DJ-1 Deficiency in Hepatocytes Improves Liver Ischemia-Reperfusion Injury by Enhancing Mitophagy

Min Xu; Hualian Hang; Miao Huang; Jichang Li; Dongwei Xu; Junzhe Jiao; Fang Wang; Hailong Wu; Xuehua Sun; Jinyang Gu; Xiaoni Kong; Yueqiu Gao

doi:10.1016/j.jcmgh.2021.03.007

DJ-1 Deficiency in Hepatocytes Improves Liver Ischemia-Reperfusion Injury by Enhancing Mitophagy

Cell Mol Gastroenterol Hepatol. 2021;12(2):567-584. doi: 10.1016/j.jcmgh.2021.03.007. Epub 2021 Mar 23.

Authors

Min Xu¹, Hualian Hang², Miao Huang³, Jichang Li¹, Dongwei Xu², Junzhe Jiao¹, Fang Wang¹, Hailong Wu⁴, Xuehua Sun¹, Jinyang Gu⁵, Xiaoni Kong⁶, Yueqiu Gao⁷

Affiliations

¹ Central Laboratory, Department of Liver Diseases, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shangha, China.
² Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
³ Department of Transplantation, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁴ Shanghai Key Laboratory for Molecular Imaging, Collaborative Research Center, Shanghai University of Medicine & Health Science, Shanghai, China.
⁵ Department of Transplantation, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: gjynyd@126.com.
⁶ Central Laboratory, Department of Liver Diseases, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shangha, China. Electronic address: xiaoni-kong@126.com.
⁷ Central Laboratory, Department of Liver Diseases, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shangha, China. Electronic address: gaoyueqiu@hotmail.com.

Abstract

Background & aims: DJ-1 is universally expressed in various tissues and organs and is involved in the physiological processes in various liver diseases. However, the role of DJ-1 in liver ischemia-reperfusion (I/R) injury is largely unknown.

Methods: In this study, we first examined the DJ-1 expression changes in the liver tissues of mice and clinical donor after hepatic I/R by both quantitative polymerase chain reaction and Western blotting assays. Then we investigated the role of DJ-1 in I/R injury by using a murine liver I/R model.

Results: We demonstrated that DJ-1 down-regulation in both human and mouse liver tissues in response to I/R injury and Dj-1 deficiency in hepatocytes but not in myeloid cells could significantly ameliorate I/R induced liver injury and inflammatory responses. This hepatoprotective effect was dependent on enhanced autophagy in Dj-1 knockout mice, because inhibition of autophagy by 3-methyladenine and chloroquine could reverse the protective effect on hepatic I/R injury in Dj-1 knockout mice.

Conclusions: Dj-1 deficiency in hepatocytes significantly enhanced mitochondrial accumulation and protein stability of PARKIN, which in turn promotes the onset of mitophagy resulting in elevated clearance of damaged mitochondria during I/R injury.

Keywords: DJ-1; Liver I/R Injury; Mitophagy; PARKIN.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autophagy
Down-Regulation
Hepatocytes / metabolism*
Inflammation / pathology
Liver / metabolism*
Liver / pathology*
Male
Mice
Mice, Knockout
Mitochondria / metabolism
Mitophagy*
Myeloid Cells / metabolism
Protective Agents / metabolism
Protein Deglycase DJ-1 / deficiency*
Protein Deglycase DJ-1 / metabolism
Protein Stability
Protein Transport
Reperfusion Injury / metabolism*
Reperfusion Injury / pathology*
Ubiquitin-Protein Ligases / metabolism

Substances

Protective Agents
Ubiquitin-Protein Ligases
parkin protein
PARK7 protein, mouse
Protein Deglycase DJ-1