2. Academic Validation
  3. FUNDC1 Interacts with GPx4 to Govern Hepatic Ferroptosis and Fibrotic Injury through a Mitophagy-Dependent Manner

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.
Yaguang Bi 1,  Shuolin Liu 1,  Xing Qin 2,  Miyesaier Abudureyimu 3,  Lu Wang 4,  Rongjun Zou 5,  Amir Ajoolabady 6,  Wenjing Zhang 7,  Hu Peng 7,  Jun Ren 8,  Yingmei Zhang 9
Affiliations

Affiliations

  • 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: jren_aldh2@outlook.com.
  • 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: zhangym197951@126.com.
PMID: 36828120 DOI: 10.1016/j.jare.2023.02.012
Abstract

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.

Keywords

FUNDC1; GPx4; Liver fibrosis; TOM/TIM complex; ferroptosis; mitophagy.

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