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Mitochondrial transplantation against gentamicin-induced toxicity on rat renal proximal tubular cells: the higher activity of female rat mitochondria

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Abstract

Mitochondrial dysfunction is a fundamental mechanism leading to drug nephrotoxicity, such as gentamicin-induced nephrotoxicity. Mitochondrial therapy (mitotherapy) or exogenous mitochondria transplantation is a method that can be used to replace dysfunctional mitochondria with healthy mitochondria. This method can help in the treatment of diseases related to mitochondria. In this research, we studied the transplantation effect of freshly isolated mitochondria on the toxicity induced by gentamicin on renal proximal tubular cells (RPTCs). Furthermore, possible gender-related effects on supplying exogenous rat kidney mitochondria on gentamicin-induced RPTCs were investigated. At first, the normality and proper functioning of fresh mitochondria were assessed by measuring mitochondrial succinate dehydrogenase activity (SDH) and changes in mitochondrial membrane potential (MMP). Then, the protective effects of mitochondrial transplantation against gentamicin-induced mitochondrial toxicity were evaluated through parameters including lactate dehydrogenase (LDH) leakiness, reactive oxygen species (ROS) production, lipid peroxidation (LPO) content, reduced glutathione (GSH) level, extracellular oxidized glutathione (GSSG) level, ATP level, MMP collapse, and caspase-3 activity. According to the statistical analysis, transplanting the healthy mitochondria decreased the cytotoxicity, ROS production, MMP collapse, LPO content, GSSG levels, and caspase-3 activity caused by gentamicin in RPTCs. Also, it has caused an increase in the level of ATP and GSH in the RPTCs. Furthermore, higher preventive effects were observed for the female group. According to the current study, mitochondrial transplantation is a potent therapeutic method in xenobiotic-caused nephrotoxicity.

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References

  • Andersson BS, Aw TY, Jones DP (1987) Mitochondrial transmembrane potential and pH gradient during anoxia. Am J Physiol 252(4 Pt 1):C349-355

    Article  CAS  PubMed  Google Scholar 

  • Ansari MY, Ball HC, Wase SJ, Novak K, Haqqi TM (2021) Lysosomal dysfunction in osteoarthritis and aged cartilage triggers apoptosis in chondrocytes through BAX mediated release of cytochrome c. Osteoarthritis Cartilage 29(1):100–112

    Article  CAS  PubMed  Google Scholar 

  • Baracca A, Sgarbi G, Solaini G, Lenaz G (2003) Rhodamine 123 as a probe of mitochondrial membrane potential: evaluation of proton flux through F(0) during ATP synthesis. Biochim Biophys Acta 1606(1–3):137–146

    Article  CAS  PubMed  Google Scholar 

  • Beach DC, Giroux E (1992) Inhibition of lipid peroxidation promoted by iron(III) and ascorbate. Arch Biochem Biophys 297(2):258–264

    Article  CAS  PubMed  Google Scholar 

  • Bereiter-Hahn J, Vöth M, Mai S, Jendrach M (2008) Structural implications of mitochondrial dynamics. Biotechnol J 3(6):765–780

    Article  CAS  PubMed  Google Scholar 

  • Boom SP, Gribnau FW, Russel FG (1992) Organic cation transport and cationic drug interactions in freshly isolated proximal tubular cells of the rat. J Pharmacol Exp Ther 263(2):445–450

    CAS  PubMed  Google Scholar 

  • Bradford MM (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

    Article  CAS  PubMed  Google Scholar 

  • Demarest TG, McCarthy MM (2015) Sex differences in mitochondrial (dys)function: implications for neuroprotection. J Bioenerg Biomembr 47(1–2):173–188

    Article  CAS  PubMed  Google Scholar 

  • Downes KJ, Hayes M, Fitzgerald JC, Pais GM, Liu J, Zane NR et al (2020) Mechanisms of antimicrobial-induced nephrotoxicity in children. J Antimicrob Chemother 75(1):1–13

    Article  CAS  PubMed  Google Scholar 

  • Everse J, Reich RM, Kaplan NO, Finn WD (1975) New instrument for rapid determination of activities of lactate dehydrogenase isoenzymes. Clin Chem 21(9):1277–1281

    Article  CAS  PubMed  Google Scholar 

  • Fujii F, Nodasaka Y, Nishimura G, Tamura M (2004) Anoxia induces matrix shrinkage accompanied by an increase in light scattering in isolated brain mitochondria. Brain Res 999(1):29–39

    Article  CAS  PubMed  Google Scholar 

  • Gomzikova MO, James V, Rizvanov AA (2021) Mitochondria donation by mesenchymal stem cells: current understanding and mitochondria transplantation strategies. Front Cell Dev Biol 9:653322

    Article  PubMed  PubMed Central  Google Scholar 

  • Hernández-Cruz EY, Amador-Martínez I, Aranda-Rivera AK, Cruz-Gregorio A, PedrazaChaverri J (2022) Renal damage induced by cadmium and its possible therapy by mitochondrial transplantation. Chem Biol Interact 36:1109961

    Google Scholar 

  • Hissin PJ, Hilf R (1976) A fluorometric method for determination of oxidized and reduced glutathione in tissues. Anal Biochem 74(1):214–226

    Article  CAS  PubMed  Google Scholar 

  • Hodiamont CJ, van den Broek AK, de Vroom SL, Prins JM, Mathôt RAA, van Hest RM (2022) Clinical pharmacokinetics of gentamicin in various patient populations and consequences for optimal dosing for gram-negative infections: an updated review. Clin Pharmacokinet 61(8):1075–1094

    Article  PubMed  PubMed Central  Google Scholar 

  • Hosseini MJ, Shaki F, Ghazi-Khansari M, Pourahmad J (2014) Toxicity of copper on isolated liver mitochondria: impairment at complexes I, II, and IV leads to increased ROS production. Cell Biochem Biophys 70(1):367–381

    Article  CAS  PubMed  Google Scholar 

  • Hosseinian S, Ali Pour P, Kheradvar A (2022) Prospects of mitochondrial transplantation in clinical medicine: aspirations and challenges. Mitochondrion 65:33–44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jabbari H, Roushandeh AM, Rostami MK, Razavi-Toosi MT, Shokrgozar MA, Jahanian-Najafabadi A et al (2020) Mitochondrial transplantation ameliorates ischemia/reperfusion-induced kidney injury in rat. Biochim Biophys Acta Mol Basis Dis 1866(8):165809

  • Justo R, Boada J, Frontera M, Oliver J, Bermúdez J, Gianotti M (2005) Gender dimorphism in rat liver mitochondrial oxidative metabolism and biogenesis. Am J Physiol Cell Physiol 289(2):C372-378

    Article  CAS  PubMed  Google Scholar 

  • Konari N, Nagaishi K, Kikuchi S, Fujimiya M (2019) Mitochondria transfer from mesenchymal stem cells structurally and functionally repairs renal proximal tubular epithelial cells in diabetic nephropathy in vivo. Sci Rep 9(1):5184

    Article  PubMed  PubMed Central  Google Scholar 

  • Kubat GB, Ozler M, Ulger O, Ekinci O, Atalay O, Celik E et al (2021) The effects of mesenchymal stem cell mitochondrial transplantation on doxorubicin-mediated nephrotoxicity in rats. J Biochem Mol Toxicol 35(1):e22612

    Article  CAS  PubMed  Google Scholar 

  • Lecoutre S, Clément K, Dugail I (2022) Obesity-related adipose tissue remodeling in the light of extracellular mitochondria transfer. Int J Mol Sci 23(2):632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lundin A (2000) Use of firefly luciferase in ATP-related assays of biomass, enzymes, and metabolites. Methods Enzymol 305:346–370

    Article  CAS  PubMed  Google Scholar 

  • Mahammad S, Parmryd I (2015) Cholesterol depletion using methyl-β-cyclodextrin. Methods in membrane lipids. Springer, pp 91–102

  • Meier O, Boucke K, Hammer SV, Keller S, Stidwill RP, Hemmi S et al (2002) Adenovirus triggers macropinocytosis and endosomal leakage together with its clathrin-mediated uptake. J Cell Biol 158(6):1119–1131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morales-Alvarez MC (2020) Nephrotoxicity of antimicrobials and antibiotics. Adv Chronic Kidney Dis 27(1):31–37

    Article  PubMed  Google Scholar 

  • Nascimento-Dos-Santos G, de-Souza-Ferreira E, Linden R, Galina A, Petrs-Silva H (2021) Mitotherapy: unraveling a promising treatment for disorders of the central nervous system and other systemic conditions. Cells 10(7):1827

  • O’Reilly M, Young L, Kirkwood NK, Richardson GP, Kros CJ, Moore AL (2019) Gentamicin affects the bioenergetics of isolated mitochondria and collapses the mitochondrial membrane potential in cochlear sensory hair cells. Front Cell Neurosci 13:416

    Article  PubMed  PubMed Central  Google Scholar 

  • Pan JS, Sheikh-Hamad D (2019) Mitochondrial dysfunction in acute kidney injury and sex-specific implications. Med Res Arch 7(2). https://doi.org/10.18103/mra.v7i2.1898

  • Popov LD (2021) One step forward: extracellular mitochondria transplantation. Cell Tissue Res 384(3):607–612

    Article  PubMed  Google Scholar 

  • Pourahmad J, Eskandari MR, Shakibaei R, Kamalinejad M (2010) A search for hepatoprotective activity of aqueous extract of Rhus coriaria L. against oxidative stress cytotoxicity. Food Chem Toxicol 48(3):854–858

    Article  CAS  PubMed  Google Scholar 

  • Pourahmad J, Mortada Y, Eskandari MR, Shahraki J (2011) Involvement of lysosomal labilisation and lysosomal/mitochondrial cross-talk in diclofenac induced hepatotoxicity. Iran J Pharm Res 10(4):877–887

    CAS  PubMed  PubMed Central  Google Scholar 

  • Preble JM, Pacak CA, Kondo H, MacKay AA, Cowan DB, McCully JD (2014) Rapid isolation and purification of mitochondria for transplantation by tissue dissociation and differential filtration. J vis Exp. https://doi.org/10.3791/51682(91):e51682

    Article  PubMed  PubMed Central  Google Scholar 

  • Quiros Y, Vicente-Vicente L, Morales AI, López-Novoa JM, López-Hernández FJ (2011) An integrative overview on the mechanisms underlying the renal tubular cytotoxicity of gentamicin. Toxicol Sci 119(2):245–256

    Article  CAS  PubMed  Google Scholar 

  • Randjelovic P, Veljkovic S, Stojiljkovic N, Sokolovic D, Ilic I (2017) Gentamicin nephrotoxicity in animals: current knowledge and future perspectives. Excli J 16:388–399

    PubMed  PubMed Central  Google Scholar 

  • Rezaei M, Salimi A, Taghidust M, Naserzadeh P, Goudarzi G, Seydi E et al (2014) A comparison of toxicity mechanisms of dust storm particles collected in the southwest of Iran on lung and skin using isolated mitochondria. Toxicol Environ Chem 96(5):814–830

    Article  CAS  Google Scholar 

  • Rieder H, Decker K (1984) Phagocytosis of hepatocyte mitochondria by rat Kupffer cells in vitro. Hoppe Seylers Z Physiol Chem 365(2):175–184

    Article  CAS  PubMed  Google Scholar 

  • Rodriguez-Cuenca S, Pujol E, Justo R, Frontera M, Oliver J, Gianotti M et al (2002) Sex-dependent thermogenesis, differences in mitochondrial morphology and function, and adrenergic response in brown adipose tissue. J Biol Chem 277(45):42958–42963

    Article  CAS  PubMed  Google Scholar 

  • Sahu BD, Tatireddy S, Koneru M, Borkar RM, Kumar JM, Kuncha M et al (2014) Naringin ameliorates gentamicin-induced nephrotoxicity and associated mitochondrial dysfunction, apoptosis and inflammation in rats: possible mechanism of nephroprotection. Toxicol Appl Pharmacol 277(1):8–20

    Article  CAS  PubMed  Google Scholar 

  • Sakahira H, Enari M, Nagata S (1998) Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis. Nature 391(6662):96–99

    Article  CAS  PubMed  Google Scholar 

  • Schafer JA, Watkins ML, Li L, Herter P, Haxelmans S, Schlatter E (1997) A simplified method for isolation of large numbers of defined nephron segments. Am J Physiol 273(4):F650-657

    CAS  PubMed  Google Scholar 

  • Sepand MR, Ghahremani MH, Razavi-Azarkhiavi K, Aghsami M, Rajabi J, Keshavarz-Bahaghighat H et al (2016) Ellagic acid confers protection against gentamicin-induced oxidative damage, mitochondrial dysfunction and apoptosis-related nephrotoxicity. J Pharm Pharmacol 68(9):1222–1232

    Article  CAS  PubMed  Google Scholar 

  • Servais H, Jossin Y, Van Bambeke F, Tulkens PM, Mingeot-Leclercq MP (2006) Gentamicin causes apoptosis at low concentrations in renal LLC-PK1 cells subjected to electroporation. Antimicrob Agents Chemother 50(4):1213–1221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shaki F, Hosseini MJ, Ghazi-Khansari M, Pourahmad J (2012) Toxicity of depleted uranium on isolated rat kidney mitochondria. BiochimBiophys Acta 1820(12):1940–1950

  • Ulger O, Kubat GB (2022) Therapeutic applications of mitochondrial transplantation. Biochimie 195:1–15

    Article  CAS  PubMed  Google Scholar 

  • Ulger O, Kubat GB, Cicek Z, Celik E, Atalay O, Suvay S et al (2021) The effects of mitochondrial transplantation in acetaminophen-induced liver toxicity in rats. Life Sci 279:119669

    Article  CAS  PubMed  Google Scholar 

  • Ventura-Clapier R, Moulin M, Piquereau J, Lemaire C, Mericskay M, Veksler V et al (2017) Mitochondria: a central target for sex differences in pathologies. Clin Sci (lond) 131(9):803–822

    Article  CAS  PubMed  Google Scholar 

  • Yu Z, Hou Y, Zhou W, Zhao Z, Liu Z, Fu A (2021) The effect of mitochondrial transplantation therapy from different gender on inhibiting cell proliferation of malignant melanoma. Int J Biol Sci 17(8):2021–2033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This research was supported by Shahid Beheshti University of Medical Sciences, Tehran, Iran.

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Authors and Affiliations

  1. Department of Toxicology and Pharmacology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, P.O. Box: 14155-6153, Tehran, Iran

    Abdollah Arjmand, Farzaneh Kamranfar & Jalal Pourahmad

  2. Student Research Committee, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Saba Shiranirad

  3. Faculty of Pharmacy, Eastern Mediterranean University, Famagusta, North Cyprus

    Fateme Ameritorzani

  4. Department of Occupational Health and Safety Engineering, School of Health, Alborz University of Medical Sciences, Karaj, Iran

    Enayatollah Seydi

  5. Research Center for Health, Safety and Environment, Alborz University of Medical Sciences, Karaj, Iran

    Enayatollah Seydi

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  1. Abdollah Arjmand
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Correspondence to Enayatollah Seydi or Jalal Pourahmad.

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Arjmand, A., Shiranirad, S., Ameritorzani, F. et al. Mitochondrial transplantation against gentamicin-induced toxicity on rat renal proximal tubular cells: the higher activity of female rat mitochondria. In Vitro Cell.Dev.Biol.-Animal 59, 31–40 (2023). https://doi.org/10.1007/s11626-022-00743-1

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