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

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.

• Authors: Baolin Niu, Xiaohong Lei, Qingling Xu, Yi Ju, Dongke Xu, Liya Mao, Jing Li, Yufan Zheng, Ning Sun, Xin Zhang, Yimin Mao, Xiaobo Li
• Journal: Cell biology and toxicology (Cell Biol Toxicol) Vol. 38 Issue 3 Pg. 505-530 (06 2022) ISSN: 1573-6822 [Electronic] Switzerland
• PMID: 34401974 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Nature B.V.

Chemical References

• Analgesics, Non-Narcotic
• Cardiolipins
• Ceramides
• VDAC1 protein, human
• Vdac1 protein, mouse
• Acetaminophen
• Voltage-Dependent Anion Channel 1

Topics

• Acetaminophen (adverse effects)
• Analgesics, Non-Narcotic (metabolism)
• Animals
• Cardiolipins (metabolism)
• Ceramides (metabolism)
• Chemical and Drug Induced Liver Injury (metabolism)
• Ferroptosis
• Hepatocytes (metabolism)
• Humans
• Liver (pathology)
• Mice
• Mice, Inbred C57BL
• Mitochondria (metabolism)
• Voltage-Dependent Anion Channel 1 (metabolism)