FUNDC1 Interacts with GPx4 to Govern Hepatic Ferroptosis and Fibrotic Injury through a Mitophagy-Dependent Manner
- J Adv Res. 2023 Feb 22;S2090-1232(23)00063-2. doi: 10.1016/j.jare.2023.02.012.
- 1. Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China.
- 2. Department of Cardiology, Xijing Hospital, Air Force Medical University, Xi'an 710032, China.
- 3. Cardiovascular Department, Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, China.
- 4. Institute 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, China.
- 5. Heart Center, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
- 6. Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China.
- 7. Department of Emergency, Shanghai Tenth People's Hospital, School of Medicine Tongji University, Shanghai, 200072, China.
- 8. Department 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. Electronic address: [email protected].
- 9. Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China. Electronic address: [email protected].
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.