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

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.