Mitochondrial calcium uniporter promotes MSU crystal-induced inflammation through inducing mitochondrial Ca2+ overload and ubiquitination of SIRT5 protein
Abstract Background The mitochondrial calcium uniporter (MCU) is the key channel regulating mitochondrial calcium (Ca²⁺) uptake. Growing evidence indicates that mitochondrial Ca²⁺ homeostasis plays a pivotal role in regulating immune cell function. However, how MCU contributes to MSU crystal-driven...
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BMC
2025-08-01
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| Series: | Arthritis Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13075-025-03627-3 |
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| author | Qingqing Yu Renjie Li Guizhao Yang Yan Xiao Xingyu Liu Yaxin Deng Xiongyan Luo Qian Dai Mei Zeng |
| author_facet | Qingqing Yu Renjie Li Guizhao Yang Yan Xiao Xingyu Liu Yaxin Deng Xiongyan Luo Qian Dai Mei Zeng |
| author_sort | Qingqing Yu |
| collection | DOAJ |
| description | Abstract Background The mitochondrial calcium uniporter (MCU) is the key channel regulating mitochondrial calcium (Ca²⁺) uptake. Growing evidence indicates that mitochondrial Ca²⁺ homeostasis plays a pivotal role in regulating immune cell function. However, how MCU contributes to MSU crystal-driven inflammation and its molecular mechanisms are unclear. Methods Using bone marrow-derived macrophages (BMDMs), wild-type (WT, MCU⁺/⁺), and MCU knockout (MCU⁻/⁻) mice, we investigated the role of MCU in MSU crystal-induced inflammation. Co-immunoprecipitation assays were employed to examine interactions among MCU, SIRT5, and TRIM21. Results MSU crystals stimulation up-regulated MCU expression and triggered mitochondrial Ca²⁺ overload in macrophages. MCU deficiency reduced mitochondrial Ca²⁺ accumulation, ameliorated mitochondrial dysfunction, and suppressed NLRP3 inflammasome activation in BMDMs treated with MSU crystals. Mechanistically, MCU promoted TRIM21 expression, leading to SIRT5 ubiquitination and degradation. Furthermore, MCU facilitated the interaction between TRIM21 and SIRT5, with MSU crystals enhancing this tripartite association. TRIM21 and SIRT5 were identified as key downstream effectors of MCU, mediating MSU crystal-induced inflammatory responses and oxidative stress. In vivo, MCU deficient mice exhibited diminished immune cell infiltration and IL-1β production in MSU crystal-induced peritonitis and arthritis models. Conclusion Our findings demonstrate that MCU drives mitochondrial Ca²⁺ overload in MSU crystal-induced inflammation and promotes SIRT5 degradation via the TRIM21-SIRT5 signaling axis. These insights highlight MCU as a potential therapeutic target in gouty inflammation. |
| format | Article |
| id | doaj-art-e443af2ace75485a9207a34be9add493 |
| institution | Kabale University |
| issn | 1478-6362 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Arthritis Research & Therapy |
| spelling | doaj-art-e443af2ace75485a9207a34be9add4932025-08-24T11:42:18ZengBMCArthritis Research & Therapy1478-63622025-08-0127112010.1186/s13075-025-03627-3Mitochondrial calcium uniporter promotes MSU crystal-induced inflammation through inducing mitochondrial Ca2+ overload and ubiquitination of SIRT5 proteinQingqing Yu0Renjie Li1Guizhao Yang2Yan Xiao3Xingyu Liu4Yaxin Deng5Xiongyan Luo6Qian Dai7Mei Zeng8Institute of Rheumatology and Immunology, the Affiliated Hospital of North Sichuan Medical College, 1# South Maoyuan Road and Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical CollegeInstitute of Rheumatology and Immunology, the Affiliated Hospital of North Sichuan Medical College, 1# South Maoyuan Road and Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical CollegeInstitute of Rheumatology and Immunology, the Affiliated Hospital of North Sichuan Medical College, 1# South Maoyuan Road and Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical CollegeInstitute of Rheumatology and Immunology, the Affiliated Hospital of North Sichuan Medical College, 1# South Maoyuan Road and Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical CollegeInstitute of Rheumatology and Immunology, the Affiliated Hospital of North Sichuan Medical College, 1# South Maoyuan Road and Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical CollegeInstitute of Rheumatology and Immunology, the Affiliated Hospital of North Sichuan Medical College, 1# South Maoyuan Road and Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical CollegeDepartment of Rheumatology and Immunology, West China Hospital, Sichuan UniversityInstitute of Rheumatology and Immunology, the Affiliated Hospital of North Sichuan Medical College, 1# South Maoyuan Road and Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical CollegeInstitute of Rheumatology and Immunology, the Affiliated Hospital of North Sichuan Medical College, 1# South Maoyuan Road and Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical CollegeAbstract Background The mitochondrial calcium uniporter (MCU) is the key channel regulating mitochondrial calcium (Ca²⁺) uptake. Growing evidence indicates that mitochondrial Ca²⁺ homeostasis plays a pivotal role in regulating immune cell function. However, how MCU contributes to MSU crystal-driven inflammation and its molecular mechanisms are unclear. Methods Using bone marrow-derived macrophages (BMDMs), wild-type (WT, MCU⁺/⁺), and MCU knockout (MCU⁻/⁻) mice, we investigated the role of MCU in MSU crystal-induced inflammation. Co-immunoprecipitation assays were employed to examine interactions among MCU, SIRT5, and TRIM21. Results MSU crystals stimulation up-regulated MCU expression and triggered mitochondrial Ca²⁺ overload in macrophages. MCU deficiency reduced mitochondrial Ca²⁺ accumulation, ameliorated mitochondrial dysfunction, and suppressed NLRP3 inflammasome activation in BMDMs treated with MSU crystals. Mechanistically, MCU promoted TRIM21 expression, leading to SIRT5 ubiquitination and degradation. Furthermore, MCU facilitated the interaction between TRIM21 and SIRT5, with MSU crystals enhancing this tripartite association. TRIM21 and SIRT5 were identified as key downstream effectors of MCU, mediating MSU crystal-induced inflammatory responses and oxidative stress. In vivo, MCU deficient mice exhibited diminished immune cell infiltration and IL-1β production in MSU crystal-induced peritonitis and arthritis models. Conclusion Our findings demonstrate that MCU drives mitochondrial Ca²⁺ overload in MSU crystal-induced inflammation and promotes SIRT5 degradation via the TRIM21-SIRT5 signaling axis. These insights highlight MCU as a potential therapeutic target in gouty inflammation.https://doi.org/10.1186/s13075-025-03627-3MCUMSU crystalsMitochondrial Ca2+TRIM21SIRT5 |
| spellingShingle | Qingqing Yu Renjie Li Guizhao Yang Yan Xiao Xingyu Liu Yaxin Deng Xiongyan Luo Qian Dai Mei Zeng Mitochondrial calcium uniporter promotes MSU crystal-induced inflammation through inducing mitochondrial Ca2+ overload and ubiquitination of SIRT5 protein Arthritis Research & Therapy MCU MSU crystals Mitochondrial Ca2+ TRIM21 SIRT5 |
| title | Mitochondrial calcium uniporter promotes MSU crystal-induced inflammation through inducing mitochondrial Ca2+ overload and ubiquitination of SIRT5 protein |
| title_full | Mitochondrial calcium uniporter promotes MSU crystal-induced inflammation through inducing mitochondrial Ca2+ overload and ubiquitination of SIRT5 protein |
| title_fullStr | Mitochondrial calcium uniporter promotes MSU crystal-induced inflammation through inducing mitochondrial Ca2+ overload and ubiquitination of SIRT5 protein |
| title_full_unstemmed | Mitochondrial calcium uniporter promotes MSU crystal-induced inflammation through inducing mitochondrial Ca2+ overload and ubiquitination of SIRT5 protein |
| title_short | Mitochondrial calcium uniporter promotes MSU crystal-induced inflammation through inducing mitochondrial Ca2+ overload and ubiquitination of SIRT5 protein |
| title_sort | mitochondrial calcium uniporter promotes msu crystal induced inflammation through inducing mitochondrial ca2 overload and ubiquitination of sirt5 protein |
| topic | MCU MSU crystals Mitochondrial Ca2+ TRIM21 SIRT5 |
| url | https://doi.org/10.1186/s13075-025-03627-3 |
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