2. Academic Validation
  3. Deficiency of FUN14 domain-containing 1 enhances the migration and invasion of fibroblast-like synoviocytes in rheumatoid arthritis through mitochondrial dysregulation

Deficiency of FUN14 domain-containing 1 enhances the migration and invasion of fibroblast-like synoviocytes in rheumatoid arthritis through mitochondrial dysregulation

  • Cell Signal. 2025 Aug:132:111829. doi: 10.1016/j.cellsig.2025.111829.
Ye Lu 1,  Ya-Xiong Fang 2,  Zhi-Ming Ou-Yang 1,  Tao Wu 1,  Qian Zhang 1,  Yao-Wei Zou 1,  Hu-Wei Zheng 1,  Jun Jing 1,  Le-Hang Lin 3,  Jian-Da Ma 4,  Zhuoyi Liang 5,  Lie Dai 6
Affiliations

Affiliations

  • 1 Department of Rheumatology and Immunology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China.
  • 2 Bioscience and Biomedical Engineering Thrust, Brain and Intelligence Research Institute, The Hong Kong University of Science and Technology (Guangzhou), Guangzhou 511453, PR China.
  • 3 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China.
  • 4 Department of Rheumatology and Immunology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China. Electronic address: majd@mail.sysu.edu.cn.
  • 5 Bioscience and Biomedical Engineering Thrust, Brain and Intelligence Research Institute, The Hong Kong University of Science and Technology (Guangzhou), Guangzhou 511453, PR China. Electronic address: zhuoyiliang@hkust-gz.edu.cn.
  • 6 Department of Rheumatology and Immunology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China. Electronic address: dailie@mail.sysu.edu.cn.
PMID: 40274085 DOI: 10.1016/j.cellsig.2025.111829
Abstract

Background: Fibroblast-like synoviocytes (FLS) display aggressive phenotypes contributing to synovitis and joint destruction in rheumatoid arthritis (RA). Disrupted mitochondrial homeostasis has been proposed to aggravate the RA pathogenesis, however, the underlying mechanism remains to be elucidated. This study aimed to elucidate the role of Mitophagy receptor FUN14 domain-containing 1 (FUNDC1) on RA-FLS migration and invasion.

Methods: We analyzed the correlation of synovial FUNDC1 expression with joint destruction and disease activity in RA patients. Single cell Sequencing data analysis combined with immunofluorescence indicated the specific expression and localization of FUNDC1 in synovial tissue and RA-FLS. The roles of FUNDC1 in the migration, invasion, and cytokine secretion of RA-FLS were examined by patient-derived primary culture as well as SCID mouse models. We investigated the effects and mechanism of FUNDC1 on Mitophagy and mitochondrial quality control network in primary RA-FLS.

Results: We found that the FUNDC1 was mainly expressed in FLS and exhibited a decreased level in RA synovium, which was correlated with severe joint destruction. Deficiency of FUNDC1 enhanced migration, invasion as well as secretion of Matrix Metalloproteinases in RA-FLS. On the contrary, overexpression of FUNDC1 in RA-FLS with low FUNDC1 inhibited the migration, invasion and secretion capacity of RA-FLS. Mechanistically, repressed FUNDC1 level in RA-FLS impaired Mitophagy, imbalanced mitochondrial quality control, and increased mitochondrial Reactive Oxygen Species (mtROS) production, leading to the overactivation of the MAPK pathway. Treatment with mtROS scavenger mtTEMPO can reverse this process and diminish the invasiveness of RA-FLS.

Conclusions: Deficiency of FUNDC1 dysregulates mitochondrial quality-control system and induces aggressive phenotype of RA-FLS, resulting in joint destruction during RA progression.

Keywords

FUN14 domain-containing 1; Mitochondrial homeostasis; Rheumatoid arthritis.

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