1. Academic Validation
  2. Protecting mitochondria via inhibiting VDAC1 oligomerization alleviates ferroptosis in acetaminophen-induced acute liver injury

Protecting mitochondria via inhibiting VDAC1 oligomerization alleviates ferroptosis in acetaminophen-induced acute liver injury

  • Cell Biol Toxicol. 2022 Jun;38(3):505-530. doi: 10.1007/s10565-021-09624-x.
Baolin Niu  # 1 Xiaohong Lei  # 2 Qingling Xu  # 3 Yi Ju 1 Dongke Xu 1 Liya Mao 1 Jing Li 2 Yufan Zheng 1 Ning Sun 1 Xin Zhang 4 Yimin Mao 5 Xiaobo Li 6
Affiliations

Affiliations

  • 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, 130 Dong'an Rd, Shanghai, 200032, China.
  • 2 Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, 145 mid-Shandong Rd, Shanghai, 200001, China.
  • 3 Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China.
  • 4 Department of Pathology, Fudan University Zhongshan Hospital, 180 Fenglin Road, Shanghai, 200032, China. xzhangbwtx@163.com.
  • 5 Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, 145 mid-Shandong Rd, Shanghai, 200001, China. maoym11968@163.com.
  • 6 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, 130 Dong'an Rd, Shanghai, 200032, China. xbli@fudan.edu.cn.
  • # Contributed equally.
Abstract

Acetaminophen (APAP) overdose is a common cause of drug-induced liver injury (DILI). Ferroptosis has been recently implicated in APAP-induced liver injury (AILI). However, the functional role and underlying mechanisms of mitochondria in APAP-induced Ferroptosis are unclear. In this study, the voltage-dependent anion channel (VDAC) oligomerization inhibitor VBIT-12 and Ferroptosis inhibitors were injected via tail vein in APAP-injured mice. Targeted metabolomics and untargeted lipidomic analyses were utilized to explore underlying mechanisms of APAP-induced mitochondrial dysfunction and subsequent Ferroptosis. As a result, APAP overdose led to characteristic changes generally observed in Ferroptosis. The use of Ferroptosis inhibitor ferrostatin-1 (or UAMC3203) and iron chelator deferoxamine further confirmed that Ferroptosis was responsible for AILI. Mitochondrial dysfunction, which is associated with the tricarboxylic acid cycle and fatty acid β-oxidation suppression, may drive APAP-induced Ferroptosis in hepatocytes. APAP overdose induced VDAC1 oligomerization in hepatocytes, and protecting mitochondria via VBIT-12 alleviated APAP-induced Ferroptosis. Ceramide and cardiolipin levels were increased via UAMC3203 or VBIT-12 in APAP-induced Ferroptosis in hepatocytes. Knockdown of Smpd1 and Taz expression responsible for ceramide and cardiolipin synthesis, respectively, aggravated APAP-induced mitochondrial dysfunction and Ferroptosis in hepatocytes, whereas Taz overexpression protected against these processes. By immunohistochemical staining, we found that levels of 4-hydroxynonenal (4-HNE) protein adducts were increased in the liver biopsy samples of patients with DILI compared to that in those of patients with autoimmune liver disease, chronic viral hepatitis B, and non-alcoholic fatty liver disease (NAFLD). In summary, protecting mitochondria via inhibiting VDAC1 oligomerization attenuated hepatocyte Ferroptosis by restoring ceramide and cardiolipin content in AILI.

Keywords

4-hydroxynonenal; Acetaminophen-induced liver injury; Ferroptosis; Mitochondria; VDAC1.

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