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Protecting mitochondria via inhibiting VDAC1 oligomerization alleviates ferroptosis in acetaminophen-induced acute liver injury.
Niu, Baolin; Lei, Xiaohong; Xu, Qingling; Ju, Yi; Xu, Dongke; Mao, Liya; Li, Jing; Zheng, Yufan; Sun, Ning; Zhang, Xin; Mao, Yimin; Li, Xiaobo.
Afiliación
  • Niu B; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, 130 Dong'an Rd, Shanghai, 200032, China.
  • Lei X; 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.
  • Xu Q; Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China.
  • Ju Y; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, 130 Dong'an Rd, Shanghai, 200032, China.
  • Xu D; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, 130 Dong'an Rd, Shanghai, 200032, China.
  • Mao L; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, 130 Dong'an Rd, Shanghai, 200032, China.
  • Li J; 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.
  • Zheng Y; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, 130 Dong'an Rd, Shanghai, 200032, China.
  • Sun N; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, 130 Dong'an Rd, Shanghai, 200032, China.
  • Zhang X; Department of Pathology, Fudan University Zhongshan Hospital, 180 Fenglin Road, Shanghai, 200032, China. xzhangbwtx@163.com.
  • Mao Y; 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.
  • Li X; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, 130 Dong'an Rd, Shanghai, 200032, China. xbli@fudan.edu.cn.
Cell Biol Toxicol ; 38(3): 505-530, 2022 06.
Article en En | MEDLINE | ID: mdl-34401974
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 ß-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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Analgésicos no Narcóticos / Canal Aniónico 1 Dependiente del Voltaje / Enfermedad Hepática Inducida por Sustancias y Drogas / Ferroptosis Límite: Animals / Humans Idioma: En Revista: Cell Biol Toxicol Asunto de la revista: TOXICOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: China Pais de publicación: Suiza
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Analgésicos no Narcóticos / Canal Aniónico 1 Dependiente del Voltaje / Enfermedad Hepática Inducida por Sustancias y Drogas / Ferroptosis Límite: Animals / Humans Idioma: En Revista: Cell Biol Toxicol Asunto de la revista: TOXICOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: China Pais de publicación: Suiza