Mitochondrial remodeling with mitochondrial fusion promoter M1 for osteoarthritis therapy

Osteoarthritis (OA) is closely associated with mitochondrial dysfunction, but whether mitochondrial dynamics restoration can serve as an effective therapeutic entry point remains unclear. This study investigated the mitochondrial fusion promoter M1 (MFPM1) as a modulator of mitochondrial dynamics in OA and explored its target-associated mechanism. Bioinformatic and transcriptomic analyses linked OA progression and MFPM1 activity to mitochondrial dynamics, oxidative stress, inflammatory activation, apoptosis, and extracellular matrix (ECM) homeostasis. In OA-like chondrocytes, MFPM1 restored the balance between DNM1L/DRP1-associated fission signaling and MFN2/OPA1-associated fusion machinery, accompanied by recovery of mitochondrial energy metabolism and redox homeostasis and attenuation of inflammatory and apoptotic injury. Target prediction, molecular docking, molecular dynamics simulation, and CETSA identified GSK3B as a prioritized MFPM1 target, while GSK3B overexpression weakened the mitochondrial and cartilage-protective effects of MFPM1, supporting its functional involvement. MFPM1 further preserved ECM homeostasis and alleviated OA progression. These findings identify mitochondrial dynamics remodeling as a mechanistic entry point for OA intervention and support MFPM1 as a mitochondria-centered therapeutic candidate.