SESN2 drives osteoarthritis progression by inducing MFN2-dependent mitochondrial hyperfusion in rats

OBJECTIVE: This study aimed to elucidate the role of SESN2 in the pathological process of osteoarthritis (OA), with a particular focus on its potential mechanism in regulating chondrocyte mitochondrial function. DESIGN: In vitro and in vivo inflammatory models were established using SpragueDawley rats via IL-1β stimulation and surgical destabilization of the medial meniscus (DMM). siRNA, overexpression plasmids, and adeno-associated viruses were used to investigate the role of SESN2 in OA progression, and mechanistic studies were performed to clarify the underlying pathways and downstream targets. RESULTS: SESN2 expression was significantly upregulated in the chondrocytes and cartilage tissues of OA rats. SESN2 overexpression exacerbated IL-1β-induced chondrocyte inflammation and DMM-induced cartilage damage (OARSI score, 2.000 [95% CI: 0.000-5.000]); conversely, SESN2 knockdown alleviated metabolic disorders and mitochondrial dysfunction in the matrix (Relative ATP content, 0.2639 [95% CI: 0.1068-0.4209]) and ameliorated cartilage degeneration in vivo (OARSI score, -2.000 [95% CI: -5.000 to -1.000]). Mechanistic studies revealed that SESN2 induced mitochondrial hyperfusion in chondrocytes (Mean branch length, 0.4821 [95% CI: 0.2707-0.6935]) and exacerbated mitochondrial dysfunction and inflammation via excessive mitochondrial fusion mediated by MFN2. Further investigation revealed that SESN2 upregulated MFN2 protein expression by promoting its dephosphorylation (Relative protein expression, 0.7693 [95% CI: 0.5392-0.9994]), thereby inducing mitochondrial hyperfusion. CONCLUSIONS: SESN2 promotes chondrocyte mitochondrial dysfunction and the pathological progression of OA by regulating MFN2 dephosphorylation to induce mitochondrial hyperfusion, thereby providing a new potential target for intervention in OA.