Jiaqing Liu , Cheng Zhang , Ruicong Ma , Chunlai Yin , Jinyi Ren , Siwen Yang , Ying Zhao , Yawei Tang , Jing Wei , Xia Li
{"title":"下调MiD49和MiD51可减轻胶原诱导的关节炎,抑制类风湿关节炎成纤维细胞样滑膜细胞的线粒体自噬和脂肪酸氧化(FAO)","authors":"Jiaqing Liu , Cheng Zhang , Ruicong Ma , Chunlai Yin , Jinyi Ren , Siwen Yang , Ying Zhao , Yawei Tang , Jing Wei , Xia Li","doi":"10.1016/j.freeradbiomed.2025.08.034","DOIUrl":null,"url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"240 ","pages":"Pages 514-531"},"PeriodicalIF":8.2000,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Knockdown of MiD49 and MiD51 alleviates collagen-induced arthritis and suppresses mitophagy and fatty acid oxidation (FAO) in rheumatoid arthritis fibroblast-like synoviocytes\",\"authors\":\"Jiaqing Liu , Cheng Zhang , Ruicong Ma , Chunlai Yin , Jinyi Ren , Siwen Yang , Ying Zhao , Yawei Tang , Jing Wei , Xia Li\",\"doi\":\"10.1016/j.freeradbiomed.2025.08.034\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>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.</div></div>\",\"PeriodicalId\":12407,\"journal\":{\"name\":\"Free Radical Biology and Medicine\",\"volume\":\"240 \",\"pages\":\"Pages 514-531\"},\"PeriodicalIF\":8.2000,\"publicationDate\":\"2025-08-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Free Radical Biology and Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0891584925009219\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Free Radical Biology and Medicine","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0891584925009219","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Knockdown of MiD49 and MiD51 alleviates collagen-induced arthritis and suppresses mitophagy and fatty acid oxidation (FAO) in rheumatoid arthritis fibroblast-like synoviocytes
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.
期刊介绍:
Free Radical Biology and Medicine is a leading journal in the field of redox biology, which is the study of the role of reactive oxygen species (ROS) and other oxidizing agents in biological systems. The journal serves as a premier forum for publishing innovative and groundbreaking research that explores the redox biology of health and disease, covering a wide range of topics and disciplines. Free Radical Biology and Medicine also commissions Special Issues that highlight recent advances in both basic and clinical research, with a particular emphasis on the mechanisms underlying altered metabolism and redox signaling. These Special Issues aim to provide a focused platform for the latest research in the field, fostering collaboration and knowledge exchange among researchers and clinicians.