Journal
CELL BIOLOGY AND TOXICOLOGY
Volume 38, Issue 3, Pages 505-530Publisher
SPRINGER
DOI: 10.1007/s10565-021-09624-x
Keywords
Acetaminophen-induced liver injury; Ferroptosis; 4-hydroxynonenal; Mitochondria; VDAC1
Categories
Funding
- National Natural Science Foundation of China [NSFC 31771308, NSFC 81970513, NSFC 81670524]
- Shanghai Municipal Natural Science Foundation [17ZR1401800]
- Shanghai Key Laboratory of Bioactive Small Molecules [ZDSYS14005]
- Major Project of National Thirteenth Five Plan [2017ZX09304016]
- Project of Shanghai Shenkang Hospital Development Center [16CR2009A]
- Project of Clinical Research Center, Shanghai Jiao Tong University School of Medicine [DLY201607]
- Innovative Research Team of High-level Local Universities in Shanghai
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APAP overdose can lead to ferroptosis, and protecting mitochondria can alleviate APAP-induced hepatocyte ferroptosis by restoring ceramide and cardiolipin content. Specifically, inhibiting VDAC1 oligomerization can protect hepatocytes from AILI damage by restoring ceramide and cardiolipin levels.
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 beta-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.
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