Skip to content
2000
image of Irisin Mitigates Myocardial Hypoxia/Reoxygenation Injury by Preserving Mitochondrial Redox Homeostasis via the UCP2-SOD2 Axis

Abstract

Introduction

Mitochondrial redox homeostasis is of utmost significance in myocardial ischemia-reperfusion (I/R) injury. Irisin, a myokine, has drawn extensive attention in research regarding the protection against cardiovascular diseases.

Methods

This study utilized Hypoxia/Reoxygenation (H/R) models in H9c2 cardiomyocytes to simulate I/R injury. Cells were pretreated with irisin (20 ng/mL) prior to reoxygenation. knockdown was achieved siRNA/shRNA transfection. Cell viability and apoptosis were assessed using CCK-8 and flow cytometry (Annexin V-FITC/PI staining), respectively. Intracellular calcium dynamics were monitored by Fluo-3/AM confocal imaging, while ROS levels were quantified DCFH-DA flow cytometry. Key oxidative stress markers (LDH, MDA, GSH-Px, and CAT) and protein expression (ASC, NLRP3, SIRT1, UCP2, and SOD2) were evaluated using commercial kits and Western blotting. Protein interactions were analyzed by co-immunoprecipitation, and ubiquitination levels were measured under proteasomal/lysosomal inhibition (MG132/Leupeptin).

Results

Irisin attenuated H/R injury in cardiomyocytes by suppressing apoptosis, calcium/ROS overload, and NLRP3 activation through a UCP2-dependent pathway. knockdown significantly attenuated irisin’s protection and reduced SOD2 protein stability. Mechanistically, UCP2 bound SOD2 and inhibited its ubiquitin-proteasomal degradation.

Discussion

This study reveals a novel mechanism where irisin enhances mitochondrial redox homeostasis by promoting UCP2’s function, which stabilizes SOD2 against ubiquitin-proteasomal degradation. This UCP2-SOD2 axis attenuates oxidative stress and inhibits NLRP3 inflammasome activation during cardiac injury, offering a promising dual-targeted therapeutic strategy for I/R injury.

Conclusion

Irisin protects cardiomyocytes against H/R injury primarily a novel UCP2-SOD2 axis.

© 2026 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/ppl/10.2174/0109298665445300260128064859
2026-03-02
2026-03-11

  • From This Site

    /content/journals/ppl/10.2174/0109298665445300260128064859
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Zhang S. Yan F. Luan F. Chai Y. Li N. Wang Y.W. Chen Z.L. Xu D.Q. Tang Y.P. The pathological mechanisms and potential therapeutic drugs for myocardial ischemia reperfusion injury. Phytomedicine 2024 129 155649 10.1016/j.phymed.2024.155649 38653154
    [Google Scholar]
  2. Li H. Yang D.H. Zhang Y. Zheng F. Gao F. Sun J. Shi G. Geniposide suppresses NLRP3 inflammasome-mediated pyroptosis via the AMPK signaling pathway to mitigate myocardial ischemia/reperfusion injury. Chin. Med. 2022 17 1 73 10.1186/s13020‑022‑00616‑5 35715805
    [Google Scholar]
  3. Peng J.F. Salami O.M. Lei C. Ni D. Habimana O. Yi G.H. Targeted mitochondrial drugs for treatment of myocardial ischaemia-reperfusion injury. J. Drug Target. 2022 30 8 833 844 10.1080/1061186X.2022.2085728 35652502
    [Google Scholar]
  4. Wang Z. Yang N. Hou Y. Li Y. Yin C. Yang E. Cao H. Hu G. Xue J. Yang J. Liao Z. Wang W. Sun D. Fan C. Zheng L. L‐arginine-loaded gold nanocages ameliorate myocardial ischemia/reperfusion injury by promoting nitric oxide production and maintaining mitochondrial function. Adv. Sci. 2023 10 26 2302123 10.1002/advs.202302123 37449329
    [Google Scholar]
  5. Perakakis N. Triantafyllou G.A. Fernández-Real J.M. Huh J.Y. Park K.H. Seufert J. Mantzoros C.S. Physiology and role of irisin in glucose homeostasis. Nat. Rev. Endocrinol. 2017 13 6 324 337 10.1038/nrendo.2016.221 28211512
    [Google Scholar]
  6. Timmons J.A. Baar K. Davidsen P.K. Atherton P.J. Is irisin a human exercise gene? Nature 2012 488 7413 E9 E10 10.1038/nature11364 22932392
    [Google Scholar]
  7. Bai J. Yu X.J. Liu K.L. Wang F.F. Jing G.X. Li H.B. Zhang Y. Huo C.J. Li X. Gao H.L. Qi J. Kang Y.M. Central administration of tert -butylhydroquinone attenuates hypertension via regulating Nrf2 signaling in the hypothalamic paraventricular nucleus of hypertensive rats. Toxicol. Appl. Pharmacol. 2017 333 100 109 10.1016/j.taap.2017.08.012 28842207
    [Google Scholar]
  8. Aronis K.N. Moreno M. Polyzos S.A. Moreno-Navarrete J.M. Ricart W. Delgado E. de la Hera J. Sahin-Efe A. Chamberland J.P. Berman R. Spiro A. Vokonas P. Fernández-Real J.M. Mantzoros C.S. Circulating irisin levels and coronary heart disease: Association with future acute coronary syndrome and major adverse cardiovascular events. Int. J. Obes. 2015 39 1 156 161 10.1038/ijo.2014.101 24916788
    [Google Scholar]
  9. Ho M.Y. Wang C.Y. Role of irisin in myocardial infarction, heart failure, and cardiac hypertrophy. Cells 2021 10 8 2103 10.3390/cells10082103 34440871
    [Google Scholar]
  10. Chen K. Xu Z. Liu Y. Wang Z. Li Y. Xu X. Chen C. Xia T. Liao Q. Yao Y. Zeng C. He D. Yang Y. Tan T. Yi J. Zhou J. Zhu H. Ma J. Zeng C. Irisin protects mitochondria function during pulmonary ischemia/reperfusion injury. Sci. Transl. Med. 2017 9 418 eaao6298 10.1126/scitranslmed.aao6298 29187642
    [Google Scholar]
  11. Nesci S. Rubattu S. UCP2, a member of the mitochondrial uncoupling proteins: An overview from physiological to pathological roles. Biomedicines 2024 12 6 1307 10.3390/biomedicines12061307 38927514
    [Google Scholar]
  12. Ji J. Li S. Jiang Z. Yu J. Sun Y. Cai Z. Dong Y. Sun X. Activating PPARβ/δ protects against endoplasmic reticulum stress-induced astrocytic apoptosis via UCP2-dependent mitophagy in depressive model. Int. J. Mol. Sci. 2022 23 18 10822 10.3390/ijms231810822 36142731
    [Google Scholar]
  13. Zhu Y. Zhang J. Yan X. Ji Y. Wang F. Exploring a new mechanism between lactate and VSMC calcification: PARP1/POLG/UCP2 signaling pathway and imbalance of mitochondrial homeostasis. Cell Death Dis. 2023 14 9 598 10.1038/s41419‑023‑06113‑3 37679327
    [Google Scholar]
  14. Wang Z. Chen K. Han Y. Zhu H. Zhou X. Tan T. Zeng J. Zhang J. Liu Y. Li Y. Yao Y. Yi J. He D. Zhou J. Ma J. Zeng C. Irisin protects heart against ischemia-reperfusion injury through a SOD2-dependent mitochondria mechanism. J. Cardiovasc. Pharmacol. 2018 72 6 259 269 10.1097/FJC.0000000000000608 29979350
    [Google Scholar]
  15. Chen C.L. Zhang L. Jin Z. Kasumov T. Chen Y.R. Mitochondrial redox regulation and myocardial ischemia-reperfusion injury. Am. J. Physiol. Cell Physiol. 2022 322 1 C12 C23 10.1152/ajpcell.00131.2021 34757853
    [Google Scholar]
  16. Hjelmeland A.B. Patel R.P. SOD2 acetylation and deacetylation: Another tale of Jekyll and Hyde in cancer. Proc. Natl. Acad. Sci. USA 2019 116 47 23376 23378 10.1073/pnas.1916214116 31694886
    [Google Scholar]
  17. Ibrahim N.K. Schreek S. Cinar B. Stasche A.S. Lee S.H. Zeug A. Dolgner T. Niessen J. Ponimaskin E. Shcherbata H. Fehlhaber B. Bourquin J.P. Bornhauser B. Stanulla M. Pich A. Gutierrez A. Hinze L. SOD2 is a regulator of proteasomal degradation promoting an adaptive cellular starvation response. Cell Rep. 2025 44 4 115434 10.1016/j.celrep.2025.115434 40131931
    [Google Scholar]
  18. Purohit P.K. Edwards R. Tokatlidis K. Saini N. MiR-195 regulates mitochondrial function by targeting mitofusin-2 in breast cancer cells. RNA Biol. 2019 16 7 918 929 10.1080/15476286.2019.1600999 30932749
    [Google Scholar]
  19. Gunaydin Akyildiz A. Boran T. Jannuzzi A.T. Alpertunga B. Mitochondrial dynamics imbalance and mitochondrial dysfunction contribute to the molecular cardiotoxic effects of lenvatinib. Toxicol. Appl. Pharmacol. 2021 423 115577 10.1016/j.taap.2021.115577 34019861
    [Google Scholar]
  20. Ko T.H. Marquez J.C. Kim H.K. Jeong S.H. Lee S. Youm J.B. Song I.S. Seo D.Y. Kim H.J. Won D.N. Cho K.I. Choi M.G. Rhee B.D. Ko K.S. Kim N. Won J.C. Han J. Resistance exercise improves cardiac function and mitochondrial efficiency in diabetic rat hearts. Pflugers Arch. 2018 470 2 263 275 10.1007/s00424‑017‑2076‑x 29032504
    [Google Scholar]
  21. Hu C. Zhang X. Wei W. Zhang N. Wu H. Ma Z. Li L. Deng W. Tang Q. Matrine attenuates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via maintaining AMPKα/UCP2 pathway. Acta Pharm. Sin. B 2019 9 4 690 701 10.1016/j.apsb.2019.03.003 31384530
    [Google Scholar]
  22. Pushparaj P.N. Aarthi J.J. Manikandan J. Kumar S.D. siRNA, miRNA, and shRNA: In vivo applications. J. Dent. Res. 2008 87 11 992 1003 10.1177/154405910808701109 18946005
    [Google Scholar]
  23. Li X.T. Li X.Y. Tian T. Yang W.H. Lyv S.G. Cheng Y. Su K. Lu X.H. Jin M. Xue F.S. The UCP2/PINK1/LC3b-mediated mitophagy is involved in the protection of NRG1 against myocardial ischemia/reperfusion injury. Redox Biol. 2025 80 103511 10.1016/j.redox.2025.103511 39874927
    [Google Scholar]
  24. Fang T. Ma C. Yang B. Zhao M. Sun L. Zheng N. Roxadustat improves diabetic myocardial injury by upregulating HIF-1α/UCP2 against oxidative stress. Cardiovasc. Diabetol. 2025 24 1 67 10.1186/s12933‑025‑02601‑2 39920720
    [Google Scholar]
  25. Geng Z. Chen W. Lu Q. Fu B. Fu X. UCP2 overexpression activates SIRT3 to regulate oxidative stress and mitochondrial dynamics induced by myocardial injury. Arch. Biochem. Biophys. 2024 753 109918 10.1016/j.abb.2024.109918 38301949
    [Google Scholar]
  26. Nauffal V. Di Achille P. Klarqvist M.D.R. Cunningham J.W. Hill M.C. Pirruccello J.P. Weng L.C. Morrill V.N. Choi S.H. Khurshid S. Friedman S.F. Nekoui M. Roselli C. Ng K. Philippakis A.A. Batra P. Ellinor P.T. Lubitz S.A. Genetics of myocardial interstitial fibrosis in the human heart and association with disease. Nat. Genet. 2023 55 5 777 786 10.1038/s41588‑023‑01371‑5 37081215
    [Google Scholar]
  27. Wei J. Wang A. Yu P. Sun Y. Wu W. Zhang Y. Yu R. Li B. Zhu M. Integrating multi-omics and machine learning strategies to explore the “gene-protein-metabolite” network in ischemic heart failure with Qi deficiency and blood stasis syndrome. Chin. Med. 2025 20 1 93 10.1186/s13020‑025‑01151‑9 40671145
    [Google Scholar]
  28. Zemanovic S. Ivanov M.V. Ivanova L.V. Bhatnagar A. Michalkiewicz T. Teng R.J. Kumar S. Rathore R. Pritchard K.A. Konduri G.G. Afolayan A.J. Dynamic phosphorylation of the C Terminus of Hsp70 regulates the mitochondrial import of SOD2 and redox balance. Cell Rep. 2018 25 9 2605 2616.e7 10.1016/j.celrep.2018.11.015 30485823
    [Google Scholar]
  29. Biosa A. Sanchez-Martinez A. Filograna R. Terriente-Felix A. Alam S.M. Beltramini M. Bubacco L. Bisaglia M. Whitworth A.J. Superoxide dismutating molecules rescue the toxic effects of PINK1 and parkin loss. Hum. Mol. Genet. 2018 27 9 1618 1629 10.1093/hmg/ddy069 29529199
    [Google Scholar]
  30. Bai Y. Wu J. Yang Z. Wang X. Zhang D. Ma J. Mitochondrial quality control in cardiac ischemia/reperfusion injury: New insights into mechanisms and implications. Cell Biol. Toxicol. 2023 39 1 33 51 10.1007/s10565‑022‑09716‑2 35951200
    [Google Scholar]
  31. Huo S. Wang M. Du M. Ren B. Yang T. Peng L. Jiang Y. Peng D. Men L. Shi W. Guo J. Zhang C. Lv J. Li S. Lin L. Macrophage-derived S100A9 promotes diabetic cardiomyopathy by disturbing mitochondrial quality control via STAT3 activation. Int. J. Biol. Sci. 2025 21 7 3061 3080 10.7150/ijbs.111128 40384874
    [Google Scholar]
  32. Krekora J. Derwich M. Drożdż J. Pawlowska E. Blasiak J. Oxidative stress, mitochondrial quality control, autophagy, and sirtuins in heart failure. Int. J. Mol. Sci. 2025 26 19 9826 10.3390/ijms26199826 41097089
    [Google Scholar]
  33. Shi H. Hao X. Sun Y. Zhao Y. Wang Y. Cao X. Gong Z. Ji S. Lu J. Yan Y. Yu X. Luo X. Wang J. Wang H. Exercise‐inducible circulating extracellular vesicle irisin promotes browning and the thermogenic program in white adipose tissue. Acta Physiol. 2024 240 3 e14103 10.1111/apha.14103 38288566
    [Google Scholar]
  34. Kim H. Wrann C.D. Jedrychowski M. Vidoni S. Kitase Y. Nagano K. Zhou C. Chou J. Parkman V.J.A. Novick S.J. Strutzenberg T.S. Pascal B.D. Le P.T. Brooks D.J. Roche A.M. Gerber K.K. Mattheis L. Chen W. Tu H. Bouxsein M.L. Griffin P.R. Baron R. Rosen C.J. Bonewald L.F. Spiegelman B.M. Irisin mediates effects on bone and fat via αv integrin receptors. Cell 2018 175 7 1756 1768.e17 10.1016/j.cell.2018.10.025 30550785
    [Google Scholar]
  35. Wen P. Sun Z. Yang D. Li J. Li Z. Zhao M. Wang D. Gou F. Wang J. Dai Y. Zhao D. Yang L. Irisin regulates oxidative stress and mitochondrial dysfunction through the UCP2-AMPK pathway in prion diseases. Cell Death Dis. 2025 16 1 66 10.1038/s41419‑025‑07390‑w 39900919
    [Google Scholar]
  36. Bao J.F. She Q.Y. Hu P.P. Jia N. Li A. Irisin, a fascinating field in our times. Trends Endocrinol. Metab. 2022 33 9 601 613 10.1016/j.tem.2022.06.003 35872067
    [Google Scholar]
  37. Busceti C.L. Cotugno M. Bianchi F. Forte M. Stanzione R. Marchitti S. Battaglia G. Nicoletti F. Fornai F. Rubattu S. Brain overexpression of uncoupling protein-2 (UCP2) delays renal damage and stroke occurrence in stroke-prone spontaneously hypertensive rats. Int. J. Mol. Sci. 2020 21 12 4289 10.3390/ijms21124289 32560241
    [Google Scholar]
  38. Diao J. Wei J. Yan R. Fan G. Lin L. Chen M. Effects of resveratrol on regulation on UCP2 and cardiac function in diabetic rats. J. Physiol. Biochem. 2019 75 1 39 51 10.1007/s13105‑018‑0648‑7 30225723
    [Google Scholar]
  39. Lu L. Ma J. Tang J. Liu Y. Zheng Q. Chen S. Gao E. Ren J. Yang L. Yang J. Irisin attenuates myocardial ischemia/reperfusion-induced cardiac dysfunction by regulating ER-mitochondria interaction through a mitochondrial ubiquitin ligase-dependent mechanism. Clin. Transl. Med. 2020 10 5 e166 10.1002/ctm2.166 32997406
    [Google Scholar]
  40. Jomova K. Alomar S.Y. Alwasel S.H. Nepovimova E. Kuca K. Valko M. Several lines of antioxidant defense against oxidative stress: Antioxidant enzymes, nanomaterials with multiple enzyme-mimicking activities, and low-molecular-weight antioxidants. Arch. Toxicol. 2024 98 5 1323 1367 10.1007/s00204‑024‑03696‑4 38483584
    [Google Scholar]
  41. Zhao K. Tang J. Xie H. Liu L. Qin Q. Sun B. Qin Z.H. Sheng R. Zhu J. Nicotinamide riboside attenuates myocardial ischemia-reperfusion injury via regulating SIRT3/SOD2 signaling pathway. Biomed. Pharmacother. 2024 175 116689 [Jun;] 10.1016/j.biopha.2024.116689 38703508
    [Google Scholar]
  42. Görlach A. Bertram K. Hudecova S. Krizanova O. Calcium and ROS: A mutual interplay. Redox Biol. 2015 6 260 271 10.1016/j.redox.2015.08.010 26296072
    [Google Scholar]
  43. Pan P. Zhang H. Su L. Wang X. Liu D. Melatonin balance the autophagy and apoptosis by regulating UCP2 in the LPS-induced cardiomyopathy. Molecules 2018 23 3 675 10.3390/molecules23030675 29547569
    [Google Scholar]
  44. Bondarenko A.I. Parichatikanond W. Madreiter C.T. Rost R. Waldeck-Weiermair M. Malli R. Graier W.F. UCP2 modulates single-channel properties of a MCU-dependent Ca2+ inward current in mitochondria. Pflugers Arch. 2015 467 12 2509 2518 10.1007/s00424‑015‑1727‑z 26275882
    [Google Scholar]
  45. Zhuo C. Xin J. Huang W. Zhang D. Yan X. Li R. Li H. Lan J. Lin L. Li L. Wang X. Liu L. Wang Y. Li X. Mao Y. Chen H. Wu S. Yang X. Jiang W. Irisin protects against doxorubicin-induced cardiotoxicity by improving AMPK-Nrf2 dependent mitochondrial fusion and strengthening endogenous anti-oxidant defense mechanisms. Toxicology 2023 494 153597 10.1016/j.tox.2023.153597 37499777
    [Google Scholar]
  46. Kumar M. Sengar A.S. Lye A. Kumar P. Mukherjee S. Kumar D. Das P. Chatterjee S. Stewart A. Maity B. FNDC5/irisin mitigates the cardiotoxic impacts of cancer chemotherapeutics by modulating ROS-dependent and -independent mechanisms. Redox Biol. 2025 80 103527 10.1016/j.redox.2025.103527 39923397
    [Google Scholar]
  47. He W. Tang Y. Li C. Zhang X. Huang S. Tan B. Yang Z. Exercise enhanced cardiac function in mice with radiation-induced heart disease via the FNDC5/irisin-dependent mitochondrial turnover pathway. Front. Physiol. 2021 12 739485 10.3389/fphys.2021.739485 34899376
    [Google Scholar]
  48. Wang L. Negro R. Wu H. TRPM2, linking oxidative stress and Ca2+ permeation to NLRP3 inflammasome activation. Curr. Opin. Immunol. 2020 62 131 135 10.1016/j.coi.2020.01.005 32058297
    [Google Scholar]
  49. Wei X.H. Chen J. Wu X.F. Zhang Q. Xia G.Y. Chu X.Y. Xia H. Lin S. Shang H.C. Salvianolic acid B alleviated myocardial ischemia-reperfusion injury via modulating SIRT3-mediated crosstalk between mitochondrial ROS and NLRP3. Phytomedicine 2025 136 156260 10.1016/j.phymed.2024.156260 39579610
    [Google Scholar]
  50. Yang Y. Liu Y. Wang Y. Chao Y. Zhang J. Jia Y. Tie J. Hu D. Regulation of SIRT1 and its roles in inflammation. Front. Immunol. 2022 13 831168 10.3389/fimmu.2022.831168 35359990
    [Google Scholar]
  51. Ren B. Feng J. Yang N. Guo Y. Chen C. Qin Q. Ginsenoside Rg3 attenuates angiotensin II-induced myocardial hypertrophy through repressing NLRP3 inflammasome and oxidative stress via modulating SIRT1/NF-κB pathway. Int. Immunopharmacol. 2021 98 107841 10.1016/j.intimp.2021.107841 34153662
    [Google Scholar]
  52. Zhang L. Ai C. Guo C. Li S. Niu J. Meng X. Zhang Z. UCP2 inhibition exaggerates diabetic cardiomyopathy by facilitating the activation of NLRP3 and pyroptosis. Diabetol. Metab. Syndr. 2025 17 1 267 10.1186/s13098‑025‑01855‑w 40671041
    [Google Scholar]
  53. Tan Y. Nie Y. ZhengWen L. Zheng Z. Comparative effectiveness of myocardial patches and intramyocardial injections in treating myocardial infarction with a MitoQ/hydrogel system. J. Mater. Chem. B Mater. Biol. Med. 2024 12 24 5838 5847 10.1039/D4TB00573B 38771306
    [Google Scholar]
  54. Zhang X. Liang L. Wang F. Jose P.A. Chen K. Zeng C. Irisin‐encapsulated mitochondria‐targeted biomimetic nanotherapeutics for alleviating acute kidney injury. Adv. Sci. 2024 11 38 2402805 10.1002/advs.202402805 39119832
    [Google Scholar]
  55. Raghu G. Berk M. Campochiaro P.A. Jaeschke H. Marenzi G. Richeldi L. Wen F.Q. Nicoletti F. Calverley P.M.A. The multifaceted therapeutic role of n-acetylcysteine (NAC) in disorders characterized by oxidative stress. Curr. Neuropharmacol. 2021 19 8 1202 1224 10.2174/18756190MTEycODQ8w 33380301
    [Google Scholar]
  56. Esfandiary A. Kutsche H.S. Schreckenberg R. Weber M. Pak O. Kojonazarov B. Sydykov A. Hirschhäuser C. Wolf A. Haag D. Hecker M. Fink L. Seeger W. Ghofrani H.A. Schermuly R.T. Weißmann N. Schulz R. Rohrbach S. Li L. Sommer N. Schlüter K.D. Protection against pressure overload-induced right heart failure by uncoupling protein 2 silencing. Cardiovasc. Res. 2019 115 7 1217 1227 10.1093/cvr/cvz049 30850841
    [Google Scholar]
/content/journals/ppl/10.2174/0109298665445300260128064859
Loading
Irisin Mitigates Myocardial Hypoxia/Reoxygenation Injury by Preserving Mitochondrial Redox Homeostasis via the UCP2-SOD2 Axis
Bentham Science Publishers ; https://doi.org/10.2174/0109298665445300260128064859
/content/journals/ppl/10.2174/0109298665445300260128064859
/content/journals/ppl/10.2174/0109298665445300260128064859
Loading

Data & Media loading...


  • Article Type:     Research Article
Keywords: ubiquitylation ; hypoxia/reoxygenation (H/R) ; oxidative stress ; SOD2 ; Irisin ; UCP2

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test