LONP1 targets HMGCS2 to protect mitochondrial function and attenuate chronic kidney disease
Abstract Mitochondria comprise the central metabolic hub of cells and their imbalance plays a pathogenic role in chronic kidney disease (CKD). Here, we studied Lon protease 1 (LONP1), a major mitochondrial protease, as its role in CKD pathogenesis is unclear. LONP1 expression was decreased in human...
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| Format: | Article |
| Language: | English |
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Springer Nature
2023-01-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202216581 |
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| author | Mi Bai Mengqiu Wu Mingzhu Jiang Jia He Xu Deng Shuang Xu Jiaojiao Fan Mengqiu Miao Ting Wang Yuting Li Xiaowen Yu Lin Wang Yue Zhang Songming Huang Li Yang Zhanjun Jia Aihua Zhang |
| author_facet | Mi Bai Mengqiu Wu Mingzhu Jiang Jia He Xu Deng Shuang Xu Jiaojiao Fan Mengqiu Miao Ting Wang Yuting Li Xiaowen Yu Lin Wang Yue Zhang Songming Huang Li Yang Zhanjun Jia Aihua Zhang |
| author_sort | Mi Bai |
| collection | DOAJ |
| description | Abstract Mitochondria comprise the central metabolic hub of cells and their imbalance plays a pathogenic role in chronic kidney disease (CKD). Here, we studied Lon protease 1 (LONP1), a major mitochondrial protease, as its role in CKD pathogenesis is unclear. LONP1 expression was decreased in human patients and mice with CKD, and tubular‐specific Lonp1 overexpression mitigated renal injury and mitochondrial dysfunction in two different models of CKD, but these outcomes were aggravated by Lonp1 deletion. These results were confirmed in renal tubular epithelial cells in vitro. Mechanistically, LONP1 downregulation caused mitochondrial accumulation of the LONP1 substrate, 3‐hydroxy‐3‐methylglutaryl‐CoA synthase 2 (HMGCS2), which disrupted mitochondrial function and further accelerated CKD progression. Finally, computer‐aided virtual screening was performed, which identified a novel LONP1 activator. Pharmacologically, the LONP1 activator attenuated renal fibrosis and mitochondrial dysfunction. Collectively, these results imply that LONP1 is a promising therapeutic target for treating CKD. |
| format | Article |
| id | doaj-art-53d49939a7af46fba73c8a251f9bfa71 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2023-01-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-53d49939a7af46fba73c8a251f9bfa712025-08-24T11:43:46ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-01-0115212210.15252/emmm.202216581LONP1 targets HMGCS2 to protect mitochondrial function and attenuate chronic kidney diseaseMi Bai0Mengqiu Wu1Mingzhu Jiang2Jia He3Xu Deng4Shuang Xu5Jiaojiao Fan6Mengqiu Miao7Ting Wang8Yuting Li9Xiaowen Yu10Lin Wang11Yue Zhang12Songming Huang13Li Yang14Zhanjun Jia15Aihua Zhang16Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical UniversityDepartment of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical UniversityDepartment of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical UniversityDepartment of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical UniversityDepartment of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical UniversityDepartment of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical UniversityDepartment of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical UniversityDepartment of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical UniversityDepartment of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical UniversityDepartment of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical UniversityDepartment of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical UniversityKey Laboratory of Molecular Pharmacology and Drug Evaluation, Yantai UniversityDepartment of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical UniversityDepartment of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical UniversityRenal Division, Peking University First HospitalDepartment of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical UniversityDepartment of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical UniversityAbstract Mitochondria comprise the central metabolic hub of cells and their imbalance plays a pathogenic role in chronic kidney disease (CKD). Here, we studied Lon protease 1 (LONP1), a major mitochondrial protease, as its role in CKD pathogenesis is unclear. LONP1 expression was decreased in human patients and mice with CKD, and tubular‐specific Lonp1 overexpression mitigated renal injury and mitochondrial dysfunction in two different models of CKD, but these outcomes were aggravated by Lonp1 deletion. These results were confirmed in renal tubular epithelial cells in vitro. Mechanistically, LONP1 downregulation caused mitochondrial accumulation of the LONP1 substrate, 3‐hydroxy‐3‐methylglutaryl‐CoA synthase 2 (HMGCS2), which disrupted mitochondrial function and further accelerated CKD progression. Finally, computer‐aided virtual screening was performed, which identified a novel LONP1 activator. Pharmacologically, the LONP1 activator attenuated renal fibrosis and mitochondrial dysfunction. Collectively, these results imply that LONP1 is a promising therapeutic target for treating CKD.https://doi.org/10.15252/emmm.202216581chronic kidney diseaseHMGCS2LONP1mitochondrial dysfunction |
| spellingShingle | Mi Bai Mengqiu Wu Mingzhu Jiang Jia He Xu Deng Shuang Xu Jiaojiao Fan Mengqiu Miao Ting Wang Yuting Li Xiaowen Yu Lin Wang Yue Zhang Songming Huang Li Yang Zhanjun Jia Aihua Zhang LONP1 targets HMGCS2 to protect mitochondrial function and attenuate chronic kidney disease EMBO Molecular Medicine chronic kidney disease HMGCS2 LONP1 mitochondrial dysfunction |
| title | LONP1 targets HMGCS2 to protect mitochondrial function and attenuate chronic kidney disease |
| title_full | LONP1 targets HMGCS2 to protect mitochondrial function and attenuate chronic kidney disease |
| title_fullStr | LONP1 targets HMGCS2 to protect mitochondrial function and attenuate chronic kidney disease |
| title_full_unstemmed | LONP1 targets HMGCS2 to protect mitochondrial function and attenuate chronic kidney disease |
| title_short | LONP1 targets HMGCS2 to protect mitochondrial function and attenuate chronic kidney disease |
| title_sort | lonp1 targets hmgcs2 to protect mitochondrial function and attenuate chronic kidney disease |
| topic | chronic kidney disease HMGCS2 LONP1 mitochondrial dysfunction |
| url | https://doi.org/10.15252/emmm.202216581 |
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