Advertisement

Amino Acids

pp 1–12 | Cite as

Cell death and mitochondrial dysfunction induced by the dietary non-proteinogenic amino acid l-azetidine-2-carboxylic acid (Aze)

  • Kate Samardzic
  • Kenneth J. RodgersEmail author
Original Article

Abstract

In addition to the 20 protein amino acids that are vital to human health, hundreds of naturally occurring amino acids, known as non-proteinogenic amino acids (NPAAs), exist and can enter the human food chain. Some NPAAs are toxic through their ability to mimic protein amino acids and this property is utilised by NPAA-containing plants to inhibit the growth of other plants or kill herbivores. The NPAA l-azetidine-2-carboxylic acid (Aze) enters the food chain through the use of sugar beet (Beta vulgaris) by-products as feed in the livestock industry and may also be found in sugar beet by-product fibre supplements. Aze mimics the protein amino acid l-proline and readily misincorporates into proteins. In light of this, we examined the toxicity of Aze to mammalian cells in vitro. We showed decreased viability in Aze-exposed cells with both apoptotic and necrotic cell death. This was accompanied by alterations in endosomal–lysosomal activity, changes to mitochondrial morphology and a significant decline in mitochondrial function. In summary, the results show that Aze exposure can lead to deleterious effects on human neuron-like cells and highlight the importance of monitoring human Aze consumption via the food chain.

Keywords

Non-protein amino acid Azetidine-2-carboxylic acid Mitochondria Multiple sclerosis 

Notes

Acknowledgements

Centre for Health Technologies, University of Technology Sydney.

Funding

This study was partly funded by the Centre for Health Technologies, University of Technology Sydney.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving human participants and/or animals

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

This article does not contain individual participants requiring informed consent.

Supplementary material

726_2019_2763_MOESM1_ESM.docx (3 mb)
Supplementary material 1 (DOCX 3106 kb)

References

  1. Alescio T (1973) Effect of a proline analogue, azetidine-2-carboxylic acid, on the morphogenesis in vitro of mouse embryonic lung. J Embryol Exp Morphol 29:439–451Google Scholar
  2. Backes S, Herrmann JM (2017) Protein translocation into the intermembrane space and matrix of mitochondria: mechanisms and driving forces. Front Mol Biosci 4:83.  https://doi.org/10.3389/fmolb.2017.00083 Google Scholar
  3. Beck CA, Metz LM, Svenson LW, Patten SB (2005) Regional variation of multiple sclerosis prevalence in Canada. Mult Scler J 11(5):516–519Google Scholar
  4. Bertin C, Weston LA, Huang T, Jander G, Owens T, Meinwald J, Schroeder FC (2007) Grass roots chemistry: meta-tyrosine, an herbicidal nonprotein amino acid. Proc Natl Acad Sci USA 104(43):16964–16969.  https://doi.org/10.1073/pnas.0707198104 Google Scholar
  5. Bessonov K, Bamm VV, Harauz G (2010) Misincorporation of the proline homologue Aze (azetidine-2-carboxylic acid) into recombinant myelin basic protein. Phytochemistry 71(5–6):502–507.  https://doi.org/10.1016/j.phytochem.2009.12.010 Google Scholar
  6. Bucciantini M, Giannoni E, Chiti F, Baroni F, Formigli L, Zurdo J, Taddei N, Ramponi G, Dobson CM, Stefani M (2002) Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 416(6880):507–511.  https://doi.org/10.1038/416507a Google Scholar
  7. Caller TA, Field NC, Chipman JW, Shi X, Harris BT, Stommel EW (2012) Spatial clustering of amyotrophic lateral sclerosis and the potential role of BMAA. Amyotroph Lateral Sci 13(1):25–32Google Scholar
  8. Chandra J, Samali A, Orrenius S (2000) Triggering and modulation of apoptosis by oxidative stress. Free Radic Biol Med 29(3):323–333.  https://doi.org/10.1016/S0891-5849(00)00302-6 Google Scholar
  9. Ciechanover A, Kwon YT (2015) Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies. Exp Mol Med 47:e147.  https://doi.org/10.1038/emm.2014.117 Google Scholar
  10. Dagda RK, Cherra SJ 3rd, Kulich SM, Tandon A, Park D, Chu CT (2009) Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J Biol Chem 284(20):13843–13855.  https://doi.org/10.1074/jbc.M808515200 Google Scholar
  11. Ding WX, Ni HM, Gao W, Hou YF, Melan MA, Chen X, Stolz DB, Shao ZM, Yin XM (2007) Differential effects of endoplasmic reticulum stress-induced autophagy on cell survival. J Biol Chem 282(7):4702–4710.  https://doi.org/10.1074/jbc.M609267200 Google Scholar
  12. Dunlop Rachael A, Dean Roger T, Rodgers Kenneth J (2008) The impact of specific oxidized amino acids on protein turnover in J774 cells. Biochem J 410(1):131Google Scholar
  13. Dunlop RA, Brunk UT, Rodgers KJ (2011) Proteins containing oxidized amino acids induce apoptosis in human monocytes. Biochem J 435(1):207–216.  https://doi.org/10.1042/BJ20100682 Google Scholar
  14. Dunlop RA, Cox PA, Banack SA, Rodgers KJ (2013) The non-protein amino acid BMAA is misincorporated into human proteins in place of l-serine causing protein misfolding and aggregation. PLoS One 8(9):1–6.  https://doi.org/10.1371/journal.pone.0075376 Google Scholar
  15. Dutta R, McDonough J, Yin X, Peterson J, Chang A, Torres T, Gudz T, Macklin WB, Lewis DA, Fox RJ, Rudick R, Mirnics K, Trapp BD (2006) Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol 59(3):478–489.  https://doi.org/10.1002/ana.20736 Google Scholar
  16. FAO (2014) FAO statistical yearbook. In: FAOSTAT (ed)Google Scholar
  17. Fichman Y, Gerdes SY, Kovács H, Szabados L, Zilberstein A, Csonka LN (2015) Evolution of proline biosynthesis: enzymology, bioinformatics, genetics, and transcriptional regulation. Biol Rev 90(4):1065–1099.  https://doi.org/10.1111/brv.12146 Google Scholar
  18. Fowden L (1956) Azetidine-2-carboxylic acid: a new cyclic imino acid occurring in plants. Biochem J 64(2):323–332Google Scholar
  19. Fowden L (1963) Amino-acid analogues and the growth of seedlings. J Exp Bot 14(3):387–398.  https://doi.org/10.1093/jxb/14.3.387 Google Scholar
  20. Fowden L (1972) Amino acid complement of plants. Phytochemistry 11(7):2271–2276.  https://doi.org/10.1016/S0031-9422(00)88389-2 Google Scholar
  21. Fraser PE, Deber CM (1985) Structure and function of the proline-rich region of myelin basic protein. Biochemistry 24(17):4593–4598.  https://doi.org/10.1021/bi00338a017 Google Scholar
  22. Geng G, Yang J (2015) Sugar beet production and industry in China. Sugar Technol 17(1):13–21.  https://doi.org/10.1007/s12355-014-0353-y Google Scholar
  23. Golini J, Jones WL, Clift IC (2017) The effect of increased fiber ingestion on lipid levels and body mass: a 4-week trial. J Food Sci Nut 3(1):1–3Google Scholar
  24. Grant MM, Brown AS, Corwin LM, Troxler RF, Franzblau C (1975) Effect of l-azetidine 2-carboxylic acid on growth and proline metabolism in Escherichia coli. Biochim Biophys Acta 404(2):180–187Google Scholar
  25. Gu F, Nguyen DT, Stuible M, Dube N, Tremblay M, Chevet E (2004) Protein tyrosine phosphatase 1B potentiates IRE1 signaling during endoplasmic reticulum stress. J Biol Chem 279(48):49689–49693Google Scholar
  26. Haankuku C, Epplin FM, Kakani VG (2015) Industrial sugar beets to biofuel: field to fuel production system and cost estimates. Biomass Bioenergy 80:267–277.  https://doi.org/10.1016/j.biombioe.2015.05.027 Google Scholar
  27. Habeeb AAM, Gad AE, EL-Tarabany A, Mustafa MM, Atta A (2017) Using of sugar beet pulp by-product in farm animals feeding. IJSRST 3(3)Google Scholar
  28. Harland JJ, Jones CK, Hufford C (2009) Co-products. In: Draycott AP (ed) Sugar beet. Blackwell Publishing, Oxford, UK, pp 443–463Google Scholar
  29. Hoozemans JJM, Scheper W (2012) Endoplasmic reticulum: the unfolded protein response is tangled in neurodegeneration. Int J Biochem Cell Biol 44(8):1295–1298.  https://doi.org/10.1016/j.biocel.2012.04.023 Google Scholar
  30. Houzen H, Niino M, Hata D, Nakano F, Kikuchi S, Fukazawa T, Sasaki H (2008) Increasing prevalence and incidence of multiple sclerosis in northern Japan. Mult Scler J 14(7):887–892.  https://doi.org/10.1177/1352458508090226 Google Scholar
  31. Huotari J, Helenius A (2011) Endosome maturation. EMBO J 30(17):3481–3500.  https://doi.org/10.1038/emboj.2011.286 Google Scholar
  32. Izyumov DS, Avetisyan AV, Pletjushkina OY, Sakharov DV, Wirtz KW, Chernyak BV, Skulachev VP (2004) “Wages of Fear”: transient threefold decrease in intracellular ATP level imposes apoptosis. Biochim Biophys Acta Bioenerg 1658(1):141–147.  https://doi.org/10.1016/j.bbabio.2004.05.007 Google Scholar
  33. Jin CM, Yang YJ, Huang HS, Kai M, Lee MK (2010) Mechanisms of l-DOPA-induced cytotoxicity in rat adrenal pheochromocytoma cells: implication of oxidative stress-related kinases and cyclic AMP. Neuroscience 170(2):390–398.  https://doi.org/10.1016/j.neuroscience.2010.07.039 Google Scholar
  34. Joneja MG (1981) Teratogenic effects of proline analogue l-azetidine-2-carboxylic acid in hamster fetuses. Teratology 23(3):365–372.  https://doi.org/10.1002/tera.1420230311 Google Scholar
  35. Jung M, Lee J, Seo H-Y, Lim JS, Kim E-K (2015) Cathepsin inhibition-induced lysosomal dysfunction enhances pancreatic beta-cell apoptosis in high glucose. PLoS One 10(1):e0116972.  https://doi.org/10.1371/journal.pone.0116972 Google Scholar
  36. Karni A, Kahana E, Zilber N, Abramsky O, Alter M, Karussis D (2003) The frequency of multiple sclerosis in Jewish and Arab populations in greater Jerusalem. Neuroepidemiology 22(1):82–86Google Scholar
  37. Kim J-S, Kim J-C, Lee S, Lee B-H, Cho KY (2006) Biological activity of l-2-azetidinecarboxylic acid, isolated from Polygonatum odoratum var. pluriflorum, against several algae. Aquat Bot 85(1):1–6.  https://doi.org/10.1016/j.aquabot.2006.01.003 Google Scholar
  38. Konovalova S, Hilander T, Loayza-Puch F, Rooijers K, Agami R, Tyynismaa H (2015) Exposure to arginine analog canavanine induces aberrant mitochondrial translation products, mitoribosome stalling, and instability of the mitochondrial proteome. Int J Biochem Cell Biol 65:268–274.  https://doi.org/10.1016/j.biocel.2015.06.018 Google Scholar
  39. Lane JM, Dehm P, Prockop DJ (1970) Effect of the proline analogue azetidine-2-carboxylic acid on collagen synthesis in vivo. Biochim Biophys Acta 236:517–527Google Scholar
  40. Lee YRJ, Nagao RT, Lin CY, Key JL (1996) Induction and regulation of heat-shock gene expression by an amino acid analog in soybean seedlings. Plant Physiol 110(1):241–248Google Scholar
  41. Lee J, Joshi N, Pasini R, Dobson RC, Allison J, Leustek T (2016a) Inhibition of Arabidopsis growth by the allelopathic compound azetidine-2-carboxylate is due to the low amino acid specificity of cytosolic prolyl-tRNA synthetase. Plant J 88(2):236–246.  https://doi.org/10.1111/tpj.13246 Google Scholar
  42. Lee W-C, Chiu C-H, Chen J-B, Chen C-H, Chang H-W (2016b) Mitochondrial fission increases apoptosis and decreases autophagy in renal proximal tubular epithelial cells treated with high glucose. DNA Cell Biol 35(11):657–665.  https://doi.org/10.1089/dna.2016.3261 Google Scholar
  43. Liu Z, Jenkinson SF, Vermaas T, Adachi I, Wormald MR, Hata Y, Kurashima Y, Kaji A, Yu CY, Kato A, Fleet GW (2015) 3-Fluoro-azetidine carboxylic acids and trans,trans-3,4-difluoroproline as peptide scaffolds: inhibition of pancreatic cancer cell growth by a fluoroazetidine iminosugar. J Org Chem.  https://doi.org/10.1021/acs.joc.5b00463 Google Scholar
  44. Löffelhardt W, Kopp B, Kubelka W (1979) Intracellular distribution of cardiac glycosides in leaves of Convallaria majalis. Phytochemistry 18(8):1289–1291.  https://doi.org/10.1016/0031-9422(79)83009-5 Google Scholar
  45. Loma I, Heyman R (2011) Multiple sclerosis: pathogenesis and treatment. Curr Neuropharmacol 9(3):409–416.  https://doi.org/10.2174/157015911796557911 Google Scholar
  46. Mahad DJ, Ziabreva I, Lassmann H, Turnbull D (2008) Mitochondrial defects in acute multiple sclerosis lesions. Brain 131(7):1722–1735.  https://doi.org/10.1093/brain/awn105 Google Scholar
  47. Mahad DJ, Ziabreva I, Campbell G, Lax N, White K, Hanson PS, Lassmann H, Turnbull DM (2009) Mitochondrial changes within axons in multiple sclerosis. Brain 132(5):1161–1174.  https://doi.org/10.1093/brain/awp046 Google Scholar
  48. Main BJ, Dunlop RA, Rodgers KJ (2016) The use of l-serine to prevent β-methylamino-l-alanine (BMAA)-induced proteotoxic stress in vitro. Toxicon 109:7–12.  https://doi.org/10.1016/j.toxicon.2015.11.003 Google Scholar
  49. Main BJ, Italiano CJ, Rodgers KJ (2018) Investigation of the interaction of β-methylamino-l-alanine with eukaryotic and prokaryotic proteins. Amino Acids 50(3):397–407.  https://doi.org/10.1007/s00726-017-2525-z Google Scholar
  50. Mallick A, More P, Syed MM, Basu S (2016) Nanoparticle-mediated mitochondrial damage induces apoptosis in cancer. ACS Appl Mater Interfaces 8(21):13218–13231.  https://doi.org/10.1021/acsami.6b00263 Google Scholar
  51. Murray TJ (2009) The history of multiple sclerosis: the changing frame of the disease over the centuries. J Neurol Sci 277:S3–S8.  https://doi.org/10.1016/S0022-510X(09)70003-6 Google Scholar
  52. Nikoletopoulou V, Markaki M, Palikaras K, Tavernarakis N (2013) Crosstalk between apoptosis, necrosis and autophagy. Biochim Biophys Acta Mol Cell Res 1833(12):3448–3459.  https://doi.org/10.1016/j.bbamcr.2013.06.001 Google Scholar
  53. Okle O, Stemmer K, Deschl U, Dietrich DR (2013) l-BMAA induced ER stress and enhanced caspase 12 cleavage in human neuroblastoma SH-SY5Y cells at low nonexcitotoxic concentrations. Toxicol Sci 131(1):217–224.  https://doi.org/10.1093/toxsci/kfs291 Google Scholar
  54. Parone PA, Martinou J-C (2006) Mitochondrial fission and apoptosis: an ongoing trial. Biochim Biophys Acta Mol Cell Res 1763(5):522–530.  https://doi.org/10.1016/j.bbamcr.2006.04.005 Google Scholar
  55. Poskanzer DC, Prenney LB, Sheridan JL, Kondy JY (1980) Multiple sclerosis in the Orkney and Shetland Islands. I: epidemiology, clinical factors, and methodology. J Epidemiol Community Health 34(4):229–239.  https://doi.org/10.1136/jech.34.4.229 Google Scholar
  56. Pugliatti M, Sotgiu S, Solinas G, Castiglia P, Rosati G (2001) Multiple sclerosis prevalence among Sardinians: further evidence against the latitude gradient theory. Neurol Sci 22(2):163–165.  https://doi.org/10.1007/s100720170017 Google Scholar
  57. Rodgers KJ (2014) Non-protein amino acids and neurodegeneration: the enemy within. Exp Neurol 253:192–196.  https://doi.org/10.1016/j.expneurol.2013.12.010 Google Scholar
  58. Rodgers KJ, Shiozawa N (2008) Misincorporation of amino acid analogues into proteins by biosynthesis. Int J Biochem Cell Biol 40(8):1452–1466.  https://doi.org/10.1016/j.biocel.2008.01.009 Google Scholar
  59. Rodgers KJ, Hume PM, Dunlop RA, Dean RT (2004) Biosynthesis and turnover of DOPA-containing proteins by human cells. Free Radic Biol Med 1(37):1756–1764Google Scholar
  60. Rodgers KJ, Ford JL, Brunk UT (2009) Heat shock proteins: keys to healthy ageing? Redox Rep 14(4):147–153.  https://doi.org/10.1179/135100009X392593 Google Scholar
  61. Rodríguez-Martín T, Pooler AM, Lau DHW, Mórotz GM, De Vos KJ, Gilley J, Coleman MP, Hanger DP (2016) Reduced number of axonal mitochondria and tau hypophosphorylation in mouse P301L tau knockin neurons. Neurobiol Dis 85:1–10.  https://doi.org/10.1016/j.nbd.2015.10.007 Google Scholar
  62. Roest G, Hesemans E, Welkenhuyzen K, Luyten T, Engedal N, Bultynck G, Parys JB (2018) The ER stress inducer l-azetidine-2-carboxylic acid elevates the levels of phospho-eIF2α and of LC3-II in a Ca(2+)-dependent manner. Cells 7(12):239.  https://doi.org/10.3390/cells7120239 Google Scholar
  63. Rojkind M (1973) Inhibition of liver fibrosis by l-Azetidine-2-carboxylic acid in rats treated with carbon tetrachloride. J Clin Investig 52:2451–2456Google Scholar
  64. Roos WP, Kaina B (2006) DNA damage-induced cell death by apoptosis. Trends Mol Med 12(9):440–450.  https://doi.org/10.1016/j.molmed.2006.07.007 Google Scholar
  65. Rosenthal GA (2001) l-Canavanine: a higher plant insecticidal allelochemical. Amino Acids 21:319–330Google Scholar
  66. Rubenstein E (2008) Misincorporation of the proline analog azetidine-2-carboxylic acid in the pathogenesis of multiple sclerosis: a hypothesis. J Neuropathol Exp Neurol 67(11):1035–1040.  https://doi.org/10.1097/NEN.0b013e31818add4a Google Scholar
  67. Rubenstein E, Zhou H, Krasinska KM, Chien A, Becker CH (2006) Azetidine-2-carboxylic acid in garden beets (Beta vulgaris). Phytochemistry 67(9):898–903.  https://doi.org/10.1016/j.phytochem.2006.01.028 Google Scholar
  68. Rubenstein E, McLaughlin T, Winant RC, Sanchez A, Eckart M, Krasinska KM, Chien A (2009) Azetidine-2-carboxylic acid in the food chain. Phytochemistry 70(1):100–104.  https://doi.org/10.1016/j.phytochem.2008.11.007 Google Scholar
  69. Sarasoja T, Wikström J, Paltamaa J, Hakama M, Sumelahti ML (2004) Occurrence of multiple sclerosis in central Finland: a regional and temporal comparison during 30 years. Acta Neurol Scand 110(5):331–336Google Scholar
  70. Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B, Tinevez JY, White DJ, Hartenstein V, Eliceiri K, Tomancak P, Cardona A (2012) Fiji: an open-source platform for biological-image analysis. Nat Methods 9(7):676–682.  https://doi.org/10.1038/nmeth.2019 Google Scholar
  71. Skulachev VP (2006) Bioenergetic aspects of apoptosis, necrosis and mitoptosis. Apoptosis 11(4):473–485.  https://doi.org/10.1007/s10495-006-5881-9 Google Scholar
  72. Smith PK, Krohn RI, Hermanson GT, Mallia AK, Gartner FH, Provenzano MD, Fujimoto EK, Goeke NM, Olson BJ, Klenk DC (1985) Measurement of protein using bicinchoninic acid. Anal Biochem 150(1):76–85.  https://doi.org/10.1016/0003-2697(85)90442-7 Google Scholar
  73. Song Y, Zhou H, Vo MN, Shi Y, Nawaz MH, Vargas-Rodriguez O, Diedrich JK, Yates JR, Kishi S, Musier-Forsyth K, Schimmel P (2017) Double mimicry evades tRNA synthetase editing by toxic vegetable-sourced non-proteinogenic amino acid. Nat Commun 8(1):2281.  https://doi.org/10.1038/s41467-017-02201-z Google Scholar
  74. Su B, Wang X, Zheng L, Perry G, Smith MA, Zhu X (2010) Abnormal mitochondrial dynamics and neurodegenerative diseases. Biochim Biophys Acta Mol Basis Dis 1802(1):135–142.  https://doi.org/10.1016/j.bbadis.2009.09.013 Google Scholar
  75. Suzuki T, Nagao A, Suzuki T (2011) Human mitochondrial tRNAs: biogenesis, function, structural aspects, and diseases. Annu Rev Genet 45(1):299–329.  https://doi.org/10.1146/annurev-genet-110410-132531 Google Scholar
  76. The UniProt C (2018) UniProt: a worldwide hub of protein knowledge. Nucleic Acids Res 47(D1):D506–D515.  https://doi.org/10.1093/nar/gky1049 Google Scholar
  77. Thompson JF, Morris CJ, Smith IK (1969) New naturally occurring amino acids. Annu Rev Biochem 38(1):137–158.  https://doi.org/10.1146/annurev.bi.38.070169.001033 Google Scholar
  78. Vaughan D, Dekock PC, Cusens E (1974) Effects of hydroxyproline and other amino acid analogues on the growth of pea root segments. Physiol Plant 30(3):255–259.  https://doi.org/10.1111/j.1399-3054.1974.tb03652.x Google Scholar
  79. Verbruggen N, van Montagu M, Messens E (1992) Synthesis of the proline analogue [2,3-3H]azetidine-2-carboxylic acid. Uptake and incorporation in Arabidopsis thaliana and Escherichia coli. FEBS Lett 308(3):261–263Google Scholar
  80. Wang X, Wang W, Li L, Perry G, Lee H-G, Zhu X (2014) Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Biochim Biophys Acta Mol Basis Dis 1842(8):1240–1247.  https://doi.org/10.1016/j.bbadis.2013.10.015 Google Scholar
  81. Witte ME, Mahad DJ, Lassmann H, van Horssen J (2014) Mitochondrial dysfunction contributes to neurodegeneration in multiple sclerosis. Trends Mol Med 20(3):179–187.  https://doi.org/10.1016/j.molmed.2013.11.007 Google Scholar
  82. Youle RJ, Karbowski M (2005) Mitochondrial fission in apoptosis. Nat Rev Mol Cell Biol 6(8):657–663Google Scholar
  83. Zagari A, Nemethy G, Scheraga HA (1990) The effect of l-azetidine-2-carboxylic acid residue on protein conformation. l. Conformations of the residue and of dipeptides. Biopolymers 30:951–959Google Scholar
  84. Zagari A, Palmer KA, Gibson KD, Nemethy G, Scheraga HA (1994) The effect of the l-azetidine-2-carboxylic acid residue on protein conformation. IV. Local substitutions in the collagen triple helix. Biopolymers 34(1):51–60.  https://doi.org/10.1002/bip.360340107 Google Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Neurotoxin Research Group, School of Life Sciences (04.06.340)University of TechnologySydneyAustralia

Personalised recommendations