Advertisement

Modulating effect of tiron on the capability of mitochondrial oxidative phosphorylation in the brain of rats exposed to radiation or manganese toxicity

  • Nadia Abdel-MagiedEmail author
  • Nahed Abdel-Aziz
  • Shereen M. Shedid
  • Amal G. Ahmed
Research Article
  • 39 Downloads

Abstract

The brain is an important organ rich in mitochondria and more susceptible to oxidative stress. Tiron (sodium 4,5-dihydroxybenzene-1,3-disulfonate) is a potent antioxidant. This study aims to evaluate the effect of tiron on the impairment of brain mitochondria induced by exposure to radiation or manganese (Mn) toxicity. We assessed the capability of oxidative phosphorylation (OXPHOS) through determination of mitochondrial redox state, the activity of electron transport chain (ETC), and Krebs cycle as well as the level of adenosine triphosphate (ATP) production. Rats were exposed to 7 Gy of γ-rays or injected i.p. with manganese chloride (100 mg/kg), then treated with tiron (471 mg/kg) for 7 days. The results showed that tiron treatment revealed positive modulation on the mitochondrial redox state manifested by a marked decrease of hydrogen peroxide (H2O2), malondialdehyde (MDA), and total nitrate/nitrite (NOx) associated with a significant increase in total antioxidant capacity (TAC), glutathione (GSH) content, manganese superoxide dismutase (MnSOD), and glutathione peroxidase (GPx) activities. Moreover, tiron can increase the activity of ETC through preventing the depletion in the activity of mitochondrial complexes (I, II, III, and IV), an elevation of coenzyme Q10 (CoQ10) and cytochrome c (Cyt-c) levels. Additionally, tiron showed a noticeable increase in mitochondrial aconitase (mt-aconitase) activity as the major component of Krebs cycle to maintain a high level of ATP production. Tiron also can restore mitochondrial metal homeostasis through positive changes in the levels of calcium (Ca), iron (Fe), Mn, and copper (Cu). It can be concluded that tiron may be used as a good mitigating agent to attenuate the harmful effects on the brain through the inhibition of mitochondrial injury post-exposure to radiation or Mn toxicity.

Keywords

MnCl2 γ-Radiation Brain Mitochondria Tiron ATP 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

References

  1. Aaseth J, Skaug MA, Cao Y, Andersen O (2015) Chelation in metal intoxication principles and paradigms. J Trace Elem Med Biol 31:260–266CrossRefGoogle Scholar
  2. Apostolova N, Victor VM (2015) Molecular strategies for targeting antioxidants to mitochondria: therapeutic implications. Antioxid Redox Signal 22:686–729CrossRefGoogle Scholar
  3. Ateyya H, HM Wagih HM, El-Sherbeeny NA (2016) Effect of tiron on remote organ injury in rats with severe acute pancreatitis induced by L-arginine. Naunyn Schmiedeberg’s Arch Pharmacol 389:873–885CrossRefGoogle Scholar
  4. Barjaktarovic Z, Schmaltz D, Shyla A, Azimzadeh O, Schulz S, Haagen J, Dörr W, Sarioglu H, Schäfer A, Atkinson MJ, Zischka H, Tapio S (2011) Radiation-induced signaling results in mitochondrial impairment in mouse heart at 4 weeks after exposure to X-rays. PLoS One 6:e27811CrossRefGoogle Scholar
  5. Basinger MA, Jones MM (1981) Tiron (sodium 4,5-dihydroxybenzene-1,3-disulfonate) as an antidote for acute uranium intoxication in mice. Res Commun Chem Pathol Pharmacol 34:351–358Google Scholar
  6. Beutler E, Duron O, Kelly BM (1963) Improved method for determination of blood glutathione. J Lab Clin Med 61:882–888Google Scholar
  7. Borrego-Soto G, Ortiz-López R, Rojas-Martínez A (2015) Ionizing radiation-induced DNA injury and damage detection in patients with breast cancer. Genet Mol Biol 38:420–432CrossRefGoogle Scholar
  8. Brown GC (1999) Nitric oxide and mitochondrial respiration. Biochim Biophys Acta 141:351–369CrossRefGoogle Scholar
  9. Brown GC (2001) Regulation of mitochondrial respiration by nitric oxide inhibition of cytochrome c oxidase. Biochim Biophys Acta 1504:46–57CrossRefGoogle Scholar
  10. Brown GC, Borutaite V (2004) Inhibition of mitochondrial respiratory complex I by nitric oxide, peroxynitrite and S-nitrosothiols. Biochim Biophys Acta 1658:44–49CrossRefGoogle Scholar
  11. Cassina A, Radi R (1996) Different inhibitory actions of NO and peroxynitrite on mitochondrial electron transport. Arch Biochem Biophys 328:309–316CrossRefGoogle Scholar
  12. Christianson DW (1997) Review structural chemistry and biology of manganese metalloenzymes. Prog Biophys Mol Biol 67:217–252CrossRefGoogle Scholar
  13. Chtourou Y, Garoui EM, Boudawara T, Zeghal N (2013) Therapeutic efficacy of silymarin from milk thistle in reducing manganese-induced hepatic damage and apoptosis in rats. Human and Exper Toxicol 32:70–81CrossRefGoogle Scholar
  14. Du H, Yan SS (2010) Mitochondrial medicine for neurodegenerative diseases. Int J Biochem Cell Biol 42:560–572CrossRefGoogle Scholar
  15. El-Tahawy NA (2009) Curcumin attenuates gamma radiation induced intestinal damage in rats. Egypt J Rad Sci Applic 22:461–475Google Scholar
  16. Fang Y, Hu XH, Jia ZG, Xu MH, Guo ZY, Gao FH (2012) Tiron protects against UVB-induced senescence-like characteristics in human dermal fibroblasts by the inhibition of superoxide anion production and glutathione depletion. Australas J Dermatol 53:172–180CrossRefGoogle Scholar
  17. Fernandes J, Hao L, Bijli KM, Chandler JD, Orr M, Hu XY, Jones DP, Go YM (2017) Manganese stimulates mitochondrial H2O2 production in SH-SY5Y human neuroblastoma cells over physiologic as well as toxicologic range. Toxicol Sci 155:213–223CrossRefGoogle Scholar
  18. Fernández-Checa JC, N. Kaplowitz N, García-Ruiz C, Colell A (1998) Mitochondrial glutathione: importance and transport. Semin Liver Dis 18:389–401Google Scholar
  19. Fernsebner K, Zorn J, Kanawati B, Walker A, Michalke B (2014) Manganese leads to an increase in markers of oxidative stress as well as to a shift in the ratio of Fe(II)/(III) in rat brain tissue. Metallomics 6:921–931CrossRefGoogle Scholar
  20. Filosto M, Scarpelli M, Cotelli MS, Vielmi V, Todeschini A, Gregorelli V, Tonin P, Tomelleri G, Padovani A (2011) The role of mitochondria in neurodegenerative diseases. J Neurol 258:1763–1774CrossRefGoogle Scholar
  21. Gomez M, Domingo JL, Llobet JM, Corbella J (1991) Evaluation of the efficacy of various chelating agents on urinary excretion and tissue distribution of vanadium in rats. Toxicol Lett 57:227–234CrossRefGoogle Scholar
  22. Han D, Canali R, Garcia J, Aguilera R, Gallaher TK, Cadenas E (2005) Sites and mechanisms of aconitase inactivation by peroxynitrite: modulation by citrate and glutathione. Biochemistry 44:11986–11996CrossRefGoogle Scholar
  23. Han D, Cannali R, Rettorl DN, kaplowitz N (2003) Effect of glutathione depletion on sites and topology of superoxide and hydrogen peroxide production in mitochondria. Mol Pharmacol 64:1136–1144CrossRefGoogle Scholar
  24. Hargreaves I (2014) Coenzyme Q10 as a therapy for mitochondrial disease. Int J Biochem Cell Biol 49:105–111CrossRefGoogle Scholar
  25. Herscher LL, Krishna MC, Cook JA, Coleman CN, Biaglow JE, Tuttle SW, Gonzalez FJ, Mitchell JB (1994) Protection against SR4233 (tirapazamine) aerobic cytotoxicity by the metal chelators desferrioxamine and tiron. Int J Radiat Oncol Biol Phys 30:879–885CrossRefGoogle Scholar
  26. Iglesias DE, Bombicino SS, Valdez LB, Boveris A (2015) Nitric oxide interacts with mitochondrial complex III producing antimycin-like effects. Free Radic Biol Med 89:602–613CrossRefGoogle Scholar
  27. Ignarro LJ, Napoli C, Loscalzo J (2002) Nitric oxide donors and cardiovascular agents modulating the bioactivity of nitric oxide: an overview. Circ Res 90:21–28CrossRefGoogle Scholar
  28. Indravathi G, Kiran Kumari K, Devi BC (2014) Manganese induced hematological alterations in albino rats: reversal effect of alpha-tocopherol. Int J Innov Res Sci Eng Technol 3:14988–14999Google Scholar
  29. Islam MT (2017) Radiation interactions with biological systems. Int J Rad Biol 93:487–493CrossRefGoogle Scholar
  30. Jin H, Kanthasamy A, Ghosh A, Anantharama V, Kalyanaraman B, Kanthasamy AG (2014) Mitochondria-targeted antioxidants for treatment of Parkinson’s disease. Preclinical and clinical outcomes. Biochim Biophys Acta 1842:1282–1294CrossRefGoogle Scholar
  31. Kam WW, Banati RB (2013) Effects of ionizing radiation on mitochondria. Free Radic Biol Med 2013(65):607–619Google Scholar
  32. Kennedy MC, Emptage MH, Dreyer JL, Beinert H (1983) The role of iron in the activation–inactivation of aconitase. J Biol Chem 258:11098–11105Google Scholar
  33. Kwakye GF, Paoliello MM, Mukhopadhyay S, Bowman A, Aschner M (2015) Manganese-induced parkinsonism and Parkinson’s disease: shared and distinguishable features. Int J Environ Res Public Health 12:7519–7540CrossRefGoogle Scholar
  34. Layne E (1975) Spectrophotometric and turbidimetric methods for measuring proteins. Methods Enzymol 3:447–455CrossRefGoogle Scholar
  35. Lu J, Guo JH, Tu XL, Zhang C, Zhao M, Zhang QW, Gao FH (2016) Tiron inhibits UVB-induced AP-1 binding sites transcriptional activation on MMP-1 and MMP-3 promoters by MAPK signaling pathway in human dermal fibroblasts. PLoS One 11:e0159998CrossRefGoogle Scholar
  36. Malecki EA (2001) Manganese toxicity is associated with mitochondrial dysfunction and DNA fragmentation in rat primary striatal neurons. Brain Res Bulletin 55:225–228CrossRefGoogle Scholar
  37. Malthankar GV, White BK, Bhushan A, Daniels CK, Rodnick KJ, James CK, Lai1 JCK (2004) Differential lowering by manganese treatment of activities of glycolytic and tricarboxylic acid (TCA) cycle enzymes investigated in neuroblastoma and astrocytoma cells is associated with manganese-induced cell death. Neurochem Res 29:709–717Google Scholar
  38. McArdle F, Pattwell DM, Vasilaki A, McArdle A, Jackson MJ (2005) Intracellular generation of reactive oxygen species by contracting skeletal muscle cells. Free Radic Biol Med 39:651–657CrossRefGoogle Scholar
  39. Miranda KM, Espey MG, Wink DA (2001) A rapid simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide 5:62–71CrossRefGoogle Scholar
  40. Morgan A, Ibrahim MA, Galal MK, Ogaly HA, Abd-Elsalam RM (2018) Innovative perception on using tiron to modulate the hepatotoxicity induced by titanium dioxide nanoparticles in male rats. Biomed Pharmacother 103:553–561CrossRefGoogle Scholar
  41. Nirala SK, Bhadauria M, Upadhyay AK, Mathur R, Mathur A (2009) Reversal of effects of intraperitoneally administered beryllium nitrate by tiron and CaNa3DTPA alone or in combination with alpha-tocopherol. Indian J Exp Biol 47:955–963Google Scholar
  42. Nirala SK, Bhadauria M, Mathur R, Mathur A (2008) Influence of alpha-tocopherol, propolis and piperine on therapeutic potential of tiferron against beryllium induced toxic manifestations. J Appl Toxicol 28:44–54CrossRefGoogle Scholar
  43. Nishikimi M, Rao NA, Yagi K (1972) The occurrence of superoxide anion in the reaction of reduced phenazine methosulfate and molecular oxygen. Biochem Biophys Res Communicat 46:849–854CrossRefGoogle Scholar
  44. Oyewole AO, Wilmot MC, Fowler M, Birch-Machin MA (2014) Comparing the effects of mitochondrial targeted and localized antioxidants with cellular antioxidants in human skin cells exposed to UVA and hydrogen peroxide. FASEB J 28:485–494CrossRefGoogle Scholar
  45. Paglia DE, Valentine WN (1967) Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Laborat Clin Med 70:158–169Google Scholar
  46. Peres TV, Schettinger MR, Chen P, Carvalho F, Avila DS, Bowman AB, Aschner M (2016) Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies. BMC Pharmacol Toxicol 17(57)Google Scholar
  47. Peskin AV, Labas YA, Tikhonov AN (1998) Superoxide radical production by sponges Sycon sp. FEBS Lett 434:201–204CrossRefGoogle Scholar
  48. Rines AK, Ardehali H (2013) Transition metals and mitochondrial metabolism in the heart. J Mol Cell Cardiol 55:50–57CrossRefGoogle Scholar
  49. Sarti PA, Giuffre MC, Barone E, Forte D, Mastronicola D, Brunori M (2003) Nitric oxide and cytochrome oxidase: reaction mechanisms from the enzyme to the cell. Free Radic Biol Med 34:509–520CrossRefGoogle Scholar
  50. Senior AE (1988) ATP synthesis by oxidative phosphorylation. Physiol Rev 68:177–231CrossRefGoogle Scholar
  51. Sharma P, Ahmad Shah Z, Kumar A, Islam F, Mishra KP (2007) Role of combined administration of tiron and glutathione against aluminum-induced oxidative stress in rat brain. J Trace Elem Med Biol 21:63–70CrossRefGoogle Scholar
  52. Sharma P, Johri S, Shukla S (2000) Beryllium-induced toxicity and its prevention by treatment with chelating agents. J Appl Toxicol 20:313–318CrossRefGoogle Scholar
  53. Silveira LR, Pereira-Da-Silva L, Juel C, Hellsten Y (2003) Formation of hydrogen peroxide and nitric oxide in rat skeletal muscle cells during contractions. Free Radic Biol Med 35:455–464CrossRefGoogle Scholar
  54. Son EW, Lee SRHS, Choi HS, Koo HJ, Huh JE, Kim MH, Pyo S (2007) Effects of supplementation with higher levels of manganese and magnesium on immune function. Arch Pharm Res 30:749Google Scholar
  55. Spitz DR, Azzam EI, Li JJ, Gius D (2004) Metabolic oxidation/reduction reactions and cellular responses to ionizing radiation: a unifying concept in stress response biology. Cancer Metastasis Rev 23:311–322CrossRefGoogle Scholar
  56. Stiburek L, Vesela K, Hansikova H, Hulkova H, Zeman J (2009) Loss of function of Sco1 and its interaction with cytochrome c oxidase. Am J Physiol Cell Physiol 296:C1218–C1226CrossRefGoogle Scholar
  57. Storrie B, Madden EA (1990) Isolation of subcellular organelles. Methods Enzymol 182:203–225CrossRefGoogle Scholar
  58. Supinski G, Nethery D, Stofan D, DiMarco A (1999) Extracellular calcium modulates generation of reactive oxygen species by the contracting diaphragm. J Appl Physiol 87:2177–2185CrossRefGoogle Scholar
  59. Taiwo FA (2008) Mechanism of tiron as scavenger of superoxide ions and free electrons. Spectroscopy 22:491–498CrossRefGoogle Scholar
  60. Tong WH, Rouault T (2007) A metabolic regulation of citrate and iron by aconitases: role of iron–sulfur cluster biogenesis. Biometals 20:549–564CrossRefGoogle Scholar
  61. Wang C, Qi S, Liu C, Yang A, Fu W, Quan C, Duan P, Yu T, Yang K (2017) Mitochondrial dysfunction and Ca2+ overload in injured Sertoli cells exposed to bisphenol A. Environ Toxicol 32:823–831CrossRefGoogle Scholar
  62. Yoshida T, Goto SM, Kawakatsu MY, Urata YTS, Li TS (2012) Mitochondrial dysfunction, a probable cause of persistent oxidative stress after exposure to ionizing radiation. Free Radic Res 46:147–153CrossRefGoogle Scholar
  63. Yoshioka T, Kawada K, Shimada T, Mori M (1979) Lipid peroxidation in maternal and cord blood and protective mechanisms against activated oxygen toxicity in the blood. Am J Obstet Gynecol 135:372–376CrossRefGoogle Scholar
  64. Yousefi BV, Sadeghi L, Shirani K, Malekirad AA, Rezaei M (2014) The toxic effect of manganese on the acetylcholinesterase activity in rat brains. J Toxicol 2014:1–4Google Scholar
  65. Zhang S, Fu J, Z Zhou Z (2004) In vitro effect of manganese chloride exposure on reactive oxygen species generation and respiratory chain complexes activities of mitochondria isolated from rat brain. Toxicol in Vitro 18:71–77CrossRefGoogle Scholar
  66. Zhang S, Zhou Z, Fu J (2003) Effect of manganese chloride exposure on liver and brain mitochondria function in rats. Environ Res 93:149–157CrossRefGoogle Scholar
  67. Zheng W, Jiang YM, Zhang Y, JiangW WX, Cowan DM (2009) Chelation therapy of manganese intoxication with para-aminosalicylic acid (PAS) in Sprague-Dawley rats. Neurotoxicology 30:240–248CrossRefGoogle Scholar
  68. Zheng W, Ren S, Graziano JH (1998) Manganese inhibits mitochondrial aconitase: a mechanism of manganese neurotoxicity. Brain Res 799:334–342CrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  • Nadia Abdel-Magied
    • 1
    Email author
  • Nahed Abdel-Aziz
    • 1
  • Shereen M. Shedid
    • 1
  • Amal G. Ahmed
    • 1
  1. 1.Department of Radiation Biology, Atomic Energy AuthorityNational Center for Radiation Research and Technology (NCRRT)Nasr CityEgypt

Personalised recommendations