Osteoarthritis (OA) is an age-related cartilage-degenerating joint disease. Mitochondrial dysfunction has been reported to promote the development of OA. Poly (ADP-ribose) polymerase family member 12 (PARP12) is a key regulator of mitochondrial function, protein translation, and inflammation. However, the role of PARP12 in OA-based cartilage degradation and the underlying mechanisms are relatively unknown. Here, we first demonstrated that PARP12 inhibits mitophagy and promotes OA progression in human OA cartilage and a monosodium iodoacetate-induced rat OA model. Using mass spectrometry and co-immunoprecipitation assay, PARP12 was shown to interact with ISG15, upregulate mitofusin 1 and 2 (MFN1/2) ISGylation, which downregulated MFN1/2 ubiquitination and SUMOylation, thereby inhibiting PINK1/Parkin-dependent chondrocyte mitophagy and promoting cartilage degradation. Moreover, inflammatory cytokine-induced interferon regulatory factor 1 (IRF1) activation was required for the upregulation of PARP12 expression, and it directly bound to the PARP12 promoter to activate transcription. XAV-939 inhibited PARP12 expression and suppressed OA pathogenesis in vitro and in vivo. Clinically, PARP12 can be used to predict the severity of OA; thus, it represents a new target for the study of mitophagy and OA progression. In brief, the IRF1-mediated upregulation of PARP12 promoted cartilage degradation by inhibiting PINK1/Parkin-dependent mitophagy via ISG15-based attenuation of MFN1/2 ubiquitylation and SUMOylation. Our data provide new insights into the molecular mechanisms underlying PARP12-based regulation of mitophagy and can facilitate the development of therapeutic strategies for the treatment of OA.

骨关节炎 （OA） 是一种与年龄相关的软骨退化关节疾病。据报道，线粒体功能障碍会促进 OA 的发展。Poly （ADP-ribose） 聚合酶家族成员 12 （PARP12） 是线粒体功能、蛋白质翻译和炎症的关键调节因子。然而，PARP12 在基于 OA 的软骨降解中的作用和潜在机制相对未知。在这里，我们首先证明 PARP12 抑制人 OA 软骨和碘乙酸单钠诱导的大鼠 OA 模型中的线粒体自噬并促进 OA 进展。使用质谱和免疫共沉淀测定，PARP12 与 ISG15 相互作用，上调线粒体融合蛋白 1 和 2 （MFN1/2） ISGylation，从而下调 MFN1/2 泛素化和 SUMO化，从而抑制 PINK1/Parkin 依赖性软骨细胞有丝分裂并促进软骨降解。此外，炎性细胞因子诱导的干扰素调节因子 1 （IRF1） 激活是 PARP12 表达上调所必需的，它直接与 PARP12 启动子结合以激活转录。XAV-939 在体外和体内抑制 PARP12 表达并抑制 OA 发病机制。临床上，PARP12 可用于预测 OA 的严重程度;因此，它代表了研究线粒体自噬和 OA 进展的新靶点。简而言之，IRF1 介导的 PARP12 上调通过基于 ISG15 的 MFN1/2 泛素化和 SUMO 化减弱抑制 PINK1/Parkin 依赖性线粒体自噬，从而促进软骨降解。我们的数据为基于 PARP12 的线粒体自噬调节的分子机制提供了新的见解，并可以促进治疗 OA 的治疗策略的开发。