Epithelial mitochondrial fission-mediated PANoptosis is crucial for ulcerative colitis and its inhibition by saquinavir through Drp1
Ulcerative colitis (UC) is characterized by increased cell death in intestinal epithelial cell (IEC), which compromises gut barrier function and activates inflammation. Aberrant mitochondrial dynamics have been implicated in various forms of cell death, but it is currently unclear if they play a rol...
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| Language: | English |
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Elsevier
2024-12-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661824004833 |
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| author | Zhiming Ye Mingxia Deng Yang Yang Yuanming Song Liangkun Weng Wanchen Qi Ping Ding Yihang Huang Can Yu Yan Wang Yixing Wu Yan Zhang Shaoying Yuan Wenkai Nie Luyong Zhang Cheng Zeng |
| author_facet | Zhiming Ye Mingxia Deng Yang Yang Yuanming Song Liangkun Weng Wanchen Qi Ping Ding Yihang Huang Can Yu Yan Wang Yixing Wu Yan Zhang Shaoying Yuan Wenkai Nie Luyong Zhang Cheng Zeng |
| author_sort | Zhiming Ye |
| collection | DOAJ |
| description | Ulcerative colitis (UC) is characterized by increased cell death in intestinal epithelial cell (IEC), which compromises gut barrier function and activates inflammation. Aberrant mitochondrial dynamics have been implicated in various forms of cell death, but it is currently unclear if they play a role in IEC death and colitis pathogenesis. This study aims to investigate the contribution of aberrant mitochondrial dynamics to colitis progression using cellular models, animal models, and clinical samples. The results revealed that IEC in mice with Dextran sulfate sodium salt (DSS)-induced colitis exhibited dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and Z-DNA binding protein 1 (ZBP1)-dependent PANoptosis, which is a combination of apoptosis, necroptosis, and pyroptosis. However, these processes and the pathogenesis of DSS-induced colitis were significantly attenuated in IEC-specific Drp1 heterozygous knockout mice. Importantly, ZBP1-PANoptosis and Drp1-mediated mitochondrial fission were observed in IEC of UC patients, exhibiting a positive correlation with disease severity. Mechanistically, hyperactivated mitochondrial fission induced mitochondrial reactive oxygen species production leading to PANoptosis through ZBP1 sulfenylation at Cys327 independently of its Zα domain. Saquinavir, an FDA-approved drug identified through in-silico screening alongside in vivo and in vitro experiments, inhibits mitochondrial fission thereby enhancing therapeutic efficacy in mice with colitis. |
| format | Article |
| id | doaj-art-a86e01045dd64b42b96d8f1a4220b16d |
| institution | OA Journals |
| issn | 1096-1186 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-a86e01045dd64b42b96d8f1a4220b16d2025-08-20T01:57:55ZengElsevierPharmacological Research1096-11862024-12-0121010753810.1016/j.phrs.2024.107538Epithelial mitochondrial fission-mediated PANoptosis is crucial for ulcerative colitis and its inhibition by saquinavir through Drp1Zhiming Ye0Mingxia Deng1Yang Yang2Yuanming Song3Liangkun Weng4Wanchen Qi5Ping Ding6Yihang Huang7Can Yu8Yan Wang9Yixing Wu10Yan Zhang11Shaoying Yuan12Wenkai Nie13Luyong Zhang14Cheng Zeng15Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, ChinaThe Guangzhou Laboratory, Guangzhou 510000, ChinaDepartment of Pharmacy, Zhuhai People’s Hospital (Zhuhai hospital affiliated with Jinan University), Zhuhai 519000, China; School of Pharmacy, Faculty of Medicine, Macau University of Science and Technology, MacaoCenter for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, ChinaCenter for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, ChinaDepartment of Pharmacy, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 519000, ChinaCenter for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, ChinaCollege of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, ChinaCenter for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, ChinaCollege of Nursing, Guangdong Pharmaceutical University, Guangzhou 510006, ChinaCollege of Nursing, Guangdong Pharmaceutical University, Guangzhou 510006, ChinaCollege of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, ChinaCollege of Nursing, Guangdong Pharmaceutical University, Guangzhou 510006, ChinaCollege of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, ChinaCenter for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, China; Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, ChinaCenter for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, China; Key specialty of Clinical Pharmacy, The first Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510699, China; Correspondence to: Center for Drug Research and Development, Guangdong Pharmaceutical University, 280 East Huan Road, Panyu District, Guangzhou City, Guangdong Province 510006, China.Ulcerative colitis (UC) is characterized by increased cell death in intestinal epithelial cell (IEC), which compromises gut barrier function and activates inflammation. Aberrant mitochondrial dynamics have been implicated in various forms of cell death, but it is currently unclear if they play a role in IEC death and colitis pathogenesis. This study aims to investigate the contribution of aberrant mitochondrial dynamics to colitis progression using cellular models, animal models, and clinical samples. The results revealed that IEC in mice with Dextran sulfate sodium salt (DSS)-induced colitis exhibited dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and Z-DNA binding protein 1 (ZBP1)-dependent PANoptosis, which is a combination of apoptosis, necroptosis, and pyroptosis. However, these processes and the pathogenesis of DSS-induced colitis were significantly attenuated in IEC-specific Drp1 heterozygous knockout mice. Importantly, ZBP1-PANoptosis and Drp1-mediated mitochondrial fission were observed in IEC of UC patients, exhibiting a positive correlation with disease severity. Mechanistically, hyperactivated mitochondrial fission induced mitochondrial reactive oxygen species production leading to PANoptosis through ZBP1 sulfenylation at Cys327 independently of its Zα domain. Saquinavir, an FDA-approved drug identified through in-silico screening alongside in vivo and in vitro experiments, inhibits mitochondrial fission thereby enhancing therapeutic efficacy in mice with colitis.http://www.sciencedirect.com/science/article/pii/S1043661824004833Ulcerative colitisMitochondrial fissionDrp1PANoptosisZBP1Saquinavir |
| spellingShingle | Zhiming Ye Mingxia Deng Yang Yang Yuanming Song Liangkun Weng Wanchen Qi Ping Ding Yihang Huang Can Yu Yan Wang Yixing Wu Yan Zhang Shaoying Yuan Wenkai Nie Luyong Zhang Cheng Zeng Epithelial mitochondrial fission-mediated PANoptosis is crucial for ulcerative colitis and its inhibition by saquinavir through Drp1 Pharmacological Research Ulcerative colitis Mitochondrial fission Drp1 PANoptosis ZBP1 Saquinavir |
| title | Epithelial mitochondrial fission-mediated PANoptosis is crucial for ulcerative colitis and its inhibition by saquinavir through Drp1 |
| title_full | Epithelial mitochondrial fission-mediated PANoptosis is crucial for ulcerative colitis and its inhibition by saquinavir through Drp1 |
| title_fullStr | Epithelial mitochondrial fission-mediated PANoptosis is crucial for ulcerative colitis and its inhibition by saquinavir through Drp1 |
| title_full_unstemmed | Epithelial mitochondrial fission-mediated PANoptosis is crucial for ulcerative colitis and its inhibition by saquinavir through Drp1 |
| title_short | Epithelial mitochondrial fission-mediated PANoptosis is crucial for ulcerative colitis and its inhibition by saquinavir through Drp1 |
| title_sort | epithelial mitochondrial fission mediated panoptosis is crucial for ulcerative colitis and its inhibition by saquinavir through drp1 |
| topic | Ulcerative colitis Mitochondrial fission Drp1 PANoptosis ZBP1 Saquinavir |
| url | http://www.sciencedirect.com/science/article/pii/S1043661824004833 |
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