Piezo1 as a Key Mechanosensitive Ion Channel Linking Mechanical Overload to Mitochondrial Dysfunction, Mitophagy, and...

Osteoarthritis (OA) is increasingly recognized as a mechanically driven whole-joint disease in which abnormal mechanotransduction initiates a cascade of mitochondrial dysfunction, chronic inflammation, and progressive cartilage degeneration. Among the mechanosensitive molecules identified to date, Piezo1 has emerged as a key mechanosensitive regulator linking pathological mechanical loading to intracellular calcium signaling and downstream cellular responses. Growing evidence indicates that persistent Piezo1 activation promotes mitochondrial calcium overload, excessive reactive oxygen species production, ATP depletion, mitochondrial membrane depolarization, and impaired mitophagy, ultimately amplifying chondrocyte dysfunction and extracellular matrix degradation. In parallel, mitochondrial damage triggers immunometabolic reprogramming through activation of the cGAS-STING pathway and the NLRP3 inflammasome. It also promotes pro-inflammatory cytokines, including interleukin-1β, tumor necrosis factor-α, and interleukin-6. Together, these responses may contribute to a self-perpetuating cycle of inflammation and tissue destruction. This review provides a comprehensive synthesis of recent advances regarding the role of Piezo1 in OA, focusing on the mechanistic links between mechanotransduction, mitochondrial dysfunction, mitophagy, and immunometabolic dysregulation. We further discuss the contribution of mitochondrial quality-control pathways, including PINK1/Parkin-, BNIP3-, and FUNDC1-mediated mitophagy, as well as alterations in mitochondrial dynamics involving DRP1, MFN1, MFN2, and OPA1. Emerging experimental models are discussed as valuable tools for accelerating therapeutic discovery. Finally, we critically evaluate current therapeutic strategies targeting the Piezo1-mitochondria axis, including mechanosensitive channel modulation, mitochondrial protection, mitophagy enhancement, gene therapy, biomaterial-assisted delivery, and nanomedicine. Collectively, current evidence supports the Piezo1-mitochondria-immune axis as an important mechanistic framework contributing to OA pathogenesis and as a potential therapeutic target. Integrating mechanobiology, mitochondrial medicine, and precision-engineered experimental models may facilitate the development of next-generation disease-modifying therapies capable of slowing or preventing osteoarthritis progression.