Skip to main content

Cardiotoxicity of acetogenins from Persea americana occurs through the mitochondrial permeability transition pore and caspase-dependent apoptosis pathways

Abstract

Acetogenins are cell-membrane permeable, naturally occurring secondary metabolites of plants such as Annonaceae, Lauraceae and other related phylogenic families. They belong to the chemical derivatives of polyketides, which are synthesized from fatty acid precursors. Although acetogenins have displayed diverse biological activities, the anti-proliferative effect on human cancer cells has been widely reported. Acetogenins are inhibitors of complex I in the electron transport chain therefore they interrupt ATP synthesis in mitochondria. We tested a new acetogenins-enriched extract from the seed of Persea americana in order to investigate if any toxicity was induced on cardiac tissue and determine the involved mechanism. In isolated perfused heart we found that contractility was completely inhibited at an accumulative dose of 77 μg/ml. In isolated cardiomyocytes, the acetogenins-enriched extract induced apoptosis through the activation of the intrinsic pathway at 43 μg/ml. In isolated mitochondria, it inhibited complex I activity on NADH-linked respiration, as would be expected, but also induced permeability transition on succinate-linked respiration. Cyclosporine A, a known blocker of permeability transition, significantly prevented the permeability transition triggered by the acetogenins-enriched extract. In addition, our acetogenins-enriched extract inhibited ADP/ATP exchange, suggesting that an important element in phosphate or adenylate transport was affected. In this manner we suggest that acetogenins-enriched extract from Persea americana could directly modulate permeability transition, an entity not yet associated with the acetogenins’ direct effects, resulting in cardiotoxicity.

This is a preview of subscription content, access via your institution.

References

  1. Rodriguez-Saona C, Millar J, Trumble J (1998) Isolation, identification, and biological activity of isopersin, a new compound from avocado idioblast oil cells. J Nat Prod 61:1168–1170

    Article  Google Scholar 

  2. Jolad S, Hoffmann J, Schram K, Cole J (1982) Uvaricin, a new antitumor agent from Uvaria accuminata (Annonaceae). J Org Chem 47:3151–3153

    Google Scholar 

  3. Ahammadsahib KI, Hollingworth RM, McGovren JP, Hui YH, McLaughlin JL (1993) Mode of action of bullatacin: a potent antitumor and pesticidal annonaceous acetogenin. Life Sci 53:1113–1120

    Article  CAS  Google Scholar 

  4. Degli Esposti M, Ghelli A, Ratta M, Cortes D, Estornell E (1994) Natural substances (acetogenins) from the family Annonaceae are powerful inhibitors of mitochondrial NADH dehydrogenase (Complex I). Biochem J 301(Pt 1):161–167

    CAS  Google Scholar 

  5. Morré DJ, de Cabo R, Farley C, Oberlies NH, McLaughlin JL (1995) Mode of action of bullatacin, a potent antitumor acetogenin: inhibition of NADH oxidase activity of HeLa and HL-60, but not liver, plasma membranes. Life Sci 56:343–348

    Article  Google Scholar 

  6. Gustafsson AB, Gottlieb RA (2007) Heart mitochondria: gates of life and death. Cardiovasc Res 77:334–343

    Article  Google Scholar 

  7. Halestrap AP (2009) What is the mitochondrial permeability transition pore? J Mol Cell Cardiol 46:821–831

    Article  CAS  Google Scholar 

  8. Liu X, Kim CN, Yang J, Jemmerson R, Wang X (1996) Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell 86:147–157

    Article  CAS  Google Scholar 

  9. Yuan S, Chang H, Chen H, Yeh Y, Kao Y (2003) Annonacin, a mono-tetrahydrofuran acetogenin, arrests cancer cells at the G1 phase and causes cytotoxicity in a Bax- and caspase-3-related pathway. Life Sci 72(25):2853–2861

    Google Scholar 

  10. Oelrichs PB, Ng JC, Seawright AA, Ward A, Schäffeler L, MacLeod JK (1995) Isolation and identification of a compound from avocado (Persea americana) leaves which causes necrosis of the acinar epithelium of the lactating mammary gland and the myocardium. Nat Toxins 3:344–349

    Article  CAS  Google Scholar 

  11. Caparros-Lefebvre D, Elbaz A (1999) Possible relation of atypical parkinsonism in the French West Indies with consumption of tropical plants: a case-control study. Caribbean Parkinsonism Study Group. Lancet 354:281–286

    Article  CAS  Google Scholar 

  12. Champy P, Höglinger GU, Féger J, Gleye C, Hocquemiller R, Laurens A et al (2003) Annonacin, a lipophilic inhibitor of mitochondrial complex I, induces nigral and striatal neurodegeneration in rats: possible relevance for atypical parkinsonism in Guadeloupe. J Neurochem 88:63–69

    Article  Google Scholar 

  13. Escobar-Khondiker M, Hollerhage M, Muriel MP, Champy P, Bach A, Depienne C et al (2007) Annonacin, a natural mitochondrial complex I inhibitor, causes tau pathology in cultured neurons. J Neurosci 27:7827–7837

    Article  CAS  Google Scholar 

  14. Neubauer S (2007) The failing heart—an engine out of fuel—N Engl J Med 15;356(11):1140–1151

    Google Scholar 

  15. Yang H, Li X, Tang Y, Zhang N, Chen J, Cai B (2009) Supercritical fluid CO2 extraction and simultaneous determination of eight annonaceous acetogenins in Annona genus plant seeds by HPLC-DAD method. J Pharm Biomed Anal 49:140–144

    Article  CAS  Google Scholar 

  16. De Jesús García-Rivas G, Guerrero-Hernández A, Guerrero-Serna G, Rodríguez-Zavala JS, Zazueta C (2005) Inhibition of the mitochondrial calcium uniporter by the oxo-bridged dinuclear ruthenium amine complex (Ru360) prevents from irreversible injury in postischemic rat heart. FEBS J 272:3477–3488

    Article  Google Scholar 

  17. Wolska BM, Solaro RJ (1996) Method for isolation of adult mouse cardiac myocytes for studies of contraction and microfluorimetry. Am J Physiol 271:H1250–H1255

    CAS  Google Scholar 

  18. de Garcia-Rivas GJ, Carvajal K, Correa F, Zazueta C (2006) Ru360 a specific mitochondrial calcium uptake inhibitor, improves cardiac post-ischaemic functional recovery in rats in vivo. Br J Pharmacol 149:829–837

    Article  CAS  Google Scholar 

  19. Waldmeier P, Feldtrauer J, Qian T (2002) Inhibition of the mitochondrial permeability transition by the nonimmunosuppressive cyclosporin derivative NIM811. Mol Pharmacol 62(1):22–29

    Google Scholar 

  20. Chávez E, García N, Zazueta C, Correa F (2003) The composition of the incubation medium influences the sensitivity of mitochondrial permeability transition to cyclosporin A. J Bioenerg Biomembr 35(2):149–156

    Google Scholar 

  21. Ortega R, Garcia N (2009) The flavonoid quercetin induces changes in mitochondrial permeability by inhibiting adenine nucleotide translocase. J Bioenerg Biomembr. Volume 41, Number 1

  22. Bulteau A-L, Lundberg KC, Ikeda-Saito M, Isaya G, Szweda LI (2005) Reversible redox-dependent modulation of mitochondrial aconitase and proteolytic activity during in vivo cardiac ischemia/reperfusion. Proc Natl Acad Sci USA 102:5987–5991

    Article  CAS  Google Scholar 

  23. Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358

    Article  CAS  Google Scholar 

  24. Burger W, Naudé T, van Rensburg I, Botha C, Pienaar A (1993) Cardiomyopathy in ostriches (Struthio camelus) due to avocado (Persea americana var. guatemalensis) intoxication. J S Afr Vet Assoc 65(3):113–118

    Google Scholar 

  25. Butt AJ, Roberts CG, Seawright AA, Oelrichs PB, Macleod JK, Liaw TY, et al. (2006) A novel plant toxin, persin, with in vivo activity in the mammary gland, induces Bim-dependent apoptosis in human breast cancer cells. Mol Cancer Ther 5:2300–2309

    Article  CAS  Google Scholar 

  26. Lee Y, Gustafsson ÅB (2009) Role of apoptosis in cardiovascular disease. Apoptosis 14:536–548

    Article  Google Scholar 

  27. Roberts CG, Gurisik E, Biden TJ, Sutherland RL, Butt AJ (2007) Synergistic cytotoxicity between tamoxifen and the plant toxin persin in human breast cancer cells is dependent on Bim expression and mediated by modulation of ceramide metabolism. Mol Cancer Ther 6:2777–2785

    Article  CAS  Google Scholar 

  28. Murai M, Ichimaru N, Abe M, Nishioka T, Miyoshi H (2006) Mode of inhibitory action of Δlac-acetogenins, a new class of inhibitors of bovine heart mitochondrial complex I. Biochemistry 45:9778–9787

    Article  CAS  Google Scholar 

  29. Alvarez Colom O, Neske A, Chahboune N, Zafra-Polo MC, Bardón A (2009) Tucupentol, a novel mono-tetrahydrofuranic acetogenin from Annona montana, as a potent inhibitor of mitochondrial complex I. Chem Biodivers 6:335–340

    Article  Google Scholar 

  30. Pastorino JG, Wilhelm TJ, Glascott PA, Kocsis JJ, Farber JL (1995) Dexamethasone induces resistance to the lethal consequences of electron transport inhibition in cultured hepatocytes. Arch Biochem Biophys 318:175–181

    Article  CAS  Google Scholar 

  31. Wolvetang EJ, Johnson KL, Krauer K, Ralph SJ, Linnane AW (1994) Mitochondrial respiratory chain inhibitors induce apoptosis. FEBS Lett 339:40–44

    Article  CAS  Google Scholar 

  32. Isenberg JS, Klaunig JE (2000) Role of the mitochondrial membrane permeability transition (MPT) in rotenone-induced apoptosis in liver cells. Toxicol Sci 53:340–351

    Article  CAS  Google Scholar 

  33. Terada H (1981) The interaction of highly active uncouplers with mitochondria. Biochim Biophys Acta 639:225–242

    Article  CAS  Google Scholar 

  34. de Graaf AO, van den Heuvel LP, Dijkman HBPM, de Abreu RA, Birkenkamp KU, de Witte T et al (2004) Bcl-2 prevents loss of mitochondria in CCCP-induced apoptosis. Exp Cell Res 299:533–540

    Article  Google Scholar 

  35. Castilho RF, Meinicke AR, Almeida AM, Hermes-Lima M, Vercesi AE (1994) Oxidative damage of mitochondria induced by Fe(II)citrate is potentiated by Ca2+ and includes lipid peroxidation and alterations in membrane proteins. Arch Biochem Biophys 308:158–163

    Article  CAS  Google Scholar 

  36. McStay GP, Clarke SJ, Halestrap AP (2002) Role of critical thiol groups on the matrix surface of the adenine nucleotide translocase in the mechanism of the mitochondrial permeability transition pore. Biochem J 367:541–548

    Article  CAS  Google Scholar 

  37. Crompton M, Virji S, Ward JM (1998) Cyclophilin-D binds strongly to complexes of the voltage-dependent anion channel and the adenine nucleotide translocase to form the permeability transition pore. Eur J Biochem 258:729–735

    Article  CAS  Google Scholar 

  38. Bernardi P (1992) Modulation of the mitochondrial cyclosporin A-sensitive permeability transition pore by the proton electrochemical gradient. Evidence that the pore can be opened by membrane depolarization. J Biol Chem 267:8834–8839

    CAS  Google Scholar 

  39. Vercesi AE (1987) The participation of NADP, the transmembrane potential and the energy-linked NAD(P) transhydrogenase in the process of Ca2+ efflux from rat liver mitochondria. Arch Biochem Biophys 252:171–178

    Article  CAS  Google Scholar 

  40. Arteaga D, Odor A, López RM, Contreras G, Pichardo J, García E et al (1992) Impairment by cyclosporin A of reperfusion-induced arrhythmias. Life Sci 51:1127–1134

    Article  CAS  Google Scholar 

  41. Parra E, Cruz D, García G, Zazueta C, Correa F, García N et al (2005) Myocardial protective effect of octylguanidine against the damage induced by ischemia reperfusion in rat heart. Mol Cell Biochem 269:19–26

    Article  CAS  Google Scholar 

  42. García-Rivas GJ, Torre-Amione G (2009) Abnormal mitochondrial function during ischemia reperfusion provides targets for pharmacological therapy. Methodist Debakey Cardiovasc J 5, 2–7

    Google Scholar 

  43. Piot C, Croisille P, Staat P, Thibault H, Rioufol G, Mewton N et al (2008) Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 359:473–481

    Article  CAS  Google Scholar 

  44. Oliveira PJ, Seiça R, Coxito PM, Rolo AP, Palmeira CM, Santos MS et al (2003) Enhanced permeability transition explains the reduced calcium uptake in cardiac mitochondria from streptozotocin-induced diabetic rats. FEBS Lett 554:511–514

    Article  CAS  Google Scholar 

  45. Javadov S, Rajapurohitam V, Kilić A, Zeidan A, Choi A, Karmazyn M (2009) Anti-hypertrophic effect of NHE-1 inhibition involves GSK-3β-dependent attenuation of mitochondrial dysfunction. J Mol Cell Cardiol 46:998–1007

    Article  CAS  Google Scholar 

  46. Barsukova AG, Bourdette D, Forte M (2011) Mitochondrial calcium and its regulation in neurodegeneration induced by oxidative stress. Eur J Neurosci 34:437–447

    Article  Google Scholar 

  47. Thomas B, Banerjee R, Starkova NN, Zhang SF, Calingasan NY, Yang Let al (2011) Mitochondrial permeability transition pore component cyclophilin D distinguishes nigrostriatal dopaminergic death paradigms in the MPTP mouse model of Parkinson’s disease. Antioxid Redox Signal. doi:10.1089/ars.2010.3849

  48. Brustovetsky N, Klingenberg M (1996) Mitochondrial ADP/ATP carrier can be reversibly converted into a large channel by Ca2. Biochemistry 35:8483–8488

    Article  CAS  Google Scholar 

  49. Leung AWC, Varanyuwatana P, Halestrap AP (2008) The mitochondrial phosphate carrier interacts with cyclophilin D and may play a key role in the permeability transition. J Biol Chem 283:26312–26323

    Article  CAS  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Gerardo García-Rivas.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Silva-Platas, C., García, N., Fernández-Sada, E. et al. Cardiotoxicity of acetogenins from Persea americana occurs through the mitochondrial permeability transition pore and caspase-dependent apoptosis pathways. J Bioenerg Biomembr 44, 461–471 (2012). https://doi.org/10.1007/s10863-012-9452-1

Download citation

Keywords

  • Mitochondria
  • Permeability transition
  • Acetogenins
  • Avocado
  • Toxicity