Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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Mitoquinol mesylate (MITOQ) attenuates diethyl nitrosamine-induced hepatocellular carcinoma through modulation of mitochondrial antioxidant defense systems

  • Adisa, Rahmat Adetutu (Laboratories for Bio-membranes and Cancer Research, Department of Biochemistry, Faculty of Basic Medical Sciences, College of Medicine of University of Lagos) ;
  • Sulaimon, Lateef Adegboyega (Laboratories for Bio-membranes and Cancer Research, Department of Biochemistry, Faculty of Basic Medical Sciences, College of Medicine of University of Lagos) ;
  • Okeke, Ebele Geraldine (Laboratories for Bio-membranes and Cancer Research, Department of Biochemistry, Faculty of Basic Medical Sciences, College of Medicine of University of Lagos) ;
  • Ariyo, Olubukola Christianah (Laboratories for Bio-membranes and Cancer Research, Department of Biochemistry, Faculty of Basic Medical Sciences, College of Medicine of University of Lagos) ;
  • Abdulkareem, Fatimah B. (Department of Anatomic and Molecular Pathology, Faculty of Basic Medical Sciences,, College of Medicine of University of Lagos)
  • Received : 2021.02.15
  • Accepted : 2021.09.07
  • Published : 2022.07.15
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Abstract

Diethyl nitrosamine (DEN) induced cirrhosis-hepatocellular carcinoma (HCC) model associates cancer progression with oxidative stress and mitochondrial dysfunction. This study investigated the effects of mitoquinol mesylate (MitoQ), a mitochondrial-targeted antioxidant on DEN-induced oxidative damage in HCC Wistar rats. Fifty male Wistar rats were randomly divided into fve groups. Healthy control, DEN, and MitoQ groups were orally administered exactly 10 mg/kg of distilled water, DEN, and MitoQ, respectively for 16 weeks. Animals in the MitoQ+DEN group were pre-treated with MitoQ for a week followed by co-administration of 10 mg/kg each of MitoQ and DEN. DEN+MitoQ group received DEN for 8 weeks, then co-administration of 10 mg/kg each of DEN and MitoQ till the end of 16th week. Survival index, tumour incidence, hematological profile, liver function indices, lipid profile, mitochondrial membrane composition, mitochondrial respiratory enzymes, and antioxidant defense status in both mitochondrial and post-mitochondrial fractions plus expression of antioxidant genes were assessed. In MitoQ+DEN and DEN+MitoQ groups, 80% survival occurred while tumour incidence decreased by 60% and 40% respectively, compared to the DEN-only treated group. Similarly, MitoQ-administered groups showed a significant (p < 0.05) decrease in the activities of liver function enzymes while hemoglobin concentration, red blood cell count, and packed cell volume were significantly elevated compared to the DEN-only treated group. Administration of MitoQ to the DEN-intoxicated groups successfully enhanced the activities of mitochondrial F1F0-ATPase and succinate dehydrogenase; and up-regulated the expression and activities of SOD2, CAT, and GPx1. Macroscopic and microscopic features indicated a reversal of DEN-induced hepatocellular degeneration in the MitoQ +DEN and DEN+MitoQ groups. These data revealed that MitoQ intervention attenuated DEN-induced oxidative stress through modulation of mitochondrial antioxidant defense systems and alleviated the burden of HCC as a chemotherapeutic agent.

Keywords

Acknowledgement

The authors appreciate the technical assistance of Mr. Chijioke Chimeremeze of the Department of Pharmacology, Faculty of Basic Medical Sciences, College of Medicine, University of Lagos, Lagos, Nigeria.

References

  1. Wei KR, Yu X, Zheng RS, Peng XB, Zhang SW, Ji MF, Liang ZH, Ou ZX, Chen WQ (2014) Incidence and mortality of liver cancer in China, 2010. Chin J Cancer 33:388-394. https://doi.org/10.5732/cjc.014.10088
  2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394-424. https://doi.org/10.3322/caac.21492
  3. Maryam M, Ali S, Abdollah M-H, Farhad T, Fatemeh H, Hamid S (2016) The incidence and mortality of liver cancer and its relationship with development in Asia. Asian Pac J Cancer Prev 17:2047. https://doi.org/10.7314/apjcp.2016.17.4.2041
  4. Jones PD, Diaz C, Wang D, Gonzalez-Diaz J, Martin P, Kobetz E (2018) The impact of race on survival after hepatocellular carcinoma in a diverse american population. Dig Dis Sci 63:515-528. https://doi.org/10.1007/s10620-017-4869-3
  5. Boffetta P, Boccia S, La Vecchia C (2014) A quick guide to cancer epidemiology. Springer briefs in cancer research. Springer, Berlin. https://doi.org/10.1007/978-3-319-05068-3_4
  6. Cao Y, Giovannucci EL (2016) Alcohol as a risk factor for cancer. Semin Oncol Nurs 32:325-331. https://doi.org/10.1016/j.soncn.2016.05.012
  7. Lindberg MC (1992) Hepatobiliary complications of oral contraceptives. J Gen Intern Med 7:199-209. https://doi.org/10.1007/BF02598014
  8. Kew MC (2009) Hepatic iron overload and hepatocellular carcinoma. In: hepatocellular carcinoma: translational research in hepatocarcinogenesis. Cancer Lett 286:38-43. https://doi.org/10.1016/j.canlet.2008.11.001
  9. Ghosh A, Ghosh D, Sarkar S, Mandal AK, Choudhury ST, Das N (2012) Anticarcinogenic activity of nano encapsulated quercetin in combating diethyl nitrosamine-induced hepatocarcinoma in rats. Eur J Cancer Prev 21:32-41. https://doi.org/10.1097/CEJ.0b013e32834a7e2b
  10. Loeppky RN, Hansen JJ, Keefer LK (1983) Reducing nitrosamine contamination in cutting fluids. Food Chem Toxicol 5:607-613. https://doi.org/10.1016/0278-6915(83)90148-5
  11. Tabone M, Pellicano R (2006) Prevention of intrahepatic hepatocarcinoma recurrence in patients with viral cirrhosis: two potential options. Minerva Gastroenterol Dietol 52:47-52
  12. Singh D, Singh M, Yadava E, Falls N, Dangi DS, Kumar V, Ramteke PW, Verma A (2018) Attenuation of diethyl nitrosamine (DEN)-induced hepatic cancer in an experimental model of Wistar rats by Carissa carandas embedded silver nanoparticles. Biomed Pharmacother 108:757-765. https://doi.org/10.1016/j.biopha.2018.09.066
  13. Beckham TH, Lu P, Jones EE, Marrison T, Lewis CS, Cheng JC, Ramshesh VK, Beeson G, Beeson CC, Drake RR, Bielawska A, Bielawski J, Szulc ZM, Ogretmen B, Norris JS, Liu X (2013) LCL124, a cationic analog of ceramide, selectively induces pancreatic cancer cell death by accumulating in mitochondria. J Pharmacol Exp Ther 344:167-178. https://doi.org/10.1124/jpet.112.199216
  14. Murphy MP, Hartley RC (2018) Mitochondria as a therapeutic target for common pathologies. Nat Rev Drug Discov 17:865-886. https://doi.org/10.1038/nrd.2018.174
  15. Szeto HH (2006) Mitochondria-targeted peptide antioxidants: novel neuroprotective agents. AAPS J8:E521-531. https://doi.org/10.1208/aapsj080362
  16. Chouchani ET, Methner C, Nadtochiy SM, Logan A, Pell VR, Ding S, James AM, Cocheme HM, Reinhold J, Lilley KS et al (2013) Cardioprotection by s-nitrosation of a cysteine switch on mitochondrial complex I. Nat Med 19:753-759. https://doi.org/10.1038/nm.3212
  17. Dare AJ, Bolton EA, Pettigrew GJ, Bradley JA, Saeb-Parsy K, Murphy MP (2015) Protection against renalischemia-reperfusion injury in vivo by the mitochondria-targeted antioxidant MitoQ. Redox Biol 5:163-168. https://doi.org/10.1016/j.redox.2015.04.008
  18. Sun C, Liu X, Di C, Wang Z, Mi X, Liu Y, Zhao Q, Mao A, Chen W, Gan L, Zhang H (2017) MitoQ regulates autophagy by inducing a pseudo-mitochondrial membrane potential. Autophagy 13:730-738. https://doi.org/10.1080/15548627.2017.1280219
  19. Turkseven S, Bolognesi M, Brocca A, Pesce P, Angeli P, Di Pascoli M (2020) Mitochondria-targeted antioxidant mitoquinone attenuates liver infammation and fibrosis in cirrhotic rats. Am J Physiol Gastrointest Liver Physiol 318:G298-G304. https://doi.org/10.1152/ajpgi.00135.2019
  20. Chacko BK, Reily C, Srivastava A, Johnson MS, Ye Y, Ulasova E, Agarwal A, Zinn KR, Murphy MP, Kalyanaraman B et al (2010) Prevention of diabetic nephropathy in ins2(+/)(-)(akitaj) mice by the mitochondria-targeted therapy MitoQ. Biochem J 432:9-19. https://doi.org/10.1042/BJ20100308
  21. Gonzalez Y, Aryal B, Chehab L, Rao VA (2014) Atg-7 and Keap-1 dependent autophagy protects breast cancer cell lines against mitoquinone induced oxidative stress. Oncotarget 5:6. https://doi.org/10.18632/oncotarget.1715
  22. Snow BJ, Rolfe FL, Lockhart MM, Frampton CM, O'Sullivan JD, Fung V, Smith RA, Murphy MP, Taylor KM (2010) A double-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as a disease-modifying therapy in Parkinson's disease. Mov Disord 25:1670-1674. https://doi.org/10.1002/mds.23148
  23. Gane EJ, Weilert F, Orr DW, Keogh GF, Gibson M, Lockhart MM, Frampton CM, Taylor KM, Smith RA, Murphy MP (2010) The mitochondria-targeted anti-oxidant mitoquinone decreases liver damage in a phase II study of hepatitis c patients. Liver Int 30:1019-1026. https://doi.org/10.1111/j.1478-3231.2010.02250.x
  24. Rossman MJ, Santos-Parker JR, Steward CAC, Bispham NZ, Cuevas LM, Rosenberg HL, Woodward KA, Chonchol M, GiosciaRyan RA, Murphy MP et al (2018) Chronic supplementation with a mitochondrial antioxidant (MitoQ) improves vascular function in healthy older adults. Hypertension 71:1056-1063. https://doi.org/10.1161/HYPERTENSIONAHA.117.10787
  25. Asin-Cayuela J, Manas AR, James AM, Smith RA, Murphy MP (2004) Fine-tuning the hydrophobicity of a mitochondria-targeted antioxidant. FEBS Lett 571:9-16 https://doi.org/10.1016/j.febslet.2004.06.045
  26. Flewelling RF, Hubbell WL (1986) The membrane dipole potential in a total membrane potential model. Applications to hydrophobic ion interactions with membranes. Biophys J 49:541-552. https://doi.org/10.1016/S0006-3495(86)83664-5
  27. Finichiu PG, James AM, Larsen L, Smith RA, Murphy MP (2013) Mitochondrial accumulation of a lipophilic cation conjugated to an ionizable group depends on membrane potential, ph gradient, and pk(a): implications for the design of mitochondrial probes and therapies. J Bioenerg Biomembr 45:165-173. https://doi.org/10.1007/s10863-012-9493-5
  28. Rodriguez-Cuenca S, Cocheme HM, Logan A, Abakumova I, Prime TA, Rose C, Vidal-Puig A, SmithAC RDC, Fearnley IM et al (2010) Consequences of long-term oral administration of the mitochondria-targeted antioxidant MitoQ to wild-type mice. Free Radic Biol Med 48:161-172. https://doi.org/10.1016/j.freeradbiomed.2009.10.039
  29. Wani WY, Gudup S, Sunkaria A, Bal A, Singh PP, Kandimalla RJ, Sharma DR, Gill KD (2011) Protective effcacy of mitochondrial-targeted antioxidant MitoQ against dichlorvos induced oxidative stress and cell death in rat brain. Neuropharmacology 61:1193-1201. https://doi.org/10.1016/j.neuropharm.2011.07.008
  30. Reily C, Mitchell T, Chacko BK, Benavides G, Murphy MP, Darley-Usmar V (2013) Mitochondrially targeted compounds and their impact on cellular bioenergetics. Redox Biol 1:86-93. https://doi.org/10.1016/j.redox.2012.11.009
  31. Pokrzywinski KL, Biel TG, Kryndushkin D, Rao VA (2016) Therapeutic targeting of the mitochondria initiates excessive superoxide production and mitochondrial depolarization causing decreased mtDNA integrity. PLoS ONE 11:e0168283. https://doi.org/10.1371/journal.pone.0168283
  32. Paradies G, Paradies V, Ruggiero FM, Petrosillo G (2014) Oxidative stress, cardiolipin and mitochondrial dysfunction in nonalcoholic fatty liver disease. World J Gastroenterol 20:14205-14218. https://doi.org/10.3748/wjg.v20.i39.14205
  33. Robertson CL, Scafdi S, McKenna MC, Fiskum G (2009) Mitochondrial mechanisms of cell death and neuroprotection in pediatric ischemic and traumatic brain injury. Exp Neurol 218:371-380. https://doi.org/10.1016/j.expneurol.2009.04.030
  34. Institute of Laboratory Animal Resources (U.S.) & National Institutes of Health (U.S.) (1985) Guide for the careand use of laboratory animals. U.S. Dept. of Health and Human Services, Public Health Service, NationalInstitutes of Health, NIH publication, Bethesda, Md, pp 85-23. https://www.worldcat.org/title/guidefor-the-care-and-use-of-laboratory-animals/oclc/14588475
  35. Ke-Qin X, Cui-Li Z, Tao Z, Xiu-Lan Z, Li-Hua Y, Zhen PZ (2012) Protective effects of garlic oil on hepatocellular carcinoma induced by N-nitrosodiethylamine in rats. Int J Biol Sci 8:363-374. https://doi.org/10.7150/ijbs.3796
  36. Johnson D, Lardy HA (1967) Isolation of liver or kidney mitochondria. Methods Enzymol 10:94-96 https://doi.org/10.1016/0076-6879(67)10018-9
  37. Chen PS, Toribara TY, Warner H (1956) Micro-determination of phosphorus. Analyt Chem 28:1756-1758. https://doi.org/10.1021/ac60119a033
  38. Lowry OH, Rosenbrough NJ, Farr AL, Randall RJ (1951) Protein measurement with Folin phenol reagent. J Biol Chem 193:265-275 https://doi.org/10.1016/S0021-9258(19)52451-6
  39. King TE (1967) Preparation of succinate dehydrogenase and reconstitution of succinate oxidase. Methods Enzymol 10:322-331. https://doi.org/10.1016/0076-6879(67)10061-X
  40. Lardy HA, Wellman H (1953) The catalyst effect of 2,4-dinitrophenol on adenosine trisphosphate hydrolysis by cell particles and soluble enzymes. J Biol Chem 201:357-370 https://doi.org/10.1016/S0021-9258(18)71378-1
  41. Misra HP, Fridovich I (1972) The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem 247:3170-3175 https://doi.org/10.1016/S0021-9258(19)45228-9
  42. Geller BL, Winge DR (1983) A method for distinguishing Cu, Zn-and Mn-containing superoxide dismutases. Anal Biochem 128:86-92. https://doi.org/10.1016/0003-2697(83)90348-2
  43. Sedlak J, Lindsay RH (1968) Estimation of total protein-bound and non-protein sulfhydryl groups in tissue with Ellman's reagent. Anal Biochem 25:192-205. https://doi.org/10.1016/0003-2697(68)90092-4
  44. Jollow DJ, Mitchell JR, Zampaglione N, Gillete JR (1974) Bromobenzene-induced liver necrosis: protective role of glutathione and evidence for 3, 4-bromobenzene oxide as the hepatotoxic metabolite. Pharmacology 11:151-169. https://doi.org/10.1159/000136485
  45. Sinha KA (1971) Colorimetric assay of catalase. Anal Biochem 47:389-394. https://doi.org/10.1016/0003-2697(72)90132-7
  46. Mohandas J, Marshall JJ, Duggin GG, Horvath JS, Tiller DJ (1984) Differential distribution of glutathione and glutathionerelated enzymes in rabbit kidney: possible implications in analgesic nephropathy. Biochem Pharmacol 33:1801-1807 https://doi.org/10.1016/0006-2952(84)90353-8
  47. Buege JA, Aust SD (1978) Microsomal lipid peroxidation. Methods Enzymol 52:302-310. https://doi.org/10.1016/s0076-6879(78)52032-6
  48. Smith RA, Murphy MP (2010) Animal and human studies with the mitochondria-targeted antioxidant MitoQ. Ann NY Acad Sci 1201:96-103. https://doi.org/10.1111/j.1749-6632.2010.05627.x
  49. Snow BJ, Rolfe FL, Lockhart MM, Frampton CM, O'Sullivan JD, Fung V et al (2010) A double-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as a diseasemodifying therapy in Parkinson's disease. Mov Disord 25:670-1674. https://doi.org/10.1002/mds.23148
  50. Chacko BK, Srivastava A, Johnson MS, Benavides GA, Chang MJ, Ye Y, Jhala N, Murphy MP, Kalyanaraman B, Darley-Usmar VM (2011) Mitochondria-targeted ubiquinone (mitoq) decreases ethanol-dependent micro and macro hepatosteatosis. Hepatology 54:153-163. https://doi.org/10.1002/hep.24377
  51. Rehman H, Liu Q, Krishnasamy Y, Shi Z, Ramshesh VK, Haque K, Schnellmann RG, Murphy MP, Lemasters JJ, Rockey DC, Zhong Z (2016) The mitochondria-targeted antioxidant MitoQ attenuates liver fbrosis in mice. Int J Physiol Pathophysiol Pharmacol 8(1):14-27. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4859875/23/09/2021
  52. Chacko B, Reily C, Srivastava A, Johnson MS, Ulasova E, Agarwal A et al (2010) Prevention of diabetic nephropathy in Ins2þ/-Akita J mice by the mitochondria-targeted therapy Mito Q. Biochem J 432:9-19. https://doi.org/10.1042/BJ20100308
  53. Chandran K, Aggarwal D, Migrino RQ, Joseph J, McAllister D, Konorev EA et al (2009) Doxorubicin inactivates myocardial cytochrome c oxidase in rats: cardioprotection by Mito-Q. Biophys J 96:1388-1398. https://doi.org/10.1016/j.bpj.2008.10.042
  54. Gane EJ, Weilert F, Orr DW, Keogh GF, Gibson M, Lockhart MM et al (2010) The mitochondria-targeted antioxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients. Liver Int 30:1019-1026. https://doi.org/10.1111/j.1478-3231.2010.02250.x
  55. Escribano-Lopez I, Diaz-Morales N, Rovira-Llopis S, de Maranon AM, Orden S, Alvarez A, Banuls C, Rocha M, Murphy MP, Hernandez-Mijares A, Victor VM (2016) The mitochondria-targeted antioxidant MitoQ modulates oxidative stress, infammation, and leukocyte-endothelium interactions in leukocytes isolated from type 2 diabetic patients. Redox Biol 10:200-205. https://doi.org/10.1016/j.redox.2016.10.017
  56. Choo SP, Tan WL, Goh BK, Tai WM, Zhu AX (2016) Comparison of hepatocellular carcinoma in eastern versus western populations. Cancer 122:3430-3446. https://doi.org/10.1002/cncr.30237
  57. Verna L, Whysner J, Williams GM (1996) N-nitrosodiethylamine mechanistic data and risk assessment: bioactivation, DNA-adduct formation, mutagenicity, and tumor initiation. Pharmacol Ther 71:57-81. https://doi.org/10.1016/0163-7258(96)00062-9
  58. Liu Y, Liu M, Li B, Zhao JL, Zhang CP, Lin LQ, Chen HS, Zhang SJ, Jin JC, Wang L, Li LJ, Liu JR (2010) Fresh raspberry phytochemical extract inhibits hepatic lesion in a Wistar rat model. Nutr Metabol 7:84. https://doi.org/10.1186/1743-7075-7-8484
  59. Wallace DC, Fan W, Procaccio V (2010) Mitochondrial energetics and therapeutics. Annu Rev Pathol 5:297-348. https://doi.org/10.1146/annurev.pathol.4.110807.092314
  60. Hsu C-C, Lee H-S, Wei Y-H (2013) Mitochondrial DNA alterations and mitochondrial dysfunction in the progression of hepatocellular carcinoma. World J Gastroenterol 19:8880-8886. https://doi.org/10.3748/wjg.v19.i47.8880
  61. Duca FA, Cote CD, Rasmussen BA, Zadeh-Tahmasebi M, Rutter GA, Filippi BM, Lam TKT (2015) Metformin activates a duodenal AMPK-dependent pathway to lower hepatic glucose production in rats. Nat Med 21:506-511. https://doi.org/10.1038/nm.3787
  62. Sun X, Wang Z, Zhai S, Cheng Y, Liu J, Liu B (2013) In vitro cytotoxicity of silver nanoparticles in primary rat hepatic stellate cells. Mol Med Rep 8:1365-1372. https://doi.org/10.3892/mmr.2013.1683
  63. Wang B, Fu J, Yu T, Xu A, Qin W, Yang Z, Chen Y, Wang H (2018) Contradictory effects of mitochondria- and non-mitochondria-targeted antioxidants on hepatocarcinogenesis by altering DNA repair. Hepatology 67:623. https://doi.org/10.1002/hep.29518
  64. Cocheme HM, Kelso GF, James AM et al (2007) Mitochondrial targeting of quinones: therapeutic implications. Mitochondrion 7S:S94-S102 https://doi.org/10.1016/j.mito.2007.02.007
  65. Paltrinieri S (2014) The diagnostic approach to anemia in the dog and cat. J Hellenic Vet Med Soc 65:149-164. https://doi.org/10.1111/anae.12918
  66. Venkatesh R, Kalaivani K (2016) Effect of Solanum villosum (Mill.) Extract and its silver nanoparticles on hematopoietic system of diethyl nitrosamine-induced hepatocellular carcinoma in rats. Inn. J Health Sci 5: 13-16. https://innovareacademics.in/journals/index.php/ijhs/article/view/15459/23/9/2021
  67. Wolf CR Jr, Harrelson CR, Nastainezyk WG, Philpot WM, Kalyanaraman RMB, Mason RP (1980) Metabolism of carbon tetrachloride in hepatic microsomes and reconstituted monooxygenase systems and its relationship to lipid peroxidation. Mol Pharmacol 18:553-558
  68. Singh BN, Singh BR, Sarma BK, Singh HB (2009) Potential chemoprevention of N-nitrosodiethylamine-induced hepatocarcinogenesis by polyphenolics from Acacia nilotica bark. Chem Biol Interact 181:20-28. https://doi.org/10.1016/j.cbi.2009.05.007
  69. Glory DM, Thiruvengadam D (2012) Potential chemopreventive role chrysin against n-nitrosodiethylamine-induced hepatocellular carcinoma in rats. Biomed Prev Nutr 2:106-112. https://doi.org/10.2174/1871520621666210203102854
  70. Dhanasekaran M, Baskar AA, Ignacimuthu S, Agastian P, Duraipandiyan V (2009) Chemopreventive potential of epoxy clerodane diterpene from Tinospora cordifolia against diethyl nitrosamine-induced hepatocellular carcinoma. Invest New Drugs 27:347-355. https://doi.org/10.1007/s10637-008-9181-9
  71. Roy SR, Gadad PC (2016) Efect of β-asarone on diethylnitrosamine-induced hepatocellular carcinoma in rats. Indian J Health Sci 9:82-88. https://doi.org/10.4103/2349-5006.183687
  72. Kumar SR, Kumar SV, Rajkapoor B, Pravin N, Mahendiran D (2016) Chemopreventive effect of Indigoferalinnaeiextract against diethyl nitrosamine induced hepatocarcinogenesis in rats. J Appl Pharm Sci 6:199-209. https://doi.org/10.7324/JAPS.2016.601131
  73. Cheng G, Zielonka J, McAllister DM, Mackinnon AC Jr, Joseph J, Dwinell MB, Kalyanaraman B (2013) Mitochondria-targeted vitamin E analogs inhibit breast cancer cell energy metabolism and promote cell death. BMC Cancer 13:285. https://doi.org/10.1186/1471-2407-13-285
  74. Smith JA, Park S, Krause JS, Banik NL (2013) Oxidative stress, DNA damage, and the telomeric complex as therapeutic targets in acute neurodegeneration. Neurochem Int 62:764-775. https://doi.org/10.1016/j.neuint.2013.02.013
  75. Ansari MA, Roberts KN, Schef SW (2008) A time course of contusion-induced oxidative stress and synaptic proteins in cortex in a rat model of TBI. J Neurotrauma 25:513-526. https://doi.org/10.1089/neu.2007.0451
  76. Shetty S, Kumar R, Bharati S (2019) Mito-TEMPO, a mitochondria-targeted antioxidant, prevents N-nitrosodiethylamine induced hepatocarcinogenesis in mice. Free Radical Biol Med 136:76-86. https://doi.org/10.1016/j.freeradbiomed.2019.03.037
  77. Rodriguez-Cuenca S et al (2010) Consequences of long-term oral administration of the mitochondria-targeted antioxidant MitoQ to wild-type mice. Free Rad Biol Med 48:161-172. https://doi.org/10.1016/j.freeradbiomed.2009.10.039
  78. Fink BD et al (2014) A mitochondrial-targeted coenzyme Q analog prevents weight gain and ameliorates hepatic dysfunction in high-fat-fed mice. J Pharmacol Exp Ther 351:699-708. https://doi.org/10.1124/jpet.114.219329
  79. Canuto RA, Biocca ME, Muzio G, Dianzani MU (1989) Fatty acid composition of phospholipids in mitochondria and microsomes during diethylnitrosamine carcinogenesis in rat liver. Cell Biochem Funct 7:11-19. https://doi.org/10.1002/cbf.290070104
  80. Adisa RA, Sulaimon LA (2017) Hepatic oxidative stress and mitochondrial membrane integrity in antimalarial-treated P. bergheiinfected mice. Acta Biochimica Polonica 64:485-491. https://doi.org/10.18388/abp.2016_1440
  81. Fouret G, Tolika E, Lecomte J, Bonafos B, Aoun M, Murphy MP, Ferreri C, Chatgilialoglu C, Dubreucq E, Coudray C, Coudray CF (2015) The mitochondrial-targeted antioxidant, MitoQ, increases liver mitochondrial cardiolipin content in obesogenic diet-fed rats. Biochim Biophys Acta Bioenerg 1847:1025-1035. https://doi.org/10.1016/j.bbabio.2015.05.019