The role of exercise in MFN2 regulation in osteoarthritis

Osteoarthritis (OA) is currently the most prevalent degenerative joint disorder worldwide, with hallmarks including cartilage deterioration, low-grade inflammation, and mitochondrial dysfunction. In spite of intensive studies conducted in decades, there is still no disease-modifying treatment available. Mitofusin 2 (MFN2), one of the major mitochondrial fusion regulators, was recently identified as a pivotal molecular interface between mitochondria dynamics and chondrocyte differentiation in osteoarthritic joints. MFN2 demonstrates contradictory functions in the development of OA: protective in the physiological state and pathological when its function is deregulated. Safe, economic, and non-pharmacologic approach, exercise is capable of altering MFN2 expression via various mechanisms including AMPK/PGC-1α-mediated mitochondrial biogenesis, mitophagy due to mechanical loading, and anti-inflammatory NF-κB signaling. This review synthesizes current evidence, primarily from preclinical studies, suggesting that MFN2 may be a key molecular hub linking exercise to mitochondrial homeostasis in OA. We propose a testable model wherein exercise regulates MFN2 expression and function, potentially contributing to chondroprotection. However, we emphasize that the causal relationship remains to be established through targeted validation studies.