FUNDC1 interacts with GPx4 to govern hepatic ferroptosis and fibrotic injury through a mitophagy-dependent manner
Introduction: Liver fibrosis is a life-threatening pathological anomaly which usually evolves into advanced liver cirrhosis and hepatocellular carcinoma although limited therapeutic option is readily available. FUN14 domain containing 1 (FUNDC1) is a mitophagy receptor with little information in liv...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-01-01
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| Series: | Journal of Advanced Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2090123223000632 |
| _version_ | 1797372948325072896 |
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| author | Yaguang Bi Shuolin Liu Xing Qin Miyesaier Abudureyimu Lu Wang Rongjun Zou Amir Ajoolabady Wenjing Zhang Hu Peng Jun Ren Yingmei Zhang |
| author_facet | Yaguang Bi Shuolin Liu Xing Qin Miyesaier Abudureyimu Lu Wang Rongjun Zou Amir Ajoolabady Wenjing Zhang Hu Peng Jun Ren Yingmei Zhang |
| author_sort | Yaguang Bi |
| collection | DOAJ |
| description | Introduction: Liver fibrosis is a life-threatening pathological anomaly which usually evolves into advanced liver cirrhosis and hepatocellular carcinoma although limited therapeutic option is readily available. FUN14 domain containing 1 (FUNDC1) is a mitophagy receptor with little information in liver fibrosis. Objective: This study was designed to examine the role for FUNDC1 in carbon tetrachloride (CCl4)-induced liver injury. Methods: GEO database analysis and subsequent validation of biological processes including western blot, immunofluorescence, and co-immunoprecipitation were applied to clarify the regulatory role of FUNDC1 on mitophagy and ferroptosis. Results: Our data revealed elevated FUNDC1 levels in liver tissues of patients with liver fibrotic injury and CCl4-challenged mice. FUNDC1 deletion protected against CCl4-induced hepatic anomalies in mice. Moreover, FUNDC1 deletion ameliorated CCl4-induced ferroptosis in vivo and in vitro. Mechanically, FUNDC1 interacted with glutathione peroxidase (GPx4), a selenoenzyme to neutralize lipid hydroperoxides and ferroptosis, via its 96–133 amino acid domain to facilitate GPx4 recruitment into mitochondria from cytoplasm. GPx4 entered mitochondria through mitochondrial protein import system-the translocase of outer membrane/translocase of inner membrane (TOM/TIM) complex, prior to degradation of GPx4 mainly through mitophagy along with ROS-induced damaged mitochondria, resulting in hepatocyte ferroptosis. Conclusion: Taken together, our data favored that FUNDC1 promoted hepatocyte injury through GPx4 binding to facilitate its mitochondrial translocation through TOM/TIM complex, where GPx4 was degraded by mitophagy to trigger ferroptosis. Targeting FUNDC1 may be a promising therapeutic approach for liver fibrosis. |
| first_indexed | 2024-03-08T18:43:11Z |
| format | Article |
| id | doaj.art-a2fe01d001a7411dbd62d8473bb71797 |
| institution | Directory Open Access Journal |
| issn | 2090-1232 |
| language | English |
| last_indexed | 2024-03-08T18:43:11Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Advanced Research |
| spelling | doaj.art-a2fe01d001a7411dbd62d8473bb717972023-12-29T04:45:06ZengElsevierJournal of Advanced Research2090-12322024-01-01554560FUNDC1 interacts with GPx4 to govern hepatic ferroptosis and fibrotic injury through a mitophagy-dependent mannerYaguang Bi0Shuolin Liu1Xing Qin2Miyesaier Abudureyimu3Lu Wang4Rongjun Zou5Amir Ajoolabady6Wenjing Zhang7Hu Peng8Jun Ren9Yingmei Zhang10Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, ChinaDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, ChinaDepartment of Cardiology, Xijing Hospital, Air Force Medical University, Xi’an 710032, ChinaCardiovascular Department, Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, ChinaInstitute of Digestive Diseases, Xijing Hospital, Air Force Medical University, Xi'an 710032, China; State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Air Force Medical University, Xi'an 710032, ChinaDepartment of Cardiovascular Surgery, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine,Guangzhou 510120, Guangdong, China; The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, ChinaDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, ChinaDepartment of Emergency, Shanghai Tenth People’s Hospital, School of Medicine Tongji University, Shanghai 200072, ChinaDepartment of Emergency, Shanghai Tenth People’s Hospital, School of Medicine Tongji University, Shanghai 200072, ChinaDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA; Corresponding authors at: Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China.Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China; Corresponding authors at: Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China.Introduction: Liver fibrosis is a life-threatening pathological anomaly which usually evolves into advanced liver cirrhosis and hepatocellular carcinoma although limited therapeutic option is readily available. FUN14 domain containing 1 (FUNDC1) is a mitophagy receptor with little information in liver fibrosis. Objective: This study was designed to examine the role for FUNDC1 in carbon tetrachloride (CCl4)-induced liver injury. Methods: GEO database analysis and subsequent validation of biological processes including western blot, immunofluorescence, and co-immunoprecipitation were applied to clarify the regulatory role of FUNDC1 on mitophagy and ferroptosis. Results: Our data revealed elevated FUNDC1 levels in liver tissues of patients with liver fibrotic injury and CCl4-challenged mice. FUNDC1 deletion protected against CCl4-induced hepatic anomalies in mice. Moreover, FUNDC1 deletion ameliorated CCl4-induced ferroptosis in vivo and in vitro. Mechanically, FUNDC1 interacted with glutathione peroxidase (GPx4), a selenoenzyme to neutralize lipid hydroperoxides and ferroptosis, via its 96–133 amino acid domain to facilitate GPx4 recruitment into mitochondria from cytoplasm. GPx4 entered mitochondria through mitochondrial protein import system-the translocase of outer membrane/translocase of inner membrane (TOM/TIM) complex, prior to degradation of GPx4 mainly through mitophagy along with ROS-induced damaged mitochondria, resulting in hepatocyte ferroptosis. Conclusion: Taken together, our data favored that FUNDC1 promoted hepatocyte injury through GPx4 binding to facilitate its mitochondrial translocation through TOM/TIM complex, where GPx4 was degraded by mitophagy to trigger ferroptosis. Targeting FUNDC1 may be a promising therapeutic approach for liver fibrosis.http://www.sciencedirect.com/science/article/pii/S2090123223000632Liver fibrosisFUNDC1GPx4MitophagyFerroptosisTOM/TIM complex |
| spellingShingle | Yaguang Bi Shuolin Liu Xing Qin Miyesaier Abudureyimu Lu Wang Rongjun Zou Amir Ajoolabady Wenjing Zhang Hu Peng Jun Ren Yingmei Zhang FUNDC1 interacts with GPx4 to govern hepatic ferroptosis and fibrotic injury through a mitophagy-dependent manner Journal of Advanced Research Liver fibrosis FUNDC1 GPx4 Mitophagy Ferroptosis TOM/TIM complex |
| title | FUNDC1 interacts with GPx4 to govern hepatic ferroptosis and fibrotic injury through a mitophagy-dependent manner |
| title_full | FUNDC1 interacts with GPx4 to govern hepatic ferroptosis and fibrotic injury through a mitophagy-dependent manner |
| title_fullStr | FUNDC1 interacts with GPx4 to govern hepatic ferroptosis and fibrotic injury through a mitophagy-dependent manner |
| title_full_unstemmed | FUNDC1 interacts with GPx4 to govern hepatic ferroptosis and fibrotic injury through a mitophagy-dependent manner |
| title_short | FUNDC1 interacts with GPx4 to govern hepatic ferroptosis and fibrotic injury through a mitophagy-dependent manner |
| title_sort | fundc1 interacts with gpx4 to govern hepatic ferroptosis and fibrotic injury through a mitophagy dependent manner |
| topic | Liver fibrosis FUNDC1 GPx4 Mitophagy Ferroptosis TOM/TIM complex |
| url | http://www.sciencedirect.com/science/article/pii/S2090123223000632 |
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