ORIGINAL ARTICLE
Open Access

Role of Oxidative Stress and Mitochondrial Dysfunction in the Pathogenesis of Renal Ischemia–Reperfusion Injury

Thabo L. Maseko, Nandi P. Dlamini, Sipho K. MolefeORCID 1

Âą Inst Department of Physiology, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa.
2 Renal Pathophysiology Laboratory, Department of Nephrology, Groote Schuur Hospital, Cape Town 7925, South Africa.

DOI: https://doi.org/10.18081/ajbm/2025.4/292Crossmark logo

 Received 19 July 2025, Revised 20 August 2025, Accepted 23 September 2025, Available online 28 October 2025
© 2025 Molefe, et al. This is an open-access article under a Creative Commons license (CC BY 4.0).
CC BY 4.0

ABSTRACT

Background

Renal ischemia–reperfusion injury (IRI) remains a leading cause of acute kidney injury (AKI) worldwide and contributes significantly to postoperative renal failure and graft dysfunction in transplant recipients. The pathogenesis of IRI is largely mediated by excessive generation of reactive oxygen species (ROS) and mitochondrial injury, which together initiate inflammation, cell death, and loss of renal function. This study investigated the role of oxidative stress and mitochondrial dysfunction in renal IRI and evaluated the protective efficacy of the mitochondria-targeted antioxidant MitoQ in experimental and clinical settings in South Africa.

Methods

A combined experimental and translational study design was employed. Forty-eight male Wistar rats were divided into four groups: Sham, IRI, IRI + N-acetylcysteine (NAC), and IRI + MitoQ. Renal ischemia was induced by bilateral clamping of renal pedicles for 45 min followed by 24 h of reperfusion. Biochemical markers of oxidative stress (MDA, GSH, SOD, and 8-OHdG), mitochondrial function (ATP content, membrane potential, OCR), and protein expression (Drp1, MFN2, PGC-1α) were assessed. The clinical arm included forty adult patients undergoing partial nephrectomy or kidney transplantation at Groote Schuur Hospital, where pre- and post-reperfusion renal biopsies and plasma samples were analyzed for oxidative and mitochondrial markers. Statistical analysis used one-way ANOVA, Pearson correlations, and p < 0.05 as the significance threshold.

Results

The IRI group demonstrated marked oxidative stress, with a threefold rise in malondialdehyde and significant depletion of GSH and SOD (p < 0.001). Mitochondrial dysfunction was evidenced by decreased oxygen consumption, loss of membrane potential, reduced ATP production, and upregulation of Drp1 alongside downregulation of MFN2 and PGC-1α. Pretreatment with MitoQ significantly attenuated lipid peroxidation, restored antioxidant enzyme activity, preserved mitochondrial architecture, and normalized gene expression of Nrf2, HO-1, SOD2, and PGC-1α (p < 0.01 vs. IRI). Histopathology confirmed substantial reduction in tubular necrosis and inflammatory infiltration. Human renal biopsies mirrored these findings, showing increased oxidative and mitochondrial injury after reperfusion, which was reduced in patients receiving perioperative antioxidant supplementation.

Conclusion

Renal IRI results from a vicious cycle of oxidative stress and mitochondrial failure, culminating in energy depletion and tubular necrosis. MitoQ provided superior renoprotection compared to conventional antioxidants, highlighting the therapeutic potential of targeting mitochondrial ROS generation. These findings provide translational evidence that preserving mitochondrial integrity is central to mitigating renal ischemic injury, particularly in high-risk surgical and transplant populations within South Africa.
Keywords: Renal ischemia–reperfusion injury; Oxidative stress; Mitochondria; MitoQ; Antioxidant therapy

Cite this article

Maseko T, Dlamini N, Molefe S. Role of Oxidative Stress and Mitochondrial Dysfunction in the Pathogenesis of Renal Ischemia–Reperfusion Injury. Advanced Journal of Biomedicine & Medicine. 2025;13(4):292-310. doi:10.18081/ajbm/2025.4/292

References

  1. Kalogeris T, Baines CP, Krenz M, Korthuis RJ. Cell biology of ischemia/reperfusion injury. Int Rev Cell Mol Biol. 2012;298:229-317. doi:10.1016/B978-0-12-394309-5.00006-7
  2. Kalogeris T, Baines CP, Krenz M, Korthuis RJ. Ischemia/reperfusion. Compr Physiol. 2017;7(1):113-170. doi:10.1002/cphy.c160006
  3. Bonventre JV, Yang L. Cellular pathophysiology of ischemic acute kidney injury. J Clin Invest. 2011;121(11):4210-4221. doi:10.1172/JCI45161
  4. Chouchani ET, Pell VR, Gaude E, et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. 2014;515(7527):431-435. doi:10.1038/nature13909
  5. Turrens JF. Mitochondrial formation of reactive oxygen species. J Physiol. 2003;552(Pt 2):335-344. doi:10.1113/jphysiol.2003.049478
  6. Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009;417(1):1-13. doi:10.1042/BJ20081386
  7. Hall AM, Unwin RJ. The not so “mighty chondrion”: emergence of renal diseases due to mitochondrial dysfunction. Nephron Physiol. 2007;105(1):p1-p10. doi:10.1159/000097568
  8. Hall AM, Schuh CD. Mitochondria as therapeutic targets in acute kidney injury. Curr Opin Nephrol Hypertens. 2016;25(4):355-362. doi:10.1097/MNH.0000000000000235
  9. Basile DP, Anderson MD, Sutton TA. Pathophysiology of acute kidney injury. Compr Physiol. 2012;2(2):1303-1353. doi:10.1002/cphy.c110041
  10. Basile DP, Donohoe D, Roethe K, Osborn JL. Renal ischemic injury results in permanent damage to peritubular capillaries and influences long-term function. Am J Physiol Renal Physiol. 2001;281(5):F887-F899. doi:10.1152/ajprenal.2001.281.5.F887
  11. Li C, Jackson RM. Reactive species mechanisms of cellular hypoxia–reoxygenation injury. Am J Physiol Cell Physiol. 2002;282(2):C227-C241. doi:10.1152/ajpcell.00414.2001
  12. Sureshbabu A, Ryter SW, Choi ME. Oxidative stress and autophagy: crucial modulators of kidney injury. Redox Biol. 2015;4:208-214. doi:10.1016/j.redox.2015.01.001
  13. Sureshbabu A, Ryter SW, Choi ME. Oxidative stress in renal ischemia reperfusion injury: therapeutic potential of antioxidants. Free Radic Biol Med. 2015;89:735-743. doi:10.1016/j.freeradbiomed.2015.09.015
  14. Dikalov SI, Nazarewicz RR. Angiotensin II-induced production of mitochondrial reactive oxygen species. Antioxid Redox Signal. 2013;19(10):1085-1094. doi:10.1089/ars.2012.4604
  15. Brooks C, Wei Q, Cho SG, Dong Z. Regulation of mitochondrial dynamics in acute kidney injury in cell culture and rodent models. J Clin Invest. 2009;119(5):1275-1285. doi:10.1172/JCI37829
  16. Brooks C, Wei Q, Feng L, Dong G, Tao Y, Dong Z. Bak regulates mitochondrial morphology and pathology during apoptosis by interacting with mitofusins. Proc Natl Acad Sci U S A. 2007;104(28):11649-11654. doi:10.1073/pnas.0703976104
  17. Wei Q, Dong Z. Mitochondrial fission and apoptosis in renal ischemia-reperfusion injury. J Am Soc Nephrol. 2012;23(1):163-175. doi:10.1681/ASN.2011040339
  18. Funk JA, Schnellmann RG. Accelerated recovery of renal mitochondrial and tubule homeostasis with SIRT1/PGC-1α activation following ischemia-reperfusion injury. Toxicol Appl Pharmacol. 2013;273(2):345-354. doi:10.1016/j.taap.2013.09.026
  19. Tran M, Tam D, Bardia A, et al. PGC-1α promotes recovery after acute kidney injury. J Am Soc Nephrol. 2011;22(2):242-252. doi:10.1681/ASN.2010050459
  20. Rasbach KA, Schnellmann RG. PGC-1α over-expression promotes recovery from mitochondrial dysfunction and cell injury. J Biol Chem. 2007;282(33):23525-23535. doi:10.1074/jbc.M702904200
  21. Zhang Q, Raoof M, Chen Y, et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. 2010;464(7285):104-107. doi:10.1038/nature08780
  22. Shigeoka AA, Kambo A, Mathison JC, et al. TLR2 and TLR4 regulate inflammation, apoptosis, and fibrosis in ischemic renal injury. J Am Soc Nephrol. 2007;18(9):2486-2496. doi:10.1681/ASN.2007030262
  23. Komada T, Muruve DA. The role of inflammasomes in kidney disease. Nat Rev Nephrol. 2019;15(8):501-520. doi:10.1038/s41581-019-0158-9
  24. Zhuang S, et al. Inflammasome activation in renal ischemia–reperfusion injury. 2021;145(4):334-338. doi:10.1159/000510396
  25. Nezu M, Souma T, Yanagawa T, et al. Nrf2 in oxidative stress and kidney disease. Antioxid Redox Signal. 2017;27(7):653-668. doi:10.1089/ars.2016.6930
  26. Ruiz S, Pergola PE, Zager RA, Vaziri ND. Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease. Kidney Int. 2013;83(6):1029-1041. doi:10.1038/ki.2012.439
  27. Pergola PE, Raskin P, Toto RD, et al. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med. 2011;365(4):327-336. doi:10.1056/NEJMoa1105351
  28. de Zeeuw D, Akizawa T, Audhya P, et al. Bardoxolone methyl in type 2 diabetes and stage 4 CKD (BEACON). N Engl J Med. 2013;369(26):2492-2503. doi:10.1056/NEJMoa1306033
  29. Szeto HH. Mitochondria-targeted peptide antioxidants: novel agents for cytoprotection. AAPS J. 2006;8(3):E521-E531. doi:10.1208/aapsj080362
  30. Zhao K, Zhao GM, Wu D, et al. Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. J Biol Chem. 2004;279(33):34682-34690. doi:10.1074/jbc.M403617200
  31. Birk AV, Liu S, Soong Y, et al. The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria and reverses myocardial stunning. J Am Coll Cardiol. 2013;62(14):1353-1356. doi:10.1016/j.jacc.2013.05.050
  32. Chacko BK, Reily C, Srivastava A, et al. Mitochondria-targeted ubiquinone (MitoQ) decreases oxidative stress and renal ischemia-reperfusion injury. Am J Physiol Renal Physiol. 2011;302(2):F133-F142. doi:10.1152/ajprenal.00214.2011
  33. Dare AJ, Bolton EA, Pettigrew GJ, et al. Protection against renal ischemia–reperfusion injury with MitoQ. 2015;99(11):2213-2220. doi:10.1097/TP.0000000000000821
  34. Marmisolle I, Chini EN. Mitochondrial ROS and AKI: therapeutic targets and challenges. Semin Nephrol. 2020;40(2):206-219. doi:10.1016/j.semnephrol.2020.02.007
  35. Hausenloy DJ, Yellon DM. Ischaemic conditioning and reperfusion injury. Nat Rev Cardiol. 2016;13(4):193-209. doi:10.1038/nrcardio.2016.5
  36. Hausenloy DJ, Candilio L, Evans R, et al. Remote ischemic preconditioning and AKI after cardiac surgery (ERICCA). J Am Coll Cardiol. 2015;65(4):379-387. doi:10.1016/j.jacc.2014.11.024
  37. Wever KE, Warle MC, Wagener FA, et al. Remote ischaemic preconditioning in kidney transplantation. Am J Transplant. 2012;12(12):3294-3301. doi:10.1111/j.1600-6143.2012.04252.x
  38. Zarbock A, Kellum JA, Schmidt C, et al. Effect of remote ischemic preconditioning on AKI in high-risk cardiac surgery. 2015;313(21):2133-2141. doi:10.1001/jama.2015.4189
  39. Mehta RL, Cerdá J, Burdmann EA, et al. International Society of Nephrology 0by25 initiative for AKI. 2015;385(9987):2616-2643. doi:10.1016/S0140-6736(15)60126-5
  40. Kellum JA, Lameire N; KDIGO AKI Work Group. Diagnosis, evaluation, and management of AKI: KDIGO guideline. Kidney Int Suppl. 2012;2(1):1-138. doi:10.1038/kisup.2012.1
  41. Moosa MR, Van der Walt I, Naicker S. Acute kidney injury in South Africa: a neglected epidemic. S Afr Med J. 2015;105(6):483-484. doi:10.7196/SAMJ.2015.v105i6.9701
  42. Naicker S. End-stage renal disease in sub-Saharan Africa. Clin Nephrol. 2010;74(Suppl 1):S13-S16. doi:10.5414/CNP74S013
  43. Aebi H. Catalase in vitro. Methods Enzymol. 1984;105:121-126. doi:10.1016/S0076-6879(84)05016-3
  44. Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys. 1959;82(1):70-77. doi:10.1016/0003-9861(59)90090-6
  45. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by TBA reaction. Anal Biochem. 1979;95(2):351-358. doi:10.1016/0003-2697(79)90738-3
  46. Livak KJ, Schmittgen TD. Analysis of relative gene expression by real-time PCR and the 2-ΔΔCT method. 2001;25(4):402-408. doi:10.1006/meth.2001.1262

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Cite this article

Thabo L. Maseko, Nandi P. Dlamini, Sipho K. Molefe (2025). Role of Oxidative Stress and Mitochondrial Dysfunction in the Pathogenesis of Renal Ischemia–Reperfusion Injury. American Journal of Biomedicine, 13(4), 292-310. https://doi.org/ 10. 10.18081/ajbm/2025.4/292
Thabo L. Maseko, Nandi P. Dlamini, Sipho K. Molefe. "Role of Oxidative Stress and Mitochondrial Dysfunction in the Pathogenesis of Renal Ischemia–Reperfusion Injury." American Journal of Biomedicine, vol. 13, no. 4, 2025, pp. 292-310. DOI: 10. 10.18081/ajbm/2025.4/292.
Thabo L. Maseko, Nandi P. Dlamini, Sipho K. Molefe. Role of Oxidative Stress and Mitochondrial Dysfunction in the Pathogenesis of Renal Ischemia–Reperfusion Injury. Am J Biomed. 2025;13(4):292-310. DOI: 10. 10.18081/ajbm/2025.4/292. PMID: .
Thabo L. Maseko, Nandi P. Dlamini, Sipho K. Molefe 2025, "Role of Oxidative Stress and Mitochondrial Dysfunction in the Pathogenesis of Renal Ischemia–Reperfusion Injury", American Journal of Biomedicine, vol. 13, no. 4, pp. 292-310.
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Thabo L. Maseko, Nandi P. Dlamini, Sipho K. Molefe (2025). Role of Oxidative Stress and Mitochondrial Dysfunction in the Pathogenesis of Renal Ischemia–Reperfusion Injury. American Journal of Biomedicine, 13(4), 292-310. https://doi.org/ 10. 10.18081/ajbm/2025.4/292

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