Mitochondrial quality control modulating chondrocyte behavior and fate in knee osteoarthritis: mechanistic insights and therapeutic prospects

Osteoarthritis (OA) is a highly prevalent and debilitating joint disorder that imposes a heavy burden on global public health due to its high incidence, prevalence, and disability rate, as well as the associated substantial healthcare costs. Early intervention is critical for OA management, yet current therapeutic options are limited by suboptimal efficacy, along with concerns regarding prosthetic lifespan and function in surgical treatment. While the complete etiology of OA remains elusive, cartilage degeneration is widely recognized as a core pathological feature of OA. A major barrier to optimizing OA therapeutic strategies is the lack of comprehensive insights into the underlying molecular mechanisms governing disease progression. Chondrocyte behavior and fate determination are pivotal to the onset and progression of OA: OA chondrocytes exhibit an imbalanced synthetic/catabolic profile, cluster formation, and autophagy dysregulation, accompanied by phenotypic alterations including hypertrophy and senescence. Additionally, multiple forms of chondrocyte death (apoptosis, chondroptosis, necrosis, necroptosis, autophagic cell death, pyroptosis, and ferroptosis) are implicated in driving OA development. Mitochondrial quality control (MQC), a cellular process encompassing redox homeostasis, mitophagy, mitochondrial dynamics (fusion and fission), and mitochondrial biogenesis, is essential for maintaining mitochondrial function and cellular homeostasis. Accumulating evidence indicates that MQC is closely involved in regulating chondrocyte behavior and fate in OA, and impaired MQC function may compromise chondrocyte viability and function, thereby promoting cartilage degeneration. Elucidating the MQC-mediated pathological mechanisms underlying abnormal chondrocyte behavior and fate in OA is expected to identify novel therapeutic targets for early-stage OA, thus providing new avenues for the development of more effective preventive and therapeutic strategies for this disorder.