GATD3A-deficiency-induced mitochondrial dysfunction facilitates senescence of fibroblast-like synoviocytes and osteoarthritis progression
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...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55335-2 |
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| author | 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 Weimin Fan |
| author_facet | 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 Weimin Fan |
| author_sort | Kai Shen |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-bb8fc745b0e64aeb990f9fcb9d285edc |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-bb8fc745b0e64aeb990f9fcb9d285edc2025-01-05T12:35:38ZengNature PortfolioNature Communications2041-17232024-12-0115111810.1038/s41467-024-55335-2GATD3A-deficiency-induced mitochondrial dysfunction facilitates senescence of fibroblast-like synoviocytes and osteoarthritis progressionKai Shen0Hao Zhou1Qiang Zuo2Yue Gu3Jiangqi Cheng4Kai Yan5Huiwen Zhang6Huanghe Song7Wenwei Liang8Jinchun Zhou9Jiuxiang Liu10Feng Liu11Chenjun Zhai12Weimin Fan13Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of Orthopaedics, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of Orthopaedics, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of Orthopaedics, The Second Affiliated Hospital of Nanjing Medical UniversityDepartment of Orthopaedics, Zhongda Hospital Affiliated to Southeast UniversityDepartment of Orthopaedics, The First Affiliated Hospital of Nanjing Medical UniversityThe Core Facility of the First Affiliated Hospital with Nanjing Medical UniversityDepartment of Orthopaedics, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of Orthopaedics, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of Orthopaedics, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of Orthopaedics, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of Orthopaedics, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of Orthopaedics, Yixing People’s HospitalDepartment of Orthopaedics, The First Affiliated Hospital of Nanjing Medical UniversityAbstract 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.https://doi.org/10.1038/s41467-024-55335-2 |
| spellingShingle | 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 Weimin Fan GATD3A-deficiency-induced mitochondrial dysfunction facilitates senescence of fibroblast-like synoviocytes and osteoarthritis progression Nature Communications |
| title | GATD3A-deficiency-induced mitochondrial dysfunction facilitates senescence of fibroblast-like synoviocytes and osteoarthritis progression |
| title_full | GATD3A-deficiency-induced mitochondrial dysfunction facilitates senescence of fibroblast-like synoviocytes and osteoarthritis progression |
| title_fullStr | GATD3A-deficiency-induced mitochondrial dysfunction facilitates senescence of fibroblast-like synoviocytes and osteoarthritis progression |
| title_full_unstemmed | GATD3A-deficiency-induced mitochondrial dysfunction facilitates senescence of fibroblast-like synoviocytes and osteoarthritis progression |
| title_short | GATD3A-deficiency-induced mitochondrial dysfunction facilitates senescence of fibroblast-like synoviocytes and osteoarthritis progression |
| title_sort | gatd3a deficiency induced mitochondrial dysfunction facilitates senescence of fibroblast like synoviocytes and osteoarthritis progression |
| url | https://doi.org/10.1038/s41467-024-55335-2 |
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