FUNDC1 interacts with GPx4 to govern hepatic ferroptosis and fibrotic injury through a mitophagy-dependent manner

作者：Bi, Yaguang; Liu, Shuolin; Qin, Xing; Abudureyimu, Miyesaier; Wang, Lu; Zou, Rongjun; Ajoolabady, Amir; Zhang, Wenjing; Peng, Hu; Ren, Jun^*; Zhang, Yingmei^*

来源：Journal of Advanced Research, 2024, 55: 45-60.

DOI：10.1016/j.jare.2023.02.012

• Liver fibrosis
• FUNDC1
• GPx4
• Mitophagy
• Ferroptosis
• TOM/TIM complex

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 hydroperox-ides 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 translo-case 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.

• 单位
  同济大学; 广州中医药大学; 复旦大学; 广东省人民医院