ATP–ADP translocase

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A cytoplasmic view of the binding pocket of ATP–ADP translocase. (From PDB: 1OKC )

ATP–ADP translocase is a transporter protein that enables ATP and ADP to traverse the inner mitochondrial membrane. ATP produced from oxidative phosphorylation is transported from the mitochondrial matrix to the cytoplasm, whereas ADP is transported from the cytoplasm to the mitochondrial matrix.[1] More than 10% of the protein in the inner mitochondrial membrane consists of ATP–ADP translocase.[2]


A side view of the translocase spanning the inner mitochondrial membrane. The six α-helices are denoted by different colors. The binding pocket is currently open to the cytoplasmic side and will bind to ADP, transporting it into the matrix. (From PDB: 1OKC )

ATP–ADP translocase is a homodimer with each subunit consisting of 297 residues and weighing approximately 30 kDa.[3] Each subunit consists of six transmembrane α-helices that form a barrel that results in a deep cone-shaped depression accessible from the outside where the substrate binds. The binding pocket, conserved throughout most isoforms, consists of mostly basic residues that allow for strong binding to ATP or ADP and has a maximal diameter of 20 Å and a depth of 30 Å.[4] Indeed, arginine 96, 204, 252, 253, and 294, as well as lysine 38, have been shown to be essential for transporter activity.[5]

Translocase mechanism[edit]

Under normal conditions, ATP and ADP cannot cross the inner mitochondrial membrane due to their high negative charges, but ATP–ADP translocase, an antiporter, couples the transport of the two molecules. The depression in ATP–ADP translocase alternatively faces the matrix and the cytoplasmic sides of the membrane. ADP binding from the cytoplasm induces eversion of the transporter and results in the release of ADP into the matrix. Binding of ATP from the matrix induces eversion and results in the release of ATP into the cytoplasm and concomitantly brings the translocase back to its original conformation.[1] ATP and ADP are the only natural nucleotides recognized by the translocase.[4]

The net process is denoted by:

ADP3−cytoplasm + ATP4−matrix → ADP3−matrix + ATP4−cytoplasm

ATP–ADP exchange is energetically expensive: about 25% of the energy yielded from electron transfer by aerobic respiration, or one hydrogen ion, is consumed to regenerate the membrane potential that is tapped by ATP–ADP translocase.[1]

Biological function[edit]

ATP–ADP translocase transports ATP synthesized from oxidative phosphorylation into the cytoplasm, where it can be used as the principal energy currency of the cell to power thermodynamically unfavorable reactions. During the consequent hydrolysis of ATP into ADP, ADP is transported back into the mitochondrial matrix, where ATP can be resynthesized. Because a human typically exchanges the equivalent of his/her own mass of ATP on a daily basis, ATP–ADP translocase is an important transporter protein with major metabolic implications.[1][4]


In 1955, Siekevitz and Potter[6] demonstrated that adenine-nucleotides were distributed in cells in two pools located in the mitochondrial and cytosolic compartments. Shortly thereafter, Pressman[7] hypothesized that the two pools could exchange nucleotides. However, the existence of an ATP–ADP transporter was not postulated until 1964 when Bruni et al. uncovered an inhibitory effect of atractyloside on the energy-transfer system (oxidative phosphorylation) and ADP binding sites of rat liver mitochondria.[8] Soon after, an overwhelming amount of research was done in proving the existence and elucidating the link between ATP–ADP translocase and energy transport.[9][10][11] cDNA of ATP–ADP translocase was sequenced for bovine in 1982[12] and a yeast species Saccharomyces cerevisiae in 1986[13] before finally Battini et al. sequenced a cDNA clone of the human transporter in 1989. The homology in the coding sequences between human and yeast ATP–ADP translocase was 47% while bovine and human sequences extended remarkable to 266 out of 297 residues, or 89.6%. In both cases, the most conserved residues lie in the ATP–ADP substrate binding pocket.[3]


Rare but severe diseases such as mitochondrial myopathies are associated with dysfunctional human ATP–ADP translocase. Mitochondrial myopathies (MM) refer to a group of clinically and biochemically heterogenous disorders that share common features of major mitochondrial structural abnormalities in skeletal muscle. The major morphological hallmark of MM is ragged, red fibers containing peripheral and intermyofibrillar accumulations of abnormal mitochondria.[14][15] In particular, autosomal dominant progressive external ophthalmoplegia (adPEO) is a common disorder associated with dysfunctional ATP–ADP translocase and can induce paralysis of muscles responsible for eye movements. General symptoms are not limited to the eyes and can include exercise intolerance, muscle weakness, hearing deficit, and more. adPEO shows Mendelian inheritance patterns but is characterized by large-scale mitochondrial DNA (mtDNA) deletions. mtDNA contains few introns, or non-coding regions of DNA, which increases the likelihood of deleterious mutations. Thus, any modification of ATP–ADP translocase mtDNA can lead to a dysfunctional transporter,[16] particularly residues involved in the binding pocket which will compromise translocase efficacy.[5] MM is commonly associated with dysfunctional ATP–ADP translocase, but MM can be induced through many different mitochondrial abnormalities.


ATP–ADP translocase is very specifically inhibited by two families of inhibitors. The first family, which includes atractyloside (ATR) and carboxyatractyloside (CATR), binds to the ATP–ADP translocase from the cytoplasmic side, locking it in a cytoplasmic side open conformation. 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.[17] The negatively charged moieties of the inhibitors bind strongly with the positively charged residues deep within the binding pocket. The high affinity (Kd in the nanomolar range) makes each inhibitor a deadly poison by obstructing cellular respiration/energy transfer to the rest of the cell.[4]

See also[edit]


  1. ^ a b c d Stryer L, Berg JM, Tymoczko JL (2007). Biochemistry. San Francisco: W.H. Freeman. pp. 529–530. ISBN 0-7167-8724-5. 
  2. ^ Brandolin G, Dupont Y, and Vignais PV. (April 1985). "Substrate-induced modifications of the intrinsic fluorescence of the isolated adenine nucleotide carrier protein: demonstration of distinct conformational states". Biochemistry 24 (8): 1991–1997. doi:10.1021/bi00329a029. PMID 2990548. 
  3. ^ a b Battini R, Ferrari S, Kaczmarek L, Calabretta B, Chen S-T, and Baserga, R (March 1987). "Molecular cloning of a cDNA for a human ADP/ATP carrier which is growth-regulated". J. Biol. Chem. 262 (2): 4355–4359. PMID 3031073. 
  4. ^ a b c d Pebay-Peyroula E, Dahout C, Kahn R, Trezeguet V, Lauquin GJ-M, Brandolin G (November 2003). "Structure of mitochondrial ADP/ATP carrier complex with carboxyatractyloside". Nature 426 (1): 39–44. doi:10.1038/nature02056. PMID 14603310. 
  5. ^ a b Nelson DR, Lawson JE, Klingenberg M, and Douglas MG (April 1993). "Site-directed mutagenesis of the yeast mitochondrial ADP/ATP translocator. Six arginines and one lysine are essential". J. Mol. Biol. 230 (4): 1159–1170. doi:10.1006/jmbi.1993.1233. PMID 8487299. 
  6. ^ Siekevitz P and Potter VR (July 1955). "Biochemical structure of mitochondria. II. Radioactive labeling of intra-mitochondrial nucleotides during oxidative phosphorylation". J. Biol. Chem. 215 (1): 237–255. PMID 14392158. 
  7. ^ Pressman BC (June 1958). "Intramitochondrial nucleotides. I. Some factors affecting net interconversions of adenine nucleotides". J. Biol. Chem. 232 (2): 967–978. PMID 13549480. 
  8. ^ Bruni A, Luciani, S, Contessa AR (March 1964). "Inhibition by atractyloside of the binding of adenine-nucleotides to rat-liver mitochondria". Nature 201 (1): 129–1220. doi:10.1038/2011219a0. PMID 14151375. 
  9. ^ Duee ED, Vignais PV (August 1965). "Exchange between extra- and intramitochondrial adenine nucleotides". Biochim. Biophys. Acta 107 (1): 184–188. doi:10.1016/0304-4165(65)90419-8. PMID 5857365. 
  10. ^ Pfaff E, Klingenberg M, Heldt HW (June 1965). "Unspecific permeation and specific exchange of adenine nucleotides in liver mitochondria". Biochim. Biophys. Acta 104 (1): 312–315. doi:10.1016/0304-4165(65)90258-8. PMID 5840415. 
  11. ^ Saks, V; Lipina N; Smirnov V; Chazov E (1 March 1976). "Studies of energy transport in heart cells The functional coupling between mitochondrial creatine phosphokinase and ATP–ADP translocase: Kinetic evidence". Archives of Biochemistry and Biophysics 173 (1): 34–41. doi:10.1016/0003-9861(76)90231-9. PMID 1259440. 
  12. ^ Aquila H, Misra D, Eulitz M, and Klingenberg M (1 January 1982). "Complete aminoacid sequence of the ADP/ATP carrier from beef heart mitochondria". Hoppe-Seyler´s Zeitschrift für physiologische Chemie 363 (1): 345–350. doi:10.1515/bchm2.1982.363.1.345. PMID 7076130. 
  13. ^ Adrian GS, McCammon MT, Montgomery DL, and Douglas MG (Feb 1986). "Sequences required for delivery and localization of the ADP/ATP translocator to the mitochondrial inner membrane.". Molecular and Cellular Biology 6 (2): 626–34. PMC 367554. PMID 3023860. 
  14. ^ Harding AE, Petty, RKH, and Morgan-Hughes JA. (Aug 1988). "Mitochondrial myopathy: a genetic study of 71 cases". Journal of medical genetics 25 (8): 528–35. doi:10.1136/jmg.25.8.528. PMC 1080029. PMID 3050098. 
  15. ^ Rose, MR (Jan 1998). "Mitochondrial myopathies: genetic mechanisms.". Archives of Neurology 55 (1): 17–24. doi:10.1001/archneur.55.1.17. PMID 9443707. 
  16. ^ Kaukonen J, Juselius JK, Tiranti V, Kyttälä A, Zeviani M, Comi GP, Keränen S, Peltonen L, Suomalainen A (4 August 2000). "Role of Adenine Nucleotide Translocator 1 in mtDNA Maintenance". Science 289 (5480): 782–785. doi:10.1126/science.289.5480.782. PMID 10926541. 
  17. ^ Kunji ER, Harding M (2003-09-26). "Projection structure of the atractyloside-inhibited mitochondrial ADP/ATP carrier of Saccharomyces cerevisiae.". The Journal of Biological Chemistry 278 (39): 36985–8. doi:10.1074/jbc.C300304200. PMID 12893834.