula & Brandolin, 2004). This method was also applied in determining ANT dysfunction in relation to mitochondrial membrane potential in myotubes expressing ANT1-harboring mutations linked to autosomal-dominant progressive external opthalmoplegia (Kawamata, Tiranti, Magrane, Chinopoulos, & Manfredi, 2011). In well coupled mitochondria the rate of ATP synthesis is coupled to ATP turnover by various types of biological work performed by the cell (metabolism, motility, ion pumps, proteasome activity, and more). Free ADP is transported from the cytoplasm to the mitochondrial matrix, while ATP produced from oxidative phosphorylation is transported from the mitochondrial matrix to the cytoplasm, thus providing the cells with its main energy currency. 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. [12] It forms six transmembrane α-helices that form a barrel that results in a deep cone-shaped depression accessible from the outside where the substrate binds. Indeed, chemical modification of ANT has long been used to modulate MPTP opening (152). Initial genetic experiments using ANT1-ANT2 double knockout mice demonstrated that neither isoform was critical for PTP function (150), although the recent discovery of a third mouse ANT gene raises questions about functional redundancy (151). 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. Expression of human and mouse adenine nucleotide translocase (ANT) isoform genes in adipogenesis. Copyright © 2021 Elsevier B.V. or its licensors or contributors. Adenine nucleotide translocase Imported Submitted name: Slc25a5-prov protein Imported. Moreover, their extraocular muscles do not show evidence of increased fatigability. Gene names i: Name:slc25a5.L Imported. Int J Biochem Cell Biol. ADP,ATP carrier protein, heart/skeletal muscle isoform T1. Along with the development of severe cardiomyopathy, tissue-specific TFAM-knockout mice exhibited increased apoptosis in the in vivo heart consistent with the finding of massive apoptosis in Tfam-knockout embryos and suggesting that defects in ETC may predispose cells to apoptosis.199 Global gene profiling analyses in tissue-specific Tfam-knockout mice revealed a metabolic switch in the early progression of cardiac mitochondrial dysfunction akin to the activation of a fetal gene-expression program in which a number of genes, encoding critical enzymes in FAO, showed decreased expression, whereas several genes encoding glycolytic enzymes showed increased expression.200 In advanced disease, the metabolic switch was followed by an increase in mitochondrial biomass or biogenesis, which did not result in increase of overall myocardial mitochondrial ATP production rate. [1][2] ANT is the most abundant protein in the inner mitochondrial membrane and belongs to mitochondrial carrier family.[3]. Histologically, the extraocular muscles from Ant1–/– mice present a relatively mild mitochondrial myopathy. Mutations in the gene for one isoform of the adenine nucleotide translocator (ANT1) have been identified in patients with autosomal dominant PEO, sometime associated with psychiatric disorders. ADP/ATP translocase is very specifically inhibited by two families of compounds. Adenine nucleotide translocase, an antiporter located in the inner mitochondrial membrane, moves ADP into and ATP out of the matrix. propose a "multi-pore model" in which ANT is at least one of the molecular components of the pore. [26] The negatively charged groups of the inhibitors bind strongly to the positively charged residues deep within the binding pocket. 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 In summary, neither the ANT nor the VDACs are essential components of the PTP. Published 2019 Aug 28. doi:10.1126/sciadv.aaw4597, "The ADP and ATP transport in mitochondria and its carrier", "The transport mechanism of the mitochondrial ADP/ATP carrier", "Discoveries, metabolic roles and diseases of mitochondrial carriers: A review", "Conflict and cooperation in eukaryogenesis: implications for the timing of endosymbiosis and the evolution of sex", "Projection structure of the atractyloside-inhibited mitochondrial ADP/ATP carrier of Saccharomyces cerevisiae", "Yeast mitochondrial ADP/ATP carriers are monomeric in detergents as demonstrated by differential affinity purification", "The yeast mitochondrial ADP/ATP carrier functions as a monomer in mitochondrial membranes", "Forward operation of adenine nucleotide translocase during F0F1-ATPase reversal: critical role of matrix substrate-level phosphorylation", "Mitochondrial consumption of cytosolic ATP: not so fast", "The "B space" of mitochondrial phosphorylation", "Alterations in voltage-sensing of the mitochondrial permeability transition pore in ANT1-deficient cells", "Structures of yeast mitochondrial ADP/ATP carriers support a domain-based alternating-access transport mechanism", "The Molecular Mechanism of Transport by the Mitochondrial ADP/ATP Carrier", "Mitochondrial myopathy: a genetic study of 71 cases", "Mitochondrial myopathies: genetic mechanisms", "Sequences required for delivery and localization of the ADP/ATP translocator to the mitochondrial inner membrane", high affinity glutamate and neutral amino-acid transporter, organic cation/anion/zwitterion transporter, System A & N, sodium-coupled neutral amino-acid transporter, https://en.wikipedia.org/w/index.php?title=Adenine_nucleotide_translocator&oldid=997974463, Creative Commons Attribution-ShareAlike License, cationic amino-acid transporter/glycoprotein-associated, glycoprotein-associated/light or catalytic subunits of, This page was last edited on 3 January 2021, at 04:05. 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