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The Effect of Melatonin on Mitochondrial Function in Endotoxemia Induced by Lipopolysaccharide

  • Liu, Jing (College of Veterinary Medicine, South China Agricultural University) ;
  • Wu, Fengming (College of Veterinary Medicine, South China Agricultural University) ;
  • Liu, Yuqing (College of Veterinary Medicine, South China Agricultural University) ;
  • Zhang, Tao (College of Veterinary Medicine, South China Agricultural University) ;
  • Tang, Zhaoxin (College of Veterinary Medicine, South China Agricultural University)
  • Received : 2010.05.13
  • Accepted : 2010.08.17
  • Published : 2011.06.01

Abstract

This study examined the metabolism of free radicals in hepatic mitochondria of goats induced by lipopolysaccharide (LPS), and investigated the effects of melatonin (MT). Forty-eight healthy goats ($10{\pm}1.2\;kg$) were randomly selected and divided into four groups: saline control, LPS, MT+LPS and MT. The goats within each group were3 sacrificed either 3 or 6 h after treatment and the livers removed to isolate mitochondria. The respiration control ratio (RCR), the ADP:O ratio, the oxidative phosphorylation ratio (OPR), the concentration of $H_2O_2$ and the activities of Complex I-IV were determined. The mitochondrial membrane potential ($\Delta\psi_m$) was analyzed by flow cytometry. The results showed that RCR, O/P and OPR of the LPS group decreased (p<0.05), as well as activities of respiratory complexes, whereas the generation of $H_2O_2$ in Complex III increased (p<0.05) after 3 h, while Complex II and III increased after 6 h. Also, it was found that the mitochondrial membrane potential of the LPS group declined (p<0.05). However, pre-treatment with MT attenuated the injury induced by LPS, which not only presented higher (p<0.05) RCR, O/P, OPR, and respiratory complex activities, but also maintained the $\Delta\psi_m$. Interestingly, it is revealed that, in the MT+LPS group, the generation of $H_2O_2$ increased firstly in 3 h, and then significantly (p<0.05).decreased after 6 h. In the MT group, the function of mitochondria, the transmenbrane potential and the generation of $H_2O_2$ were obviously improved compared to the control group. Conclusion: melatonin prevents damage caused by LPS on hepatic mitochondria of goats.

Keywords

References

  1. Acuna-Castroviejo, D., G. Escames, J. Leon, A. Carozo and H. Khaldy. 2003. Mitochondrial regulation by melatonin and its metabolites. Adv. Exp. Med. Biol. 527:549-557. https://doi.org/10.1007/978-1-4615-0135-0_63
  2. Acuna-Castroviejo, D., M. Martin, M. Macias, G. Escames, J. Leon, H. Khaldy and R. J. Reiter. 2001. Melatonin, mitochondria, and cellular bioenergetics. J. Pineal Res. 30:65-74. https://doi.org/10.1034/j.1600-079X.2001.300201.x
  3. Allegra, M., R. J. Reiter, D. X. Tan, C. Gentile, L. Tesoriere and M. A. Livrea. 2003. The chemistry of melatonin's interaction with reactive species. J. Pineal Res. 34:1-10. https://doi.org/10.1034/j.1600-079X.2003.02112.x
  4. Anatoly, A. S. and F. Gary. 2003. Regulation of brain mitochondrial $H_2O_2$ production by membrane potential and NAD(P)H redox state. J. Neurochem. 86:1101-1107. https://doi.org/10.1046/j.1471-4159.2003.01908.x
  5. Andrey, V. K., S. Katrin and H. Susanne. 2006. Different effects of endotoxic shock on the respiratory function of liver and heart mitochondria in rats. Am. J. Physiol. Gastrointest. Liver Physol. 290:543-549. https://doi.org/10.1152/ajpgi.00331.2005
  6. Andreyev, A. Yu, Kushnareva Yu. E. and A. A. Starkov. 2005. Mitochondrial metabolism of reactive oxygen species. Biochem. (Moscow) 70:200-214. https://doi.org/10.1007/s10541-005-0102-7
  7. Aydogen, S., M. B. Yerer and A. Goktas. 2006. Melatonin and nitric oxide. J. Endocrinol. Invest. 29:281-287. https://doi.org/10.1007/BF03345555
  8. Barja, G. 1999. Mitochondrial oxygen radicals generation and leak: sites of production in states 4 and 3, organ specificity, and relation to aging and longevity. J. Bios. Bioe. 31:347-366.
  9. Bass, D. A., J. W. Parce, L. R. Dechatelet, P. Szejda, M. C. Seeds and M. Thomas M. 1983. Flow cytometric studies of oxidative product formation by neutrophils: A graded response to membrane stimulation. J. Immunol. 130:1910-1915.
  10. Bettahi, I., J. M. Guerrero, R. J. Reiter and C. Osuna. 1998. Physiological concentrations of melatonin inhibit the norepinephrineinduced activation of prostaglandin E2 and cyclic AMP production in rat hypothalamus: a mechanism involving inhibiton of nitric oxide synthase. J. Pineal Res. 25: 34-40. https://doi.org/10.1111/j.1600-079X.1998.tb00383.x
  11. Bi, M. H., S. W. Zhang and B. E. Wang. 2004. The impairment and mechanism of endotoxemia in rat liver mitochondria. J. Chi. Integ. Med. 20:90-91.
  12. Brealey, D., M. Brand, I. Hargreaves, S. Heales, J. Land, R. Smolenski, N. A. Davies, C. E. Cooper and M. Singer. 2002. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 360:9-223. https://doi.org/10.1016/S0140-6736(02)11799-5
  13. Cawthon, D. C., R. McNew, K. W. Beers and W. G. Bottje. 1999. Evidence of mitochondrial dysfunction in broilers with pulmonary hypertension syndrome (ascites): Effect of t-butyl hydroperoxide on hepatic mitochondrial function, glutathione, and related thiols. Poult. Sci. 78:114-124. https://doi.org/10.1093/ps/78.1.114
  14. Costa, E. J., C. S. Shida, M. H. Biaggi, A. S. Ito, M. T. Lamy- Freund. 1997. How melatonin interacts with lipid bilayers: a study by fluorescence and ESR spectroscopies. FEBS Lett. 416: 103-106. https://doi.org/10.1016/S0014-5793(97)01178-2
  15. Crespo, E., M. Macias, D. Pozo, G. Escames, M. Martin, F. Vives, J. M. Guerrero and D. Acuna-Castroviejo. 1999. Melatonin inhibits expression of the inducible NO synthase II in liver and lung and prevents endotoxemia in lipopolysaccharideinduced multiple organ dysfunction syndrome in rats. FASEB J. 13: 1537-1546.
  16. Crouser, E. D. 2004. Mitochondrial dysfunction in septic shock and multiple organ dysfunction syndrome. Mitochondrion 4: 729-741. https://doi.org/10.1016/j.mito.2004.07.023
  17. Crouser, E. D., M. W. Julian, D. V. Blaho and D. R. Pfeiffer. 2002. Endotoxin-induced mitochondrial damage correlates with impaired respiratory activity. Crit. Care Med. 30:276-284. https://doi.org/10.1097/00003246-200202000-00002
  18. Crouser, E. D., M. W. Julian and P. M. Dorinsky. 1999. Ileal VO2- DO2 alterations induced by endotoxin correlate with severity of mitochondrial injury. Am. J. Respir. Crit. Care Med. 160: 1347-1353. https://doi.org/10.1164/ajrccm.160.4.9810116
  19. Elizabeth, A. M. and F. A. Karam. 2004. Effects of enhancing mitochondrial oxidative phosphorylation with reducing equivalents and ubiquinone on 1-methyl-4-phenylpyridinium toxicity and complex I-IV damage in neuroblastoma cells. Biomed. Pharmacother. 67:1167-1184.
  20. Escames, G., J. Leon, M. Macias, H. Khaldy and D. Acuna- Castroviejo. 2003. Melatonin counteracts lipopolysaccharideinduced expression and activity of mitochondrial nitric oxide synthase in rats. FASEB J. 17:932-934.
  21. Fink, M. P. 2001. Cytopathic hypoxia: mitochondrial dysfunction as mechanism contributing to organ dysfunction in sepsis. Crit. Care Clin. 17:219-237. https://doi.org/10.1016/S0749-0704(05)70161-5
  22. Francesca, P., T. Jukka and W. Christian. 2006. Effects of prolonged endotoxemia on liver, skeletal muscle and kidney mitochondrial function. Crit. Care 10:118-130. https://doi.org/10.1186/cc4825
  23. Galente, Y. M. and Y. Hatefi. 1978. Resolution of Complex I and isolation of NADH dehydrogenase and an iron-sulfur protein. Meth. Enzymol. 53:15-21. https://doi.org/10.1016/S0076-6879(78)53007-3
  24. Garcia, J. J., R. J. Reiter, J. Pie, G. G. Ortiz, J. Cabrera, R. M. Sainz and D. Acuna-Castroviejo. 1999. Role of pinoline and melatonin in stabilizing hepatic microsomal membranes against oxidative stress. J. Bioenerg. Biomembr. 31:609-616. https://doi.org/10.1023/A:1005425213253
  25. Giuseppe, P. M.P.a.F.M.R. 2000. The effect of reactive oxygen species generated from the mitochondrial electron transport chain on the cytochrome c oxidase activity and on the cardiolipin content in bovine heart submitochondrial particles. FEBS Lett. 466:323-326. https://doi.org/10.1016/S0014-5793(00)01082-6
  26. Haider R., J. Annie, M. B. Eric, B. Sheela and K. Amr. 2006. Alterations in mitochondrial respiratory functions, redox metabolism and apoptosis by oxidant 4-hydroxynonenal and antioxidants curcumin and melatonin in PC 12 cells. Toxicol. Appl. Pharmacol. 226:161-168.
  27. Hartmut, J., J. G. Gregory, I. C. Arthur, A. H. Jack, P. Dominique and J. L. John. 2002. Mech Hepatotox. Toxicol. Sci. 65:166-176. https://doi.org/10.1093/toxsci/65.2.166
  28. Hatefi, Y. and D. L. Stiggall. 1978. Preparation and properties of succinate: ubiquinone reductase (Complex II). Meth. Enzymol. 53: 21-27. https://doi.org/10.1016/S0076-6879(78)53008-5
  29. Hiroyuki, T. 2006. Mitochondrial oxidative stress and heart failure. Inter. Med. 45:809-813. https://doi.org/10.2169/internalmedicine.45.1765
  30. Iqbal, M., D. Cawthon, R. F. Widenman, Jr., K. W. Beers and W. G. Bottje. 2001a. Lung mitochondrial dysfunction in pulmonary hypertension syndrome. II. Oxidative stress and inability to improve function with repeated additions of ADP. Poult. Sci. 80:656-665. https://doi.org/10.1093/ps/80.5.656
  31. Jane, A. L. and L. Joseph. 2005. Oxidative enzymopathies and vascular disease. Arterioscler. Thromb. Vas. Biol. 25:1102-1111. https://doi.org/10.1161/01.ATV.0000163262.83456.6d
  32. Kantrow, S. P., D. E. Taylor, M. S. Carraway and C. A. Piantadosi. 1997. Oxidative metabolism in rat hepatocytes and mitochondria during sepsis. Arch. Biochem. Biophys. 345:278-288. https://doi.org/10.1006/abbi.1997.0264
  33. Kubes, P. 2005. The complexities of leukocyte recruitment. Semin. Immuno. 14:65-72.
  34. Leon, J., D. Acuna-Castroviejo, G. Escames, D. X. Tan and R. J. Reiter. 2005. Melatonin mitigates mitochondrial malfunction. J. Pineal Res. 38:1-9. https://doi.org/10.1111/j.1600-079X.2004.00181.x
  35. Leon, J., M. Macias, G. Escames, E. Camacho, H. Khaldy, M. Martin, A. Espinosa, M. A. Gallo and D. Acuna-Castroviejo. 2000. Structure-related inhibition of calmodulin-dependent neuronal nitric-oxide synthase activity by melatonin and synthetic kynurenines. Mol. Pharm. 58:967-975.
  36. Leon, J., F. Vives, E. Crespo, E. Camacho, A. Espinosa, M. A. Gallo, G. Escames and D. Acuna-Castroviejo. 1998. Modification of nitric oxide synthase activity and neuronal response in rat striatum by melatonin and kynurenine derivatives. J. Neuroendocrinol. 10:297-302.
  37. Lobo, S. M., D. De Backer, Q. Sun, Z. Tu, G. Dimopoulos, J. C. Preiser, N. Nagy, B. Vray, V. Vercrury, R. G. Terzi and J. L. Vincent. 2003. Gut mucosal damage during endotoxic shock is due to mechanisms other than gut ischemia. J. Appl. Phys. 95:2047-2054.
  38. Lothar, K. and H. Judy. 2006. The mechanism of superoxide production by NADH: ubiquinone oxidoreductase (complex I) from bovine heart mitochondria. Proc. Nat. Ac. Sci. 103:7607-7612. https://doi.org/10.1073/pnas.0510977103
  39. Lu, S. M., S. M. Song, J. C. Liu, H. M. Yang, P. Li and Z. G. Wang. 2003. Changes of proton transportation across the inner mitochondrial membrane and H-ATPase in endotoxic shock rats. Chin. J. Traumatol. 6:292-296.
  40. Ly, J. D., D. R. Grubb, and A. Lawen. 2003. The mitochondrial membrane potential [Deltapsi(m)] in apoptosis: an update. Apoptosis 8:115-118. https://doi.org/10.1023/A:1022945107762
  41. Marieke, K. B. V. D. W. and Emile De Heer. 1996. Cisplatininduced nephrotoxicity in porcine proximal tubular cells: Mitochondrial dysfunction by inhibition of complexes I to IV of the respiratory chain. J. Pharmacol. Exp. Ther. 280:638-649.
  42. Marion, M. B. 1976. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72:248-254. https://doi.org/10.1016/0003-2697(76)90527-3
  43. Martinez, G. R., E. A. Almeida, C. F. Klitzke, J. Onuki, F. M. Prado, M. H. Medeiros and P. Di Mascio. 2005. Measurement of melatonin and its metabolites: importance for the evaluation of their biological roles. Endocrine 27:111-118. https://doi.org/10.1385/ENDO:27:2:111
  44. Matthew, M., L. Michael, R. T. David and T. R. Michael. 2006. Mitochondrial respiratory chain supercomplexes are destabilized in barth syndrome patients. J. Mol. Biol. 261:462-469.
  45. Menendez-Pelaez, A. and R. J. Reiter. 1993. Distribution of melatonin in mammalian tissues: the relative importance of nuclear versus cytosolic localization. J. Pineal Res. 15:59-69. https://doi.org/10.1111/j.1600-079X.1993.tb00511.x
  46. Michael, R. D. 2000. Mitochondria and calcium: from cell signaling to cell death. J. Phys. 529:57-68. https://doi.org/10.1111/j.1469-7793.2000.00057.x
  47. Michael, R. D. 2004. Section III: mitochondria, $\beta$-cell function, and type 2 diabetes. Role of mitochondria in health and disease. Diabetes 53:S96-S102. https://doi.org/10.2337/diabetes.53.2007.S96
  48. Octavio, G., A. Angeles, M. Lourdes and P. B. Juan. 2005. Increased mitochondrial respiration maintains the mitochondrial membrane potential and promotes survival of cerebellar neurons in an endogenous model of glutamate receptor activation. J. Neurochem. 92:183-190. https://doi.org/10.1111/j.1471-4159.2004.02851.x
  49. Ojano-Dirain, C., M. Iqbal, T. Wing, M. Cooper and W. Bottje. 2005. Glutathione and respiratory chain complex activity in duodenal mitonchondria of broilers with low and high feed efficiency. Poult. Sci. 84:785-788.
  50. Pozo, D., R. J. Reiter, J. R. Calvo and J. M. Guerrero. 1994. Physiological concentrations of melatonin inhibit nitric oxide synthase in rat cerebellum. Life Sci. 55:PL455-PL460. https://doi.org/10.1016/0024-3205(94)00532-X
  51. Qun, C., J. V. Edwin, M. Shadi and L. H. Charles. 2003. Production of reactive oxygen species by mitochondria: Central role of complex III. J. Biol. Chem. 278:36027-36031. https://doi.org/10.1074/jbc.M304854200
  52. Raam, B. J., S. Wim, W. de Elly, R. Dirk, J. V. Arthur and W. K. Taco. 2008. Mitochondrial membrane potential in human neutrophils is maintained by complex III activity in the absence of supercomplex organization. PLoS ONE 3:e2013. https://doi.org/10.1371/journal.pone.0002013
  53. Reiter, R. J., D. X. Tan, L. C. Manchester and W. Qi. 2001a. Biochemical reactivity of melatonin with reactive oxygen and nitrogen species. Cel. Physiol. Biochem. 34:237-256.
  54. Reiter, R. J., D. X. Tan and C. Osuna. 2000. Actions of melatonin in the reduction of oxidative stress: a review. J. Biomed. Sci. 7: 444-458. https://doi.org/10.1007/BF02253360
  55. Reiter, R. J., D. X. Tan, L. C. Manchester and M. R. El-Sawi. 2002. Melatonin reduces oxidant damage and promotes mitochondrial respiration: implications for aging. Ann. NY Acad. Sci. 959:238-250.
  56. Rodriquez, C., J. C. Mayo and R. J. Saina. 2004. Regulation of antioxidant enzymes: a significant role for melatonin. J. Pineal Res. 36:1-9. https://doi.org/10.1046/j.1600-079X.2003.00092.x
  57. Rongen, G. A., P. Smits and T. Thien. 1994. Endothelium and the regulation of vascular tone with emphasis on the role of nitric oxide. Physiology, pathophysiology and clinical implications. Neth. J. Med. 44:26-35.
  58. Shauna, M. D. and K. Aly. 2006. Lipopolysaccharide signaling in endothelial cells. Lab. Invest. 86:9-22. https://doi.org/10.1038/labinvest.3700366
  59. Singer, M. and D. Brealey. 1999. Mitochondrial dysfunction in sepsis. Biochem. Soc. Symp. 66:149-166.
  60. Singer, M., V. De Santis, D. Vitale and W. Jeffcoate. 2004. Multiorgan failure is an adaptive, endocrine-mediated, metabolic response to overwhelming systemic inflammation. Lancet 364:545-548. https://doi.org/10.1016/S0140-6736(04)16815-3
  61. Tan, D. X., L. D. Chen and B. Poeggeler. 1993. Melatonin: a potent, endogenous hydroxyl radical scavenger. Endocr. J. 1: 57-60.
  62. Tan, D. X., L. C. Manchester, R. J. Reiter, B. F. Plummer, J. Limson, S. T. Weintraub and W. Qi. 2000a. Melatonin directly scavenges hydrogen peroxide: a potentially new metabolic pathway of melatonin. Free Radic. Biol. Med. 29:1177-1185. https://doi.org/10.1016/S0891-5849(00)00435-4
  63. Tan, D. X., L. D. Chen, B. Poeggeler, L. C. Manchester and R. J. Reiter. 1993a. Melatonin: a potent endogenous hydroxyl radical scavenger. Endocr. J. 1:57-60.
  64. Tan, D. X., B. Poeggeler, R. J. Reiter, L. D. Chen, S. Chen, L. C. Manchester and L. R. Barlow-Walden. 1993b. The pineal hormone melatonin inhibits DNA-adduct formation induced by the chemical carcinogen safrole in vivo. Cancer Lett. 70:65-71. https://doi.org/10.1016/0304-3835(93)90076-L
  65. Tang, Z., M. Iqbal and D. Cawthon. 2002. Heart and breast muscle mitochondrial dysfunction in pulmonary hypertension syndrome in broilers (gallus domesticus). Comp. Biochem. Physiol. Part A 132:527-540. https://doi.org/10.1016/S1095-6433(02)00005-3
  66. Tatyana, V. V. and J. R. Ian. 2001. ${\Delta}{\Psi}_m$-Dependent and - independent production of reactive oxygen species by rat brain mitochondria. J. Neurochem. 79:266-277.
  67. Tsutsui, H. 2006. Mitochondrial oxidative stress and heart failure. Jap. Soc. Inter. Med. 45:809-813.
  68. Turrens, J. F. 1997. Superoxie production by the mitochondrial respiratory chain. Biosci. Rep. 17:3-8. https://doi.org/10.1023/A:1027374931887
  69. Vera, A. V. and C. Christos. 2006. Bioenergetics and the formation of mitochondrial reactive oxygen species. Trends Pharmacol. Sci. 27:639-645. https://doi.org/10.1016/j.tips.2006.10.005
  70. Wang, Y. L., S. Zhang and Z. X. Tang. 2006. Effect of ainoguanidine on liver mitochondrial free radical metabolism in broilers with endotoxemia. Chin. J. Vet. Sci. 36:143-146.
  71. Wu, K. K. and P. Thiagarajan. 1996. Role of endothelium in thrombosis and hemostasis. Annu. Rev. Med. 47:315-331. https://doi.org/10.1146/annurev.med.47.1.315
  72. Ximenes, V. F., S. O. Silva, M. R. Rodrigues, L. H. Catalani, G. J. Maghzal, A. J. Kettle and A. Campa. 2005. Superoxide dependent oxidation of melatonin by myeloperoxidase. J. Biol. Chem. 280:38160-38169. https://doi.org/10.1074/jbc.M506384200
  73. Zavodnik, I. B., E. A. Lapshima, L. B. Zavodnik, M. Labieniec, M. Bryszewska and R. J. Reiter. 2004. Hypochlorous acidinduced oxidative stress in Chinese hamster B14 cells: viability, DNA and protein damage and the protective action of melatonin. Mutat. Res. 559:39-48. https://doi.org/10.1016/j.mrgentox.2003.12.009

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