The Induction of Mitochondrial Membrane Permeability Transition Pore Opening and DNA fragmentation by Certain Solvent Fractions of Mangifera indica
The opening of mitochondrial permeability transition (mPT) pore is a crucial step for apoptotic cell death. Certain bioactive agents in medicinal plants elicit their chemo-protective effect against tumor via the induction of the mPT pore opening.
This study therefore investigated the effects of different solvent fractions of Mangifera indica on mitochondrial-mediated apoptosis via mPT pore opening to ascertain the most potent fraction.
Methanol extract of Mangifera indica was partitioned successively to obtain n-hexane (NFMI), dichloromethane (DFMI), ethylacetate (EFMI) and methanol (MFMI) fractions. Rat liver and uterine mitochondria were isolated by differential centrifugation. The effects of DFMI, EFMI and MFMI on mPT pore, cytochrome c release, mitochondrial ATPase activity, lipid peroxidation and hepatic and uterine DNA fragmentation were assessed spectrophotometrically while caspases 9 and 3 activities were determined using ELISA technique.
The in vitro results showed that there was a concentration-dependent induction of mPT pore opening by MFMI and EFMI. However, MFMI was more potent than EFMI while DFMI did not have any effect. Similar pattern of results were recorded on cytochrome c release and mitochondrial ATPase activity. The in vivo results on mPT pore also showed MFMI to be the most potent, followed by EFMI while DFMI had no effect. The results on DNA fragmentation and caspases also showed MFMI to be the most potent of the three solvent fractions.
The results of this study suggest that MFMI is the most potent containing the bioactive agents that may induce mitochondrial-mediated apoptosis.
Keywords: Mangifera indica, apoptosis, mitochondrial permeability transition pore
1. McIlwain, D. R., Berger, T. and Mak, T. W. (2013). Caspase functions in cell death and disease. Cold Spring Harb. Perspect. Biol. 5, a008656. doi:10.1101/cshperspect.a008656
2. Reed, J (2004). Apoptosis mechanisms: implications for cancer drug discovery. Oncology 18:11–20..
3. Kallenberger Stefan M., Joël Beaudouin, Juliane Claus, Carmen Fischer, Peter K. Sorger, Stefan Legewie (2014) . Intra- and Interdimeric Caspase-8 Self-Cleavage Controls Strength and Timing of CD95-Induced Apoptosis. Sci. Signal. 11 Mar 2014: Vol. 7, Issue 316, pp. ra23
4. Crompton , M. (1999). The mitochondrial permeability transition pore and its role in cell death. Biochem J. 1999 Jul 15; 341(Pt 2): 233–249.
5. Wang, H.; Khor, T.O.; Shu, L.; Su, Z.Y.; Fuentes, F.; Lee, J.H.; Kong, A.N. (2012). Plants vs. cancer: A review on natural phytochemicals in preventing and treating cancers and their druggability. Anticancer Agents Med. Chem., 12, 1281–1305.
6. Martins K.R. (2006). Targeting apoptosis with dietary bioactive agents. Minireview, 117-130
7. Barreto J, Trevisan M, Hull W, Erben G, De Brito E, Pfundstein B, Würtele G, Spiegelhalder B, Owen R. Characterization and quantitation of polyphenolic compounds in bark, kernel, leaves, and peel of mango (Mangifera indica L.). Journal of Agricultural and Food Chemistry. 2008;56(14):5599–5610.
8. Shah K, Patel M, Patel R, Parmar P. Mangifera indica (mango). Pharmacog Rev. 2010;4(7):42.
9. Gabino G, Deyarina G, Cheyla R, Nunez- Selles A, Rene D. Scavenger effect of a mango (Mangifera indica L.) food supplement's active ingredient on free radicals produced by human polymorphonuclear cells and hypoxanthine–xanthine oxidase chemiluminescence systems; 2008.
10. Johnson, D. and Lardy, H. Isolation of liver or kidney mitochondria. Methods Enzymol, 1067; 10: 94-96.
11. Olorunsogo, O.O., Bababunmi, E.A. and Bassir, O. Uncoupling effect of N-phosphonomethylglycine on rat liver mitochondria. Biochem. Pharm., 1979; 27: 925-927.
12. Lowry, O.H., Rosenbrough, N.J., Farr, A.L. and Randall, R.J. Protein measurement with Folin phenol reagent. J Biol Chem., 1951; 1051(193): 265-275.
13. Olorunsogo O.O and Malomo S.O. Sensitivity of Oligomycin-inhibitedrespiration of isolated rat liver mitochondriato perfluidone, a fluorinated arylalkylsulfonamide. Toxicology, 1985; 35(3): 231-40.
14. Bassir, O. Handbook of Practical Biochemistry. (1963). Ibadan University Press, Ibadan, Nigeria, 13.
15. Varshney, R. and Kale,R.K.. Effect of calmodulin antagonists on radiation-induced lipid peroxidation in microsomes. Int. Radiat Biol., 1990; 58: 773-743.
16. Javadov, S. and Karmazyn, M. (2007). Mitochondrial permeability transition pore as end point to cell death and as a putative target for cardioprotection. Cell Physio Biochem;20 1-22
17. Lapidus, R.G. and Sokolove, P.M. (1993). Inhibition by spermine of the inner membrane permeability transition of isolated heart mitochondria. FEBS. Lett.3. 314-318.
18. Green, D. R. and Kroemer, G. (2004). The pathophysiology of mitochondrial cell death, Science, 305, 626–629.
19. A.O. Olowofolahan, O. A. Adeosun , O. T. Afolabi and O. O. Olorunsogo (2018).
Effect of Methanol Extract of Mangifera Indica on Mitochondrial Membrane
Permeability Transition Pore in Normal Rat Liver and Monosodium Glutamate-Induced
Liver and Uterine Damage. Journal of Complementary and Alternative Medical Research
5(2): 1-14 DOI:10.9734/JOCAMR/2018/40587
20. Wu, Chin-Chung Mei-Ling Chan, Wen-Ying Chen, Ching-Yi Tsai, Fang-Rong Chang and Yang-Chang Wu DOI: 10.1158/1535-7163.MCT-05-0027 Published August 2005
21. Costa, A.D.T., Casey, L., Andrukhiv, A., West, I.C., Jaburek, M., Garlid, K.D., (2006). The direct physiological effects of mitoKATP opening on heart mitochondria. Am. J. Physiol. Heart Circ. Physiol. 290, H406–H415.
22. Sadowski-Debbing K, Coy JF, Mier W, Hug H, Los M. Caspases – Their role in apoptosis and other physiological processes as revealed by knock-out studies. Archivum Immunologiae et Therapiae Experimentalis. 2002;50:19–34.