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Review Open Access

Targeting mitochondrial oxidative stress: A novel therapeutic strategy for degenerative joint diseases (Review)

  • Authors:
    • Yang Hou
    • Xiaolei Yang
    • Tianyi Zhao
    • Yongfei Guo
    • Jiangang Shi
  • View Affiliations / Copyright

    Affiliations: Department of Orthopaedic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
    Copyright: © Hou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 26
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    Published online on: December 15, 2025
       https://doi.org/10.3892/br.2025.2099
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Abstract

Degenerative joint diseases, such as osteoarthritis (OA), intervertebral disc degeneration (IVDD) and rheumatoid arthritis (RA), cause pain and disability worldwide. Globally, OA affects >500 million individuals, IVDD affects 40‑60% of adults and RA affects 0.5‑1% of the global population. Current treatments (such as non‑steroidal anti‑inflammatory drugs and corticosteroids for OA, conservative management and spinal surgery for IVDD, and disease‑modifying anti‑rheumatic drugs/biologics for RA) focus on symptom relief and inflammation control, but they do not prevent disease progression nor restore damaged tissue. Furthermore, these treatments are often associated with risks of systemic side effects (such as gastrointestinal bleeding, cardiovascular events and immunosuppression) or surgical complications (such as infection and implant failure). Although accumulating evidence implicates mitochondrial dysfunction and excessive reactive oxygen species (ROS) in the pathogenesis of these disorders, strategies that directly target mitochondrial oxidative stress are yet to be developed and translated into the clinic. In the present study this gap in the knowledge was addressed by systematically reviewing mitochondria‑targeted antioxidant therapies and mitochondrial quality‑control mechanisms due to their potential as novel, disease‑modifying approaches for degenerative joint diseases. The preclinical efficacy of mitochondria‑directed antioxidants (such as mitoquinone, MitoTEMPO, 10‑(6'‑plastoquinonyl) decyltriphenylphosphonium and Szeto‑Schiller‑31) in alleviating ROS‑induced cellular damage, inhibiting apoptosis/pyroptosis and preserving extracellular matrix integrity in OA, IVDD and RA models were summarized. Additionally, strategies to enhance mitophagy (such as through PTEN‑induced kinase 1/Parkin), rebalance mitochondrial dynamics (such as through the dynamin‑related protein 1/mitofusin 1/2) and activate antioxidant signaling pathways (such as nuclear factor erythroid 2‑related factor 2 and sirtuin 3) were highlighted. The present study identified key translational challenges (such as optimal delivery systems, long‑term safety and clinical validation) and suggested integrated therapeutic frameworks that combine targeted antioxidants with advanced drug carriers and adjunctive treatments. Mitochondria‑focused interventions may have potential as the next generation of disease‑modifying treatments for OA, IVDD and RA.
View Figures

Figure 1

Schematic illustration of
mitochondrial reactive oxygen species generation and the
antioxidant defense systems. During mitochondrial respiration,
electron leakage from the electron transport chain leads to the
formation of superoxide anions, which are subsequently converted to
hydrogen peroxide and hydroxyl radicals through enzymatic and
non-enzymatic reactions. To counteract oxidative stress,
mitochondria utilize several antioxidant mechanisms, such as SOD
that catalyzes the dismutation of superoxide into
H2O2, which is further detoxified by Gpx and
PRX. The glutathione system, composed of reduced GSH, oxidized GSSG
and GR, maintains redox homeostasis. In parallel, the Trx/TRR
system reduces oxidized proteins and supports peroxiredoxin
activity. Cyt C is also a key electron carrier and its release into
the cytosol can trigger apoptotic signaling. Gpx, glutathione
peroxidase; PRX, peroxiredoxin; SOD, superoxide dismutase; Cyt C,
cytochrome c; GR, glutathione reductase; GSSG, glutathione
disulfide; GSH, glutathione; TRR, thioredoxin reductase; Trx,
thioredoxin; ox, oxidized; red, reduced.

Figure 2

Mitochondrial stress responses
following ROS-induced damage and the protective signaling pathways
that maintain mitochondrial quality. ROS overproduction disrupts
mitochondrial dynamics, leading to altered fusion (mediated by Mfn1
and 2, and Opa1) and fission (promoted by Drp1 and Fis1). Damaged
mitochondria activate mitophagy, in which PINK1 accumulates on the
outer mitochondrial membrane to recruit PARKIN, an E3 ubiquitin
ligase, facilitating ubiquitination of outer membrane proteins.
Receptors such as FUNDC1, NIX and BNIP3 interact with LC3 to
promote autophagosome formation, while PHB2 functions as an inner
membrane mitophagy receptor. Additionally, the Keap1-Nrf2-ARE
signaling axis provides antioxidant defense, with sMaf proteins
serving as transcriptional partners of Nrf2 in activating
antioxidant response elements. These pathways together coordinate
mitochondrial turnover and cytoprotective responses. ROS, reactive
oxygen species; Mfn1, mitofusin 1; Mfn2, mitofusin 2; Opa1, optic
atrophy 1; Drp1, dynamin-related protein 1; Fis1, fission protein
1; PINK1, PTEN-induced kinase 1; PARKIN, E3 ubiquitin ligase
involved in mitophagy; FUNDC1, FUN14 domain-containing protein 1;
NIX, BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like;
BNIP3, BCL-2/adenovirus E1B 19 kDa protein-interacting protein 3;
LC3, microtubule-associated protein 1 light chain 3; Nrf2, nuclear
factor erythroid 2-related factor 2; sMaf, small musculoaponeurotic
fibrosarcoma oncogene homologs that dimerize with Nrf2; Keap1,
Kelch-like ECH-associated protein 1; ARE, antioxidant response
element; PHB2, prohibitin 2.
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Copy and paste a formatted citation
Spandidos Publications style
Hou Y, Yang X, Zhao T, Guo Y and Shi J: Targeting mitochondrial oxidative stress: A novel therapeutic strategy for degenerative joint diseases (Review). Biomed Rep 24: 26, 2026.
APA
Hou, Y., Yang, X., Zhao, T., Guo, Y., & Shi, J. (2026). Targeting mitochondrial oxidative stress: A novel therapeutic strategy for degenerative joint diseases (Review). Biomedical Reports, 24, 26. https://doi.org/10.3892/br.2025.2099
MLA
Hou, Y., Yang, X., Zhao, T., Guo, Y., Shi, J."Targeting mitochondrial oxidative stress: A novel therapeutic strategy for degenerative joint diseases (Review)". Biomedical Reports 24.2 (2026): 26.
Chicago
Hou, Y., Yang, X., Zhao, T., Guo, Y., Shi, J."Targeting mitochondrial oxidative stress: A novel therapeutic strategy for degenerative joint diseases (Review)". Biomedical Reports 24, no. 2 (2026): 26. https://doi.org/10.3892/br.2025.2099
Copy and paste a formatted citation
x
Spandidos Publications style
Hou Y, Yang X, Zhao T, Guo Y and Shi J: Targeting mitochondrial oxidative stress: A novel therapeutic strategy for degenerative joint diseases (Review). Biomed Rep 24: 26, 2026.
APA
Hou, Y., Yang, X., Zhao, T., Guo, Y., & Shi, J. (2026). Targeting mitochondrial oxidative stress: A novel therapeutic strategy for degenerative joint diseases (Review). Biomedical Reports, 24, 26. https://doi.org/10.3892/br.2025.2099
MLA
Hou, Y., Yang, X., Zhao, T., Guo, Y., Shi, J."Targeting mitochondrial oxidative stress: A novel therapeutic strategy for degenerative joint diseases (Review)". Biomedical Reports 24.2 (2026): 26.
Chicago
Hou, Y., Yang, X., Zhao, T., Guo, Y., Shi, J."Targeting mitochondrial oxidative stress: A novel therapeutic strategy for degenerative joint diseases (Review)". Biomedical Reports 24, no. 2 (2026): 26. https://doi.org/10.3892/br.2025.2099
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