2. Academic Validation
  3. Mitoquinone protects against acetaminophen-induced liver injury in an FSP1-dependent and GPX4-independent manner

Mitoquinone protects against acetaminophen-induced liver injury in an FSP1-dependent and GPX4-independent manner

  • Toxicol Appl Pharmacol. 2023 Mar 7;116452. doi: 10.1016/j.taap.2023.116452.
Xue He 1,  Shi-Min Liang 1,  Hong-Qian Wang 1,  Li Tao 1,  Fei-Fei Sun 1,  Yan Wang 2,  Cheng Zhang 2,  Yi-Chao Huang 2,  De-Xiang Xu 3,  Xi Chen 4
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Anhui Provincial Key Laboratory of Digestive Disease, the First Affiliated Hospital of Anhui Medical University, Hefei 230032, China.
  • 2 Department of Toxicology, Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China.
  • 3 Department of Toxicology, Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China. Electronic address: xudex@126.com.
  • 4 Department of Gastroenterology, Anhui Provincial Key Laboratory of Digestive Disease, the First Affiliated Hospital of Anhui Medical University, Hefei 230032, China. Electronic address: ayfychenxi@163.com.
PMID: 36894071 DOI: 10.1016/j.taap.2023.116452
Abstract

Mitochondrial oxidative stress has been a crucial mediator in acetaminophen (APAP)-induced hepatotoxicity. MitoQ, an analog of coenzyme Q10, is targeted towards mitochondria and acts as a potent antioxidant. This study aimed to explore the effect of MitoQ on APAP-induced liver injury and its possible mechanisms. To investigate this, CD-1 mice and AML-12 cells were treated with APAP. MDA and 4-HNE, two markers of hepatic lipid peroxidation (LPO), were elevated as early as 2 h after APAP. Oxidized lipids were rapidly upregulated in APAP-exposed AML-12 cells. Hepatocyte death and mitochondrial ultrastructure alterations were observed in APAP-induced acute liver injury. The in vitro experiments showed that mitochondrial membrane potentials and OXPHOS subunits were downregulated in APAP-exposed hepatocytes. MtROS and oxidized lipids were elevated in APAP-exposed hepatocytes. We discovered that APAP-induced hepatocyte death and liver injury were ameliorated by attenuation of protein nitration and LPO in MitoQ-pretreated mice. Mechanistically, knockdown of GPX4, a key Enzyme for LPO defense systems, exacerbated APAP-induced oxidized lipids, but did not influence the protective effect of MitoQ on APAP-induced LPO and hepatocyte death. Whereas knockdown of FSP1, another key Enzyme for LPO defense systems, had little effect on APAP-induced lipid oxidation but partially weakened the protection of MitoQ on APAP-induced LPO and hepatocyte death. These results suggest that MitoQ may alleviate APAP-evoked hepatotoxicity by eliminating protein nitration and suppressing hepatic LPO. MitoQ prevents APAP-induced liver injury partially dependent of FSP1 and independent of GPX4.

Keywords

Acetaminophen; Acute Liver Injury; Ferroptosis Suppressor Protein 1; Lipid Peroxidation; Mitoquinone.

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