Liu Jiaqing, Zhang Cheng, Ma Ruicong, Yin Chunlai, Ren Jinyi, Yang Siwen, Zhao Ying, Tang Yawei, Wei Jing, Li Xia
Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, Liaoning, China.
The Second Hospital of Dalian Medical University, Dalian, Liaoning, China.
Free Radic Biol Med. 2025 Aug 20;240:514-531. doi: 10.1016/j.freeradbiomed.2025.08.034.
Increasing evidence confirms that imbalances in mitochondrial dynamics can impair mitochondrial function, thereby disrupting cellular homeostasis and potentially contributing to a variety of diseases. This study investigated whether mitochondrial dynamics proteins of 49 and 51 kDa (MiD49 and MiD51, MiDs) contribute to the maintenance of the abnormal functions of fibroblast-like synoviocytes (FLS), thereby participating in the pathological process of rheumatoid arthritis (RA), and to elucidate the specific mechanisms. We found that MiDs were significantly upregulated in the FLS of synovial tissues from RA patients and collagen-induced arthritis (CIA) models, as well as in the serum of RA patients. The elevated expression of MiDs in RA serum exhibited a positive correlation with clinical markers. Moreover, knocking down MiD49 or MiD51 alleviated CIA symptoms and attenuated the aggressive behavior of RA-FLS. We found the potential interactions between MiDs and the PTEN-induced kinase 1 (PINK1)-PARK2 E3 ubiquitin-protein ligase (Parkin) pathway, as well as the correlation between the PINK1-Parkin pathway and lipid metabolism, were revealed through protein-protein interaction (PPI) analysis. The PINK1-Parkin-dependent mitophagy and carnitine palmitoyltransferase-1A (CPT-1A) mediated-fatty acid β oxidation (FAO) were impaired following siRNA-mediated knockdown of MiD49 or MiD51. We found that siRNA-mediated knockdown of PINK1 and Parkin effectively reversed the aggressive phenotype of RA-FLS. Finally, we further verified that shRNA targeting MiD49 or MiD51 inhibited Pink1-Parkin-dependent mitophagy and CPT-1A-regulated FAO in FLS derived from the synovial tissues of CIA models. Our study highlights the involvement of MiDs-mediated mitochondrial dynamics dysfunction helps maintain the invasiveness of FLS, and thereby participates in the pathogenesis of RA. These findings provide a theoretical basis for the development of potential therapies for RA in the future.
越来越多的证据证实，线粒体动力学失衡会损害线粒体功能，从而破坏细胞内环境稳态，并可能导致多种疾病。本研究调查了49 kDa和51 kDa的线粒体动力学蛋白（MiD49和MiD51，MiDs）是否有助于维持成纤维样滑膜细胞（FLS）的异常功能，从而参与类风湿关节炎（RA）的病理过程，并阐明其具体机制。我们发现，MiDs在RA患者和胶原诱导性关节炎（CIA）模型的滑膜组织FLS中以及RA患者血清中显著上调。RA血清中MiDs的表达升高与临床指标呈正相关。此外，敲低MiD49或MiD51可减轻CIA症状，并减弱RA-FLS的侵袭性行为。通过蛋白质-蛋白质相互作用（PPI）分析，我们发现了MiDs与PTEN诱导激酶1（PINK1）-PARK2 E3泛素蛋白连接酶（Parkin）途径之间的潜在相互作用，以及PINK1-Parkin途径与脂质代谢之间的相关性。在siRNA介导的MiD49或MiD51敲低后，PINK1-Parkin依赖性线粒体自噬和肉碱棕榈酰转移酶-1A（CPT-1A）介导的脂肪酸β氧化（FAO）受损。我们发现，siRNA介导的PINK1和Parkin敲低可有效逆转RA-FLS的侵袭性表型。最后，我们进一步验证了靶向MiD49或MiD51的shRNA抑制了CIA模型滑膜组织来源的FLS中Pink1-Parkin依赖性线粒体自噬和CPT-1A调节的FAO。我们的研究强调了MiDs介导的线粒体动力学功能障碍参与维持FLS的侵袭性，从而参与RA的发病机制。这些发现为未来开发RA的潜在治疗方法提供了理论依据。
