The impact of mitochondrial dysfunction on osteoarthritis cartilage: current insights and emerging mitochondria-targeted therapies

Abstract

Osteoarthritis (OA) is a degenerative joint disease associated with age, prominently marked by articular cartilage degradation. In OA cartilage, the pathological manifestations show elevated chondrocyte hypertrophy and apoptosis. The mitochondrion serves as key energy supporter in eukaryotic cells and is tightly linked to a myriad of diseases including OA. As age advances, mitochondrial function declines progressively, which leads to an imbalance in chondrocyte energy homeostasis, partially initiating the process of cartilage degeneration. Elevated oxidative stress, impaired mitophagy and mitochondrial dynamics jointly contribute to chondrocyte pathology, with mitochondrial DNA haplogroups, particularly haplogroup J, influencing OA progression. Therapeutic approaches directed at mitochondria have demonstrated remarkable efficacy in treating various diseases, with triphenylphosphonium (TPP) emerging as the most widely utilized molecule. Other strategies encompass Dequalinium (DQA), the Szeto-Schiller (SS) tetrapeptide family, the KLA peptide, and mitochondrial-penetrating peptides (MPP), etc. These molecules share common properties of lipophilicity and positive charge. Through various technological modifications, they are conjugated to nanocarriers, enabling targeted drug delivery to mitochondria. Therapeutic interventions targeting mitochondria offer a hopeful direction for OA treatment. In the future, mitochondria-targeted therapy is anticipated to improve the well-being of life for the majority of OA patients. This review summarizes the link between chondrocyte mitochondrial dysfunction and OA, as well as discusses promising mitochondria-targeted therapies and potential therapeutic compounds.

Fig. 1

Articular cartilage structure and OA pathology. a Organization of articular cartilage. Articular cartilage mainly consists of chondrocytes and extracellular matrix (ECM). Oxygen and nutrients are delivered through the passive diffusion from the synovial fluid, thus forms a concentration gradient. b The microscopic pathological manifestations of OA cartilage show chondrocyte hypertrophy and apoptosis, as well as ECM loss and calcification

Fig. 2

Excessive level of ROS promotes cytochrome c release via two distinct mechanisms: (1) MPT-dependent pathways, where ROS oxidize thiol groups on the adenine nucleotide translocator (ANT), inducing MPT, matrix swelling, and OMM rupture; and (2) MPT-independent pathways, involving cardiolipin peroxidation—which destabilizes cytochrome c binding to IMM—and subsequent release through OMM channels (e.g., VDAC) or Bax/Bak oligomerization. Cytochrome c then enters the cytoplasm and activates the caspase cascade to trigger chondrocyte apoptosis

Fig. 3

The structure of the mitochondrion. IMM and OMM are phospholipid bilayers surrounding mitochondrial matrix. The components of mitochondrial electron transport chain are located on IMM, including complexes I-IV and ATP synthase, among which the complexes I and III are the major source of O₂^•−. SOD2 catalyses the dismutation of O₂^•− into H₂O₂ and O₂, subsequently other antioxidants such as CAT converting H₂O₂ into H₂O. The activity of SOD2 can be upregulated by the deacetylation of SIRT3. ΔΨ, mitochondrial membrane potential; mPTP, mitochondrial permeability transition pore; MPT, mitochondrial permeability transition; OMM, outer mitochondrial membrane; IMM, inner mitochondrial membrane

Fig. 4

Summary of the key proteins and signaling pathways involved in mitochondrial dynamics. Mitochondrial fission is mainly mediated by DRP1, which binds to the OMM in a ring-like structure, and then the organelle divides into two separate mitochondria. OPA1, together with MFN1/2, mediates mitochondrial fusion, with MFN1/2 mainly regulating OMM fusion and OPA1 primarily controlling IMM fusion. Red arrows indicate activation or upregulation of pathway; while blue lines indicate repression or inhibition of the pathway. OMM, outer mitochondrial membrane; IMM, inner mitochondrial membrane; DRP1, Dynamin-Related Protein 1; MFN1 and MFN2, mitofusin 1 and mitofusin 2; OPA1, Optic Atrophy Protein 1