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

Kai Shen, Hao Zhou, Qiang Zuo, Yue Gu, Jiangqi Cheng, Kai Yan, Huiwen Zhang, Huanghe Song, Wenwei Liang, Jinchun Zhou, Jiuxiang Liu, Feng Liu, Chenjun Zhai () and Weimin Fan ()
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Kai Shen: The First Affiliated Hospital of Nanjing Medical University
Hao Zhou: The First Affiliated Hospital of Nanjing Medical University
Qiang Zuo: The First Affiliated Hospital of Nanjing Medical University
Yue Gu: The Second Affiliated Hospital of Nanjing Medical University
Jiangqi Cheng: Zhongda Hospital Affiliated to Southeast University
Kai Yan: The First Affiliated Hospital of Nanjing Medical University
Huiwen Zhang: The Core Facility of the First Affiliated Hospital with Nanjing Medical University
Huanghe Song: The First Affiliated Hospital of Nanjing Medical University
Wenwei Liang: The First Affiliated Hospital of Nanjing Medical University
Jinchun Zhou: The First Affiliated Hospital of Nanjing Medical University
Jiuxiang Liu: The First Affiliated Hospital of Nanjing Medical University
Feng Liu: The First Affiliated Hospital of Nanjing Medical University
Chenjun Zhai: Yixing People’s Hospital
Weimin Fan: The First Affiliated Hospital of Nanjing Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-55335-2

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