GATD3A-deficiency-induced mitochondrial dysfunction facilitates senescence of fibroblast-like synoviocytes and osteoarthritis progression

衰老 骨关节炎 成纤维细胞 线粒体 医学 细胞生物学 癌症研究 生物 生物信息学 遗传学 病理 细胞培养 替代医学
作者
Kai Shen,Hao Zhou,Qiang Zuo,Yue Gu,Jiangqi Cheng,Kai Yan,Huiwen Zhang,Huanghe Song,Wen-Wei Liang,Jinchun Zhou,Jiuxiang Liu,Feng Liu,Chenjun Zhai,Weimin Fan
出处
期刊:Nature Communications [Springer Nature]
卷期号:15 (1)
标识
DOI:10.1038/s41467-024-55335-2
摘要

Accumulating evidence indicates that cellular senescence is closely associated with osteoarthritis. However, there is limited research on the mechanisms underlying fibroblast-like synoviocyte senescence and its impact on osteoarthritis progression. Here, we elucidate a positive correlation between fibroblast-like synoviocyte senescence and osteoarthritis progression and reveal that GATD3A deficiency induces fibroblast-like synoviocyte senescence. Mechanistically, GATD3A deficiency enhances the binding of Sirt3 to MDH2, leading to deacetylation and decreased activity of MDH2. Reduced MDH2 activity impairs tricarboxylic acid cycle flux, resulting in mitochondrial dysfunction and fibroblast-like synoviocyte senescence. Intra-articular injection of recombinant adeno-associated virus carrying GATD3A significantly alleviates the osteoarthritis phenotype in male mice. This study increases our current understanding of GATD3A function. In particular, we reveal a novel mechanism of fibroblast-like synoviocyte senescence, suggesting that targeting GATD3A is a potential therapeutic approach for osteoarthritis. The mechanisms underlying fibroblast-like synoviocyte senescence and its impact on osteoarthritis progression are unclear. Here, the authors show that GATD3A deficiency induces fibroblast-like synoviocyte senescence in mice and demonstrate that targeting GATD3A alleviates symptoms in mouse models of osteoarthritis.
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