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. 2022 Jun;38(3):505-530.
doi: 10.1007/s10565-021-09624-x. Epub 2021 Aug 17.

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

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

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

Baolin Niu et al. Cell Biol Toxicol. 2022 Jun.

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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