Department of Sports Medicine, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
Department of Sports Medicine, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
Biomaterials. 2025 Mar;314:122903. doi: 10.1016/j.biomaterials.2024.122903. Epub 2024 Oct 23.
N7-methylguanosine (mG) modification is one of the most prevalent RNA modifications, and methyltransferase-like protein-1 (METTL1) is a key component of the mG methyltransferase complex. METTL1-catalyzed mG as a new RNA modification pathway that regulates RNA structure, biogenesis, and cell migration. Increasing evidence indicates that mG modification has been implicated in the pathophysiological process of osteoarthritis (OA). However, the underlying molecular mechanisms of mG modification remains incompletely elucidated during the progression of OA. Here we found that METTL1 and mG levels were markedly increased in OA chondrocytes. In addition, METTL1-mediated mG modification upregulated mt-tRF3b-LeuTAA expression to exacerbate chondrocyte degeneration. Mechanistically, mt-tRF3b-LeuTAA decreased the SUMO-specific protease 1 (SENP1) protein expression and upregulated the level of sirtuin 3 (SIRT3) SUMOylation to inhibit PTEN induced kinase 1 (PINK1)/Parkin-mediated mitochondrial mitophagy. Intra-articular injection of PMC-tRF3b-LeuTAA inhibitor (Polyamidoamine-polyethylene glycol surface-modified with Minimal self-peptides and Chondrocyte-affinity peptides, PMC) attenuated destabilization of the medial meniscus (DMM) mouse cartilage degeneration in vivo. Our study demonstrates that METTL1/mG/mt-tRF3b-LeuTAA axis accelerate cartilage degradation by inhibiting mitophagy and promoting mitochondrial dysfunction through SIRT3 SUMOylation, and suggest that targeting METTL1 and its downstream signaling axis could be a promising therapeutic target for OA treatment.
N7-甲基鸟苷（mG）修饰是最普遍的 RNA 修饰之一，甲基转移酶样蛋白 1（METTL1）是 mG 甲基转移酶复合物的关键组成部分。METTL1 催化的 mG 作为一种新的 RNA 修饰途径，调节 RNA 结构、生物发生和细胞迁移。越来越多的证据表明，mG 修饰参与了骨关节炎（OA）的病理生理过程。然而，mG 修饰在 OA 进展过程中的潜在分子机制仍不完全清楚。在这里，我们发现 METTL1 和 mG 水平在 OA 软骨细胞中显著升高。此外，METTL1 介导的 mG 修饰上调 mt-tRF3b-LeuTAA 的表达，加剧软骨细胞退变。在机制上，mt-tRF3b-LeuTAA 降低了 SUMO 特异性蛋白酶 1（SENP1）蛋白表达，并上调了 SIRT3 SUMOylation 水平，抑制了 PTEN 诱导的激酶 1（PINK1）/Parkin 介导的线粒体自噬。关节内注射 PMC-tRF3b-LeuTAA 抑制剂（聚酰胺-胺-聚乙二醇表面修饰最小自身肽和软骨细胞亲和肽，PMC）可减轻体内内侧半月板不稳定（DMM）小鼠软骨退变。我们的研究表明，METTL1/mG/mt-tRF3b-LeuTAA 轴通过 SIRT3 SUMOylation 抑制自噬并促进线粒体功能障碍，加速软骨降解，并表明靶向 METTL1 及其下游信号轴可能是 OA 治疗的有前途的治疗靶点。
