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The SLC25 Mitochondrial Carrier Family: Structure and Mechanism

Jonathan J. Ruprecht, Edmund R.S. Kunji

Trends in Biochemical Sciences · 2020 · Review · CC BY

doi:10.1016/j.tibs.2019.11.001

Abstract

Members of the mitochondrial carrier family (SLC25) provide the transport steps for amino acids, carboxylic acids, fatty acids, cofactors, inorganic ions, and nucleotides across the mitochondrial inner membrane and are crucial for many cellular processes. Here, we use new insights into the transport mechanism of the mitochondrial ADP/ATP carrier to examine the structure and function of other mitochondrial carriers. They all have a single substrate-binding site and two gates, which are present on either side of the membrane and involve salt-bridge networks. Transport is likely to occur by a common mechanism, in which the coordinated movement of six structural elements leads to the alternating opening and closing of the matrix or cytoplasmic side of the carriers.

References 79

  1. 1.

    Palmieri F, Klingenberg M. On the possible role of structural protein in the binding and translocation of adenine nucleotides in mitochondria. Biochim Biophys Acta. 1967;131:582-585.

    Not in our library10.1016/0005-2728(67)90018-7

  2. 2.

    Aquila H, et al. Complete amino acid sequence of the ADP/ATP carrier from beef heart mitochondria. Hoppe Seylers Z Physiol Chem. 1982;363:345-349.

    Not in our library

  3. 3.

    Klingenberg M. The ADP and ATP transport in mitochondria and its carrier. Biochim Biophys Acta. 2008;1778:1978-2021.

    Not in our library10.1016/j.bbamem.2008.04.011

  4. 4.

    Kunji ERS, et al. The transport mechanism of the mitochondrial ADP/ATP carrier. Biochim Biophys Acta. 2016;1863:2379-2393.

    Not in our library10.1016/j.bbamcr.2016.03.015

  5. 5.

    Ruprecht JJ, Kunji ERS. Structural changes in the transport cycle of the mitochondrial ADP/ATP carrier. Curr Opin Struct Biol. 2019;57:135-144.

    Not in our library10.1016/j.sbi.2019.03.029

  6. 6.

    Dolce V, et al. A fourth ADP/ATP carrier isoform in man: identification, bacterial expression, functional characterization and tissue distribution. FEBS Lett. 2005;579:633-637.

    Not in our library10.1016/j.febslet.2004.12.034

  7. 7.

    Austin J, Aprille JR. Carboxyatractyloside-insensitive influx and efflux of adenine nucleotides in rat liver mitochondria. J Biol Chem. 1984;259:154-160.

    Not in our library

  8. 8.

    Fiermonte G, et al. Identification of the mitochondrial ATP-Mg/Pi transporter. Bacterial expression, reconstitution, functional characterization, and tissue distribution. J Biol Chem. 2004;279:30722-30730.

    Not in our library10.1074/jbc.m400445200

  9. 9.

    del Arco A, Satrustegui J. Identification of a novel human subfamily of mitochondrial carriers with calcium-binding domains. J Biol Chem. 2004;279:24701-24713.

    Not in our library10.1074/jbc.m401417200

  10. 10.

    Harborne SP, et al. Calcium regulation of the human mitochondrial ATP-Mg/Pi carrier SLC25A24 uses a locking pin mechanism. Sci Rep. 2017;7:45383.

    Not in our library10.1038/srep45383

  11. 11.

    Harborne SP, et al. Calcium-induced conformational changes in the regulatory domain of the human mitochondrial ATP-Mg/Pi carrier. Biochim Biophys Acta. 2015;1847:1245-1253.

    Not in our library10.1016/j.bbabio.2015.07.002

  12. 12.

    Harborne SPD, Kunji ERS. Calciumregulated mitochondrial ATP-Mg/Pi carriers evolved from a fusion of an EF-hand regulatory domain with a mitochondrial ADP/ATP carrier-like domain. IUBMB Life. 2018;70:1222-1232.

    Not in our library10.1002/iub.1931

  13. 13.

    Yang Q, et al. A self-sequestered calmodulin-like Ca(2)(+) sensor of mitochondrial SCaMC carrier and its implication to Ca(2)(+)-dependent ATP-Mg/ P(i) transport. Structure. 2014;22:209-217.

    Not in our library10.1016/j.str.2013.10.018

  14. 14.

    Traba J, et al. Characterization of SCaMC-3-Like/slc25a41 a novel calcium-independent mitochondrial ATP-Mg/Pi carrier. Biochem J. 2008;418:125-133.

    Not in our library10.1042/bj20081262

  15. 15.

    Johnson RN, Chappell JB. The influx and efflux of phosphate in liver mitochondria. Biochem J. 1970;116:37P.

    Not in our library

  16. 16.

    Runswick MJ, et al. Sequence of the bovine mitochondrial phosphate carrier protein: structural relationship to ADP/ATP translocase and the brown fat mitochondria uncoupling protein. EMBO J. 1987;6:1367-1373.

    Not in our library10.1002/j.1460-2075.1987.tb02377.x

  17. 17.

    Kunji ERS, Robinson AJ. Coupling of proton and substrate translocation in the transport cycle of mitochondrial carriers. Curr Opin Struct Biol. 2010;20:440-447.

    Not in our library10.1016/j.sbi.2010.06.004

  18. 18.

    Nicholls DG. The bioenergetics of brown adipose tissue mitochondria. FEBS Lett. 1976;61:103-110.

    Not in our library10.1016/0014-5793(76)81014-9

  19. 19.

    Nicholls DG, Rial E. A history of the first uncoupling protein. UCP1. J. Bioenerg. Biomembr. 1999;31:399-406.

    Not in our library10.1023/a:1005436121005

  20. 20.

    Aquila H, et al. The uncoupling protein from brown fat mitochondria is related to the mitochondrial ADP/ATP carrier. EMBO J. 1985;4:2369-2376.

    Not in our library10.1002/j.1460-2075.1985.tb03941.x

  21. 21.

    Rial E, et al. Brown-adipose-tissue mitochondria: the regulation of the 32000-Mr uncoupling protein by fatty acids and purine nucleotides. Eur J Biochem. 1983;137:197-203.

    Not in our library10.1111/j.1432-1033.1983.tb07815.x

  22. 22.

    Klingenberg M. UCP1 - a sophisticated energy valve. Biochimie. 2017;134:19-27.

    Not in our library10.1016/j.biochi.2016.10.012

  23. 23.

    Cannon B, Nedergaard J. What ignites UCP1? Cell Metab. 2017;26:697-698.

    Not in our library10.1016/j.cmet.2017.10.012

  24. 24.

    Fedorenko A, et al. Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria. Cell. 2012;151:400-413.

    Not in our library10.1016/j.cell.2012.09.010

  25. 25.

    Nicholls DG. The hunt for the molecular mechanism of brown fat thermogenesis. Biochimie. 2017;134:9-18.

    Not in our library10.1016/j.biochi.2016.09.003

  26. 26.

    Crichton PG, et al. The molecular features of uncoupling protein 1 support a conventional mitochondrial carrier-like mechanism. Biochimie. 2017;134:35-50.

    Not in our library10.1016/j.biochi.2016.12.016

  27. 27.

    Azzi A, et al. Penetration of the mitochondrial membrane by glutamate and aspartate. Biochem Biophys Res Commun. 1967;29:148-152.

    Not in our library10.1016/0006-291x(67)90556-6

  28. 28.

    Palmieri L, et al. Citrin and aralar1 are Ca(2+)- stimulated aspartate/glutamate transporters in mitochondria. EMBO J. 2001;20:5060-5069.

    Not in our library10.1093/emboj/20.18.5060

  29. 29.

    Thangaratnarajah C, et al. Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers. Nat Commun. 2014;5:5491.

    Not in our library10.1038/ncomms6491

  30. 30.

    Kunji ERS, Crichton PG. Mitochondrial carriers function as monomers. Biochim. Biophys Acta. 2010;1797:817-831.

    Not in our library10.1016/j.bbabio.2010.03.023

  31. 31.

    Lindhurst MJ, et al. Knockout of Slc25a19 causes mitochondrial thiamine pyrophosphate depletion, embryonic lethality, CNS malformations, and anemia. Proc Natl Acad Sci USA. 2006;103:15927-15932.

    Not in our library10.1073/pnas.0607661103

  32. 32.

    Pande SV. A mitochondrial carnitine acylcarnitine translocase system. Proc Natl Acad Sci USA. 1975;72:883-887.

    Not in our library10.1073/pnas.72.3.883

  33. 33.

    Indiveri C, Palmieri F. Purification of the mitochondrial carnitine carrier by chromatography on hydroxyapatite and celite. FEBS Lett. 1989;253:217-220.

    Not in our library10.1016/0014-5793(89)80962-7

  34. 34.

    Huizing M, et al. Cloning of the human carnitine-acylcarnitine carrier cDNA and identification of the molecular defect in a patient. Am J Hum Genet. 1997;61:1239-1245.

    Not in our library10.1086/301628

  35. 35.

    Sluse F, Ranson M. Transport of 2-oxoglutarate in rat-heart mitochondria. Arch Int Physiol Biochim. 1971;79:634-636.

    Not in our library

  36. 36.

    Palmieri F, et al. Kinetics and specificity of the oxoglutarate carrier in rat-liver mitochondria. Eur J Biochem. 1972;29:408-416.

    Not in our library10.1111/j.1432-1033.1972.tb02003.x

  37. 37.

    Iacobazzi V, et al. Sequences of the human and bovine genes for the mitochondrial 2-oxoglutarate carrier. DNA Seq. 1992;3:79-88.

    Not in our library10.3109/10425179209034000

  38. 38.

    Chappell JB. The oxidation of citrate, isocitrate and cis-aconitate by isolated mitochondria. Biochem J. 1964;90:225-237.

    Not in our library10.1042/bj0900225

  39. 39.

    Kaplan RS, et al. Purification and characterization of the reconstitutively active tricarboxylate transporter from rat liver mitochondria. J Biol Chem. 1990;265:13379-13385.

    Not in our library

  40. 40.

    Iacobazzi V, et al. Organization and sequence of the human gene for the mitochondrial citrate transport protein. DNA Seq. 1997;7:127-139.

    Not in our library10.3109/10425179709034029

  41. 41.

    Majd H, et al. Pathogenic mutations of the human mitochondrial citrate carrier SLC25A1 lead to impaired citrate export required for lipid, dolichol, ubiquinone and sterol synthesis. Biochim Biophys Acta. 2018;1859:1-7.

    Not in our library10.1016/j.bbabio.2017.10.002

  42. 42.

    Vignais PV, et al. Gummiferin, an inhibitor of the adenine-nucleotide translocation. Study of its binding properties to mitochondria. FEBS Lett. 1971;17:281-288.

    Not in our library10.1016/0014-5793(71)80165-5

  43. 43.

    Vignais PV, et al. Adenosine diphosphate translocation in mitochondria. Nature of the receptor site for carboxyatractyloside (gummiferin). Biochemistry. 1973;12:1508-1519.

    Not in our library10.1021/bi00732a007

  44. 44.

    Luciani S, et al. Effects of carboxyatractyloside a structural analogue of atractyloside on mitochondrial oxidative phosphorylation. Life Sci II. 1971;10:961-968.

    Not in our library10.1016/0024-3205(71)90099-3

  45. 45.

    Henderson PJ, Lardy HA. Bongkrekic acid. An inhibitor of the adenine nucleotide translocase of mitochondria. J Biol Chem. 1970;245:1319-1326.

    Not in our library

  46. 46.

    Lauquin GJ, et al. Isobongkrekic acid, a new inhibitor of mitochondrial ADP-ATP transport: radioactive labeling and chemical and biological properties. Biochemistry. 1976;15:2323-2327.

    Not in our library10.1021/bi00656a012

  47. 47.

    Kunji ERS, Harding M. Projection structure of the atractyloside-inhibited mitochondrial ADP/ATP carrier of Saccharomyces cerevisiae. J Biol Chem. 2003;278:36985-36988.

    Not in our library10.1074/jbc.c300304200

  48. 48.

    Pebay-Peyroula E, et al. Structure of mitochondrial ADP/ATP carrier in complex with carboxyatractyloside. Nature. 2003;426:39-44.

    Not in our library10.1038/nature02056

  49. 49.

    Ruprecht JJ, et al. Structures of yeast mitochondrial ADP/ATP carriers support a domain-based alternating-access transport mechanism. Proc Natl Acad Sci USA. 2014;111:E426-E434.

    Not in our library10.1073/pnas.1320692111

  50. 50.

    Nury H, et al. Structural basis for lipidmediated interactions between mitochondrial ADP/ATP carrier monomers. FEBS Lett. 2005;579:6031-6036.

    Not in our library10.1016/j.febslet.2005.09.061

  51. 51.

    Robinson AJ, et al. The mechanism of transport by mitochondrial carriers based on analysis of symmetry. Proc Natl Acad Sci USA. 2008;105:17766-17771.

    Not in our library10.1073/pnas.0809580105

  52. 52.

    Nelson DR, et al. Highly conserved charge-pair networks in the mitochondrial carrier family. J Mol Biol. 1998;277:285-308.

    Not in our library10.1006/jmbi.1997.1594

  53. 53.

    Beyer K, Klingenberg M. ADP/ATP carrier protein from beef heart mitochondria has high amounts of tightly bound cardiolipin, as revealed by 31P nuclear magnetic resonance. Biochemistry. 1985;24:3821-3826.

    Not in our library10.1021/bi00336a001

  54. 54.
  55. 55.

    Pfaff E, Klingenberg M. Adenine nucleotide translocation of mitochondria. 1. Specificity and control. Eur J Biochem. 1968;6:66-79.

    Not in our library10.1111/j.1432-1033.1968.tb00420.x

  56. 56.

    Mifsud J, et al. The substrate specificity of the human ADP/ATP carrier AAC1. Mol Membr Biol. 2013;30:160-168.

    Not in our library10.3109/09687688.2012.745175

  57. 57.
  58. 58.

    Kunji ERS, Robinson AJ. The conserved substrate binding site of mitochondrial carriers. Biochim Biophys Acta. 2006;1757:1237-1248.

    Not in our library10.1016/j.bbabio.2006.03.021

  59. 59.

    Robinson AJ, Kunji ERS. Mitochondrial carriers in the cytoplasmic state have a common substrate binding site. Proc Natl Acad Sci USA. 2006;103:2617-2622.

    Not in our library10.1073/pnas.0509994103

  60. 60.

    Dehez F, et al. Binding of ADP in the mitochondrial ADP/ATP carrier is driven by an electrostatic funnel. J Am Chem Soc. 2008;130:12725-12733.

    Not in our library10.1021/ja8033087

  61. 61.

    Wang Y, Tajkhorshid E. Electrostatic funneling of substrate in mitochondrial inner membrane carriers. Proc Natl Acad Sci USA. 2008;105:9598-9603.

    Not in our library10.1073/pnas.0801786105

  62. 62.

    Jardetzky O. Simple allosteric model for membrane pumps. Nature. 1966;211:969-970.

    Not in our library10.1038/211969a0

  63. 63.

    Drew D, Boudker O. Shared molecular mechanisms of membrane transporters. Annu Rev Biochem. 2016;85:543-572.

    Not in our library10.1146/annurev-biochem-060815-014520

  64. 64.

    Dalbon P, et al. Mapping of the nucleotide-binding sites in the ADP/ATP carrier of beef heart mitochondria by photolabeling with 2-azido[alpha-32P]adenosine diphosphate. Biochemistry. 1988;27:5141-5149.

    Not in our library10.1021/bi00414a029

  65. 65.

    Gropp T, et al. Kinetics of electrogenic transport by the ADP/ATP carrier. Biophys J. 1999;77:714-726.

    Not in our library10.1016/s0006-3495(99)76926-2

  66. 66.

    Brustovetsky N, et al. Electrical currents associated with nucleotide transport by the reconstituted mitochondrial ADP/ATP carrier. Proc Natl Acad Sci USA. 1996;93:664-668.

    Not in our library10.1073/pnas.93.2.664

  67. 67.

    Cappello AR, et al. Functional and structural role of amino acid residues in the odd-numbered transmembrane alpha-helices of the bovine mitochondrial oxoglutarate carrier. J Mol Biol. 2007;369:400-412.

    Not in our library10.1016/j.jmb.2007.03.048

  68. 68.

    Miniero DV, et al. Functional and structural role of amino acid residues in the matrix alpha-helices, termini and cytosolic loops of the bovine mitochondrial oxoglutarate carrier. Biochim Biophys Acta. 2011;1807:302-310.

    Not in our library10.1016/j.bbabio.2010.12.005

  69. 69.

    Rupp B. Bio Molecular Crystallography: Principles, Practice, and Application to Structural Biology. Garland Science. 2010.

    Not in our library

  70. 70.

    King MS, et al. Formation of a cytoplasmic salt bridge network in the matrix state is a fundamental step in the transport mechanism of the mitochondrial ADP/ATP carrier. Biochim Biophys Acta. 2016;1857:14-22.

    Not in our library10.1016/j.bbabio.2015.09.013

  71. 71.

    Springett R, et al. Modelling the free energy profile of the mitochondrial ADP/ATP carrier. Biochim Biophys Acta. 2017;1858:906-914.

    Not in our library10.1016/j.bbabio.2017.05.006

  72. 72.

    Klingenberg M. Ligand-protein interaction in biomembrane carriers. The induced transition fit of transport catalysis. Biochemistry. 2005;44:8563-8570.

    Not in our library10.1021/bi050543r

  73. 73.

    Lamarca V, et al. Two isoforms of PSAP/ MTCH1 share two proapoptotic domains and multiple internal signals for import into the mitochondrial outer membrane. Am J Physiol Cell Physiol. 2007;293:C1347-C1361.

    Not in our library10.1152/ajpcell.00431.2006

  74. 74.

    Zaltsman Y, et al. MTCH2/MIMP is a major facilitator of tBID recruitment to mitochondria. Nat Cell Biol. 2010;12:553-562.

    Not in our library10.1038/ncb2057

  75. 75.

    Abrams AJ, et al. Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder. Nat Genet. 2015;47:926-932.

    Not in our library10.1038/ng.3354

  76. 76.

    Robinson AJ, et al. Mitochondrial carrier homolog 2 (MTCH2): the recruitment and evolution of a mitochondrial carrier protein to a critical player in apoptosis. Exp Cell Res. 2012;318:1316-1323.

    Not in our library10.1016/j.yexcr.2012.01.026

  77. 77.

    Visser WF, et al. Identification of human PMP34 as a peroxisomal ATP transporter. Biochem Biophys Res Commun. 2002;299:494-497.

    Not in our library10.1016/s0006-291x(02)02663-3

  78. 78.

    Palmieri F, Monne M. Discoveries, metabolic roles and diseases of mitochondrial carriers: a review. Biochim Biophys Acta. 2016;1863:2362-2378.

    Not in our library10.1016/j.bbamcr.2016.03.007

  79. 79.

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