Mitophagy and endoplasmic reticulum-phagy accelerated by a p62 ZZ ligand alleviates paracetamol-induced hepatotoxicity

Hee Yeon Kim, Hee Soo Yoon, Ah Jung Heo, Eui Jung Jung, Chang Hoon Ji, Su Ran Mun, Min Ju Lee, Yong Tae Kwon, Joo Won Park

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Background and Purpose: Paracetamol (acetaminophen)-induced hepatotoxicity is the leading cause of drug-induced liver injury worldwide. Autophagy is a degradative process by which various cargoes are collected by the autophagic receptors such as p62/SQSTM1/Sequestosome-1 for lysosomal degradation. Here, we investigated the protective role of p62-dependent autophagy in paracetamol-induced liver injury. Experimental Approach: Paracetamol-induced hepatotoxicity was induced by a single i.p. injection of paracetamol (500 mg·kg−1) in C57/BL6 male mice. YTK-2205 (20 mg·kg−1), a p62 agonist targeting ZZ domain, was co- or post-administered with paracetamol. Western blotting and immunocytochemistry were performed to explore the mechanism. Key Results: N-terminal arginylation of the molecular chaperone calreticulin retro-translocated from the endoplasmic reticulum (ER) was induced in the livers undergoing paracetamol-induced hepatotoxicity, and YTK-2205 exhibited notable therapeutic efficacy in acute hepatotoxicity as assessed by the levels of serum alanine aminotransferase and hepatic necrosis. This efficacy was significantly attributed to accelerated degradation of ubiquitin (Ub) conjugates as well as damaged mitochondria (mitophagy) and endoplasmic reticulum (ER-phagy). In primary murine hepatocytes treated with paracetamol, YTK-2205 induced the co-localization of p62+LC3+ phagophores to the sites of mitophagy and ER-phagy. A similar activity of YTK-2205 was observed with N-acetyl-p-benzoquinone imine, a putative toxic metabolite of paracetamol in Hep3B cells. Conclusion and Implications: Our results elucidated that p62-dependent autophagy plays a key role in the removal of cytotoxic materials such as damaged mitochondria in paracetamol-induced hepatotoxicity. Small molecule ligands to p62 may be developed into drugs to treat this pathological condition.

Original languageEnglish
Pages (from-to)1247-1266
Number of pages20
JournalBritish Journal of Pharmacology
Volume180
Issue number9
DOIs
StatePublished - May 2023

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korean government, the Ministry of Science and ICT [MSIT] (Grants NRF‐2020R1A5A1019023 to Y.T.K. and NRF‐2022R1A2C1006737 to J.W.P.) and the Ministry of Education (Grant 2021R1A2B5B03002614 to Y.T.K.). We thank the AUTOTAC Inc.'s employees for their critical discussion and comments.

Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korean government, the Ministry of Science and ICT [MSIT] (Grants NRF-2020R1A5A1019023 to Y.T.K. and NRF-2022R1A2C1006737 to J.W.P.) and the Ministry of Education (Grant 2021R1A2B5B03002614 to Y.T.K.). We thank the AUTOTAC Inc.'s employees for their critical discussion and comments.

Publisher Copyright:
© 2022 British Pharmacological Society.

Keywords

  • ZZ ligand
  • acetaminophen
  • hepatotoxicity
  • p62
  • paracetamol
  • ubiquitination

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