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image of The Mitochondrial Targeting Drug SkQ1 Attenuates the Progression of Post-Traumatic Osteoarthritis through Suppression of Mitochondrial Oxidative Stress
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Abstract

Background

Post-traumatic osteoarthritis (PTOA) constitutes a distinct subtype of osteoarthritis (OA). Despite extensive research, no effective pharmacological intervention has been established to prevent or halt the progression of PTOA. Current therapeutic approaches are primarily limited to symptomatic management and pain relief. SkQ1, a novel mitochondria-targeted antioxidant, has emerged as a promising therapeutic agent due to its dual capacity to scavenge excessive intracellular reactive oxygen species (ROS) and modulate inflammatory responses.

Objective

This study aimed to investigate the therapeutic potential of SkQ1 in the early stages of PTOA and elucidate its underlying molecular mechanisms.

Methods

Chondrocytes were cultured under varying concentrations of SkQ1 to evaluate its cytotoxicity. Additionally, an oxidative stress model was established to assess the antioxidant effects of SkQ1 across different concentration levels, from which the optimal concentration for PTOA treatment was determined. The rat PTOA model was established through medial meniscal tear (MMT) surgery, followed by intra-articular administration of SkQ1 postoperatively. The gait characteristics of rats in each group were assessed biweekly following surgery. Outcome measures were evaluated at 2 and 6 weeks postoperatively, including pathological evaluation of knee cartilage, ROS levels, markers of oxidative damage, such as malondialdehyde (MDA) and 8-hydroxy-deoxyguanosine (8-OHdG), mitochondrial membrane potential, mitochondrial DNA copy number, and apoptosis-related cytokines.

Results

, lower concentrations of SkQ1 (500 nM) exhibited superior antioxidant efficacy while minimizing cytotoxicity. The results indicated that SkQ1 administration significantly enhanced knee joint functionality and mitigated articular cartilage degeneration in both the acute and subacute phases of PTOA by inhibiting oxidative stress pathways. In a rat model of PTOA, SkQ1 not only alleviated gait abnormalities, but also substantially reduced levels of oxidative stress biomarkers, including ROS, MDA, and 8-OHdG. Furthermore, SkQ1 effectively preserved mitochondrial membrane potential and increased mitochondrial DNA copy number. Mechanistically, SkQ1 inhibited the release of cytochrome C (Cyt-C) and apoptosis-inducing factor (AIF) and downregulated key components of the mitochondria-mediated apoptotic pathway, such as Bax, Bak, cleaved caspase-3, and cleaved caspase-9.

Conclusion

The findings suggested that SkQ1 exerts its therapeutic effects via multiple mechanisms, including the reduction of ROS accumulation, mitigation of oxidative damage, preservation of mitochondrial function, and inhibition of apoptotic pathways. These diverse actions position SkQ1 as a promising disease-modifying agent for PTOA treatment, potentially offering benefits that extend beyond those provided by current symptom-focused therapies.

2024 © 2024 The Author(s). Published by Bentham Science Publisher. The Author(s)
This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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2025-03-17
2025-05-03

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References

  1. Brown T.D. Johnston R.C. Saltzman C.L. Marsh J.L. Buckwalter J.A. Posttraumatic osteoarthritis: A first estimate of incidence, prevalence, and burden of disease. J. Orthop. Trauma 2006 20 10 739 744 10.1097/01.bot.0000246468.80635.ef 17106388
    [Google Scholar]
  2. Salman L.A. Ahmed G. Dakin S.G. Kendrick B. Price A. Osteoarthritis: A narrative review of molecular approaches to disease management. Arthritis Res. Ther. 2023 25 1 27 10.1186/s13075‑023‑03006‑w 36800974
    [Google Scholar]
  3. Dilley J.E. Bello M.A. Roman N. McKinley T. Sankar U. Post-traumatic osteoarthritis: A review of pathogenic mechanisms and novel targets for mitigation. Bone Rep. 2023 18 101658 10.1016/j.bonr.2023.101658 37425196
    [Google Scholar]
  4. Maia C.R. Annichino R.F. de Azevedo e Souza Munhoz M. Machado E.G. Marchi E. Castano-Betancourt M.C. Post-traumatic osteoarthritis: The worst associated injuries and differences in patients’ profile when compared with primary osteoarthritis. BMC Musculoskelet. Disord. 2023 24 1 568 10.1186/s12891‑023‑06663‑9 37438788
    [Google Scholar]
  5. Bedingfield S.K. Colazo J.M. Di Francesco M. Yu F. Liu D.D. Di Francesco V. Himmel L.E. Gupta M.K. Cho H. Hasty K.A. Decuzzi P. Duvall C.L. Top-down fabricated microPlates for prolonged, intra-articular matrix metalloproteinase 13 siRNA nanocarrier delivery to reduce post-traumatic osteoarthritis. ACS Nano 2021 15 9 14475 14491 10.1021/acsnano.1c04005 34409835
    [Google Scholar]
  6. Zhou D. Wei Y. Sheng S. Wang M. Lv J. Zhao B. Chen X. Xu K. Bai L. Wu Y. Song P. Cao L. Zhou F. Zhang H. Shi Z. Su J. MMP13-targeted siRNA-loaded micelles for diagnosis and treatment of posttraumatic osteoarthritis. Bioact. Mater. 2024 37 378 392 10.1016/j.bioactmat.2024.04.010 38689658
    [Google Scholar]
  7. Brockman B.S. Maupin J.J. Thompson S.F. Hollabaugh K.M. Thakral R. Complication rates in total knee arthroplasty performed for osteoarthritis and post-traumatic arthritis: A comparison study. J. Arthroplasty 2020 35 2 371 374 10.1016/j.arth.2019.09.022 31606293
    [Google Scholar]
  8. Liu Y. Zhao X.D. Zou C. Lingering risk: A meta-analysis of outcomes following primary total knee arthroplasty for patients with post-traumatic arthritis. Int. J. Surg. 2020 77 163 172 10.1016/j.ijsu.2020.03.053 32247846
    [Google Scholar]
  9. Koike M. Nojiri H. Ozawa Y. Watanabe K. Muramatsu Y. Kaneko H. Morikawa D. Kobayashi K. Saita Y. Sasho T. Shirasawa T. Yokote K. Kaneko K. Shimizu T. Mechanical overloading causes mitochondrial superoxide and SOD2 imbalance in chondrocytes resulting in cartilage degeneration. Sci. Rep. 2015 5 1 11722 10.1038/srep11722 26108578
    [Google Scholar]
  10. Coleman M.C. Ramakrishnan P.S. Brouillette M.J. Martin J.A. Injurious loading of articular cartilage compromises chondrocyte respiratory function. Arthritis Rheumatol. 2016 68 3 662 671 10.1002/art.39460 26473613
    [Google Scholar]
  11. Riggs K.C. Sankar U. Inflammatory mechanisms in post-traumatic osteoarthritis: A role for CaMKK2. Immunometabolism (Cobham) 2023 5 4 e00031 10.1097/IN9.0000000000000031 37849987
    [Google Scholar]
  12. Riegger J. Schoppa A. Ruths L. Haffner-Luntzer M. Ignatius A. Oxidative stress as a key modulator of cell fate decision in osteoarthritis and osteoporosis: A narrative review. Cell. Mol. Biol. Lett. 2023 28 1 76 10.1186/s11658‑023‑00489‑y 37777764
    [Google Scholar]
  13. Coleman M.C. Goetz J.E. Brouillette M.J. Seol D. Willey M.C. Petersen E.B. Anderson H.D. Hendrickson N.R. Compton J. Khorsand B. Morris A.S. Salem A.K. Fredericks D.C. McKinley T.O. Martin J.A. Targeting mitochondrial responses to intra-articular fracture to prevent posttraumatic osteoarthritis. Sci. Transl. Med. 2018 10 427 eaan5372 10.1126/scitranslmed.aan5372 29437147
    [Google Scholar]
  14. Coleman M. Brouillette M. Andresen N. Oberley-Deegan R. Martin J. Differential effects of superoxide dismutase mimetics after mechanical overload of articular cartilage. Antioxidants 2017 6 4 98 10.3390/antiox6040098 29189731
    [Google Scholar]
  15. Chen Y. Le Y. Yang J. Yang Y. Feng X. Cai J. Shang Y. Sugiarto S. Wei Q. Kai D. Zheng L. Zhao J. 3D bioprinted Xanthan hydrogels with dual antioxidant and chondrogenic functions for post-traumatic cartilage regeneration. ACS Biomater. Sci. Eng. 2024 10 3 1661 1675 10.1021/acsbiomaterials.3c01636 38364815
    [Google Scholar]
  16. Chen B. He Q. Chen C. Lin Y. Xiao J. Pan Z. Combination of curcumin and catalase protects against chondrocyte injury and knee osteoarthritis progression by suppressing oxidative stress. Biomed Pharmacother. 2023 168 115751 10.1016/j.biopha.2023.115751
    [Google Scholar]
  17. Skulachev V.P. Cationic antioxidants as a powerful tool against mitochondrial oxidative stress. Biochem. Biophys. Res. Commun. 2013 441 2 275 279 10.1016/j.bbrc.2013.10.063 24161394
    [Google Scholar]
  18. Huang B. Zhang N. Qiu X. Mitochondria-targeted SkQ1 nanoparticles for dry eye disease: Inhibiting NLRP3 inflammasome activation by preventing mitochondrial DNA oxidation. J Control Release. 2024 365 1 15 10.1016/j.jconrel.2023.11.021
    [Google Scholar]
  19. Battogtokh G. Choi Y.S. Kang D.S. Park S.J. Shim M.S. Huh K.M. Cho Y.Y. Lee J.Y. Lee H.S. Kang H.C. Mitochondria-targeting drug conjugates for cytotoxic, anti-oxidizing and sensing purposes: current strategies and future perspectives. Acta Pharm. Sin. B 2018 8 6 862 880 10.1016/j.apsb.2018.05.006 30505656
    [Google Scholar]
  20. Kezic A. Spasojevic I. Lezaic V. Bajcetic M. Mitochondria‐targeted antioxidants: Future perspectives in kidney ischemia reperfusion injury. Oxid. Med. Cell. Longev. 2016 2016 1 2950503 10.1155/2016/2950503 27313826
    [Google Scholar]
  21. Jia B. Ye J. Gan L. Li R. Zhang M. Sun D. Weng L. Xiong Y. Xu J. Zhang P. Huang W. Zheng M. Wang T. Mitochondrial antioxidant SkQ1 decreases inflammation following hemorrhagic shock by protecting myocardial mitochondria. Front. Physiol. 2022 13 1047909 10.3389/fphys.2022.1047909 36467681
    [Google Scholar]
  22. Song J. Sheng J. Lei J. Gan W. Yang Y. Mitochondrial targeted antioxidant SKQ1 ameliorates acute kidney injury by inhibiting ferroptosis. Oxid. Med. Cell. Longev. 2022 2022 1 19 10.1155/2022/2223957 36193064
    [Google Scholar]
  23. Lyamzaev K.G. Huan H. Panteleeva A.A. Simonyan R.A. Avetisyan A.V. Chernyak B.V. Exogenous iron induces mitochondrial lipid peroxidation, lipofuscin accumulation, and ferroptosis in H9c2 cardiomyocytes. Biomolecules 2024 14 6 730 10.3390/biom14060730 38927133
    [Google Scholar]
  24. Wan Mohammad W.M.Z. Zahiruddin W.M. Sample size calculation in animal studies using resource equation approach. Malays. J. Med. Sci. 2017 24 5 101 105 10.21315/mjms2017.24.5.11 29386977
    [Google Scholar]
  25. Ren G. Geng L. Ren D. Hou H. Yao S. Shi Z. Wang P. Chronic intermittent hypobaric hypoxia alleviates early-stage posttraumatic osteoarthritis via NF-κB/Nrf2 pathway in mice. J. Orthop. Surg. Res. 2024 19 1 878 10.1186/s13018‑024‑05376‑6 39726016
    [Google Scholar]
  26. Gerwin N. Bendele A.M. Glasson S. Carlson C.S. The OARSI histopathology initiative – recommendations for histological assessments of osteoarthritis in the rat. Osteoarthritis Cartilage 2010 18 Suppl. 3 S24 S34 10.1016/j.joca.2010.05.030 20864021
    [Google Scholar]
  27. Mishra J.S. Blesson C.S. Kumar S. Testosterone decreases placental mitochondrial content and cellular bioenergetics. Biology 2020 9 7 176 10.3390/biology9070176 32698476
    [Google Scholar]
  28. Ayala S. Delco M.L. Fortier L.A. Cohen I. Bonassar L.J. Cartilage articulation exacerbates chondrocyte damage and death after impact injury. J Orthop Res. 2021 39 10 2130 2140 10.1002/jor.24936
    [Google Scholar]
  29. Jiang Q. Yin J. Chen J. Ma X. Wu M. Liu G. Yao K. Tan B. Yin Y. Mitochondria-targeted antioxidants: A step towards disease treatment. Oxid. Med. Cell. Longev. 2020 2020 1 18 10.1155/2020/8837893 33354280
    [Google Scholar]
  30. Rokitskaya T.I. Klishin S.S. Severina I.I. Skulachev V.P. Antonenko Y.N. Kinetic analysis of permeation of mitochondria-targeted antioxidants across bilayer lipid membranes. J. Membr. Biol. 2008 224 1-3 9 19 10.1007/s00232‑008‑9124‑6 18807085
    [Google Scholar]
  31. Antonenko Y.N. Roginsky V.A. Pashkovskaya A.A. Rokitskaya T.I. Kotova E.A. Zaspa A.A. Chernyak B.V. Skulachev V.P. Protective effects of mitochondria-targeted antioxidant SkQ in aqueous and lipid membrane environments. J. Membr. Biol. 2008 222 3 141 149 10.1007/s00232‑008‑9108‑6 18493812
    [Google Scholar]
  32. Zinovkin R.A. Zamyatnin A.A. Mitochondria-targeted drugs. Curr. Mol. Pharmacol. 2019 12 3 202 214 10.2174/1874467212666181127151059 30479224
    [Google Scholar]
  33. Somayajulu M. McClellan S.A. Wright R. Pitchaikannu A. Croniger B. Zhang K. Hazlett L.D. Airborne exposure of the cornea to PM10 induces oxidative stress and disrupts Nrf2 mediated anti-oxidant defenses. Int. J. Mol. Sci. 2023 24 4 3911 10.3390/ijms24043911 36835320
    [Google Scholar]
  34. Antonenko Y.N. Avetisyan A.V. Bakeeva L.E. Chernyak B.V. Chertkov V.A. Domnina L.V. Ivanova O.Y. Izyumov D.S. Khailova L.S. Klishin S.S. Korshunova G.A. Lyamzaev K.G. Muntyan M.S. Nepryakhina O.K. Pashkovskaya A.A. Pletjushkina O.Y. Pustovidko A.V. Roginsky V.A. Rokitskaya T.I. Ruuge E.K. Saprunova V.B. Severina I.I. Simonyan R.A. Skulachev I.V. Skulachev M.V. Sumbatyan N.V. Sviryaeva I.V. Tashlitsky V.N. Vassiliev J.M. Vyssokikh M.Y. Yaguzhinsky L.S. Zamyatnin A.A. Jr Skulachev V.P. Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 1. Cationic plastoquinone derivatives: Synthesis and in vitro studies. Biochemistry (Mosc.) 2008 73 12 1273 1287 10.1134/S0006297908120018 19120014
    [Google Scholar]
  35. Sacks B. Onal H. Martorana R. Sehgal A. Harvey A. Wastella C. Ahmad H. Ross E. Pjetergjoka A. Prasad S. Barsotti R. Young L.H. Chen Q. Mitochondrial targeted antioxidants, mitoquinone and SKQ1, not vitamin C, mitigate doxorubicin-induced damage in H9c2 myoblast: Pretreatment vs. co-treatment. BMC Pharmacol. Toxicol. 2021 22 1 49 10.1186/s40360‑021‑00518‑6 34530934
    [Google Scholar]
  36. Nazarov P.A. Zinovkina L.A. Brezgunova A.A. Lyamzaev K.G. Golovin A.V. Karakozova M.V. Kotova E.A. Plotnikov E.Y. Zinovkin R.A. Skulachev M.V. Antonenko Y.N. Relationship of cytotoxic and antimicrobial effects of triphenylphosphonium conjugates with various quinone derivatives. Biochemistry (Mosc.) 2024 89 2 212 222 10.1134/S0006297924020032 38622091
    [Google Scholar]
  37. Valipour F. Valioğlu F. Rahbarghazi R. Navali A.M. Rashidi M.R. Davaran S. Thermosensitive and biodegradable PCL-based hydrogels: Potential scaffolds for cartilage tissue engineering. J. Biomater. Sci. Polym. Ed. 2023 34 5 695 714 10.1080/09205063.2022.2088530 36745508
    [Google Scholar]
  38. Hodgkinson T. Kelly D.C. Curtin C.M. O’Brien F.J. Mechanosignalling in cartilage: An emerging target for the treatment of osteoarthritis. Nat. Rev. Rheumatol. 2022 18 2 67 84 10.1038/s41584‑021‑00724‑w 34934171
    [Google Scholar]
  39. Ilari S. Nucera S. Passacatini L.C. Caminiti R. Mazza V. Macrì R. Serra M. Scarano F. Malafoglia V. Palma E. Oppedisano F. Maiuolo J. Tomino C. Mollace V. Muscoli C. SIRT1: A likely key for future therapeutic strategies for pain management. Pharmacol. Res. 2025 213 107670 10.1016/j.phrs.2025.107670 39983332
    [Google Scholar]
  40. He X.D. Zhang F. Huang Y. Hao J.J. Zhang M. He J.B. Pu X.M. Li Y.J. Zi L. Yu J. Yang X.X. Potential indicators of mitochondrial structure and function. Curr. Pharm. Des. 2022 28 21 1738 1744 10.2174/1381612828666220520161200 35619320
    [Google Scholar]
  41. Bolduc J.A. Collins J.A. Loeser R.F. Reactive oxygen species, aging and articular cartilage homeostasis. Free Radic. Biol. Med. 2019 132 73 82 10.1016/j.freeradbiomed.2018.08.038 30176344
    [Google Scholar]
  42. Arra M. Swarnkar G. Ke K. Otero J.E. Ying J. Duan X. Maruyama T. Rai M.F. O’Keefe R.J. Mbalaviele G. Shen J. Abu-Amer Y. LDHA-mediated ROS generation in chondrocytes is a potential therapeutic target for osteoarthritis. Nat. Commun. 2020 11 1 3427 10.1038/s41467‑020‑17242‑0 32647171
    [Google Scholar]
  43. Zhang W. Wu J. Zhang F. Dou X. Ma A. Zhang X. Shao H. Zhao S. Ling P. Liu F. Han G. Lower range of molecular weight of xanthan gum inhibits apoptosis of chondrocytes through MAPK signaling pathways. Int. J. Biol. Macromol. 2019 130 79 87 10.1016/j.ijbiomac.2019.01.071 30659877
    [Google Scholar]
  44. Yu H. Huang T. Lu W.W. Tong L. Chen D. Osteoarthritis Pain. Int. J. Mol. Sci. 2022 23 9 4642 10.3390/ijms23094642 35563035
    [Google Scholar]
  45. Liu Y. Nie M. Li X. Wang H. Ren S. Zou D. Liu J. Li R. Garlic-derived exosomes alleviate osteoarthritis through inhibiting the MAPK signaling pathway. Appl. Biochem. Biotechnol. 2025 197 1 518 533 10.1007/s12010‑024‑05047‑6 39190086
    [Google Scholar]
  46. Zhao R. Wei X. Zhang C. Wu H. Xiang C. Li H. Duan W. Duan Z. Li C. Zhao Y. Huang L. α2-macroglobulin-rich serum as a master inhibitor of inflammatory factors attenuates cartilage degeneration in a mini pig model of osteoarthritis induced by “idealized” anterior cruciate ligament reconstruction. Front. Pharmacol. 2022 13 849102 10.3389/fphar.2022.849102 36133821
    [Google Scholar]
  47. Dominic A. Le N.T. Takahashi M. Loop between NLRP3 inflammasome and reactive oxygen species. Antioxid. Redox Signal. 2022 36 10-12 784 796 10.1089/ars.2020.8257 34538111
    [Google Scholar]
  48. Kryl’skii E.D. Popova T.N. Zhaglin D.A. Razuvaev G.A. Oleynik S.A. SkQ1 improves immune status and normalizes activity of NADPH-Generating and antioxidant enzymes in rats with adjuvant-induced rheumatoid arthritis. Biochemistry (Mosc.) 2023 88 8 1092 1104 10.1134/S0006297923080047 37758309
    [Google Scholar]
  49. Hwang H. Kim H. Chondrocyte apoptosis in the pathogenesis of osteoarthritis. Int. J. Mol. Sci. 2015 16 11 26035 26054 10.3390/ijms161125943 26528972
    [Google Scholar]
  50. Markouli M. Pagoni M.N. Diamantopoulos P. BCL-2 inhibitors in hematological malignancies: Biomarkers that predict response and management strategies. Front. Oncol. 2025 14 1501950 10.3389/fonc.2024.1501950 39906657
    [Google Scholar]
  51. Yang H. Xie Y. Yang D. Ren D. Oxidative stress-induced apoptosis in granulosa cells involves JNK, p53 and Puma. Oncotarget 2017 8 15 25310 25322 10.18632/oncotarget.15813 28445976
    [Google Scholar]
  52. Yuan H. Yi N. Li D. Xu C. Yin G.R. Zhuang C. Wang Y.J. Ni S. PPARγ regulates osteoarthritis chondrocytes apoptosis through caspase-3 dependent mitochondrial pathway. Sci. Rep. 2024 14 1 11237 10.1038/s41598‑024‑62116‑w 38755283
    [Google Scholar]
/content/journals/cmp/10.2174/0118761429383749250312082958
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The Mitochondrial Targeting Drug SkQ1 Attenuates the Progression of Post-Traumatic Osteoarthritis through Suppression of Mitochondrial Oxidative Stress
Bentham Science Publishers , e18761429383749; https://doi.org/10.2174/0118761429383749250312082958
/content/journals/cmp/10.2174/0118761429383749250312082958
/content/journals/cmp/10.2174/0118761429383749250312082958
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  • Article Type:     Research Article
Keywords: Apoptosis ; Post-traumatic osteoarthritis ; ROS ; Oxidative stress ; SkQ1 ; Mitochondrial dysfunction

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