Double deletion of PINK1 and Parkin impairs hepatic mitophagy and exacerbates acetaminophen-induced liver injury in mice

View/ Open
Issue Date
2019-02-20Author
Wang, Hua
Ni, Hong-Min
Chao, Xiaojuan
Ma, Xiaowen
Rodriguez, Yssa Ann
Chavan, Hemantkumar
Wang, Shaogui
Krishnamurthy, Partha
Dobrowsky, Rick
Xu, De-Xiang
Jaeschke, Hartmut
Ding, Wen-Xing
Publisher
Elsevier
Type
Article
Article Version
Scholarly/refereed, publisher version
Rights
© 2019 The Authors. Published by Elsevier B.V.
Metadata
Show full item recordAbstract
Mitochondria damage plays a critical role in acetaminophen (APAP)-induced necrosis and liver injury. Cells can adapt and protect themselves by removing damaged mitochondria via mitophagy. PINK1-Parkin pathway is one of the major pathways that regulate mitophagy but its role in APAP-induced liver injury is still elusive. We investigated the role of PINK1-Parkin pathway in hepatocyte mitophagy in APAP-induced liver injury in mice. Wild-type (WT), PINK1 knockout (KO), Parkin KO, and PINK1 and Parkin double KO (DKO) mice were treated with APAP for different time points. Liver injury was determined by measuring serum alanine aminotransferase (ALT) activity, H&E staining as well as TUNEL staining of liver tissues. Tandem fluorescent-tagged inner mitochondrial membrane protein Cox8 (Cox8-GFP-mCherry) can be used to monitor mitophagy based on different pH stability of GFP and mCherry fluorescent proteins. We overexpressed Cox8-GFP-mCherry in mouse livers via tail vein injection of an adenovirus Cox8-GFP-mCherry. Mitophagy was assessed by confocal microscopy for Cox8-GFP-mCherry puncta, electron microscopy (EM) analysis for mitophagosomes and western blot analysis for mitochondrial proteins. Parkin KO and PINK1 KO mice improved the survival after treatment with APAP although the serum levels of ALT were not significantly different among PINK1 KO, Parkin KO and WT mice. We only found mild defects of mitophagy in PINK1 KO or Parkin KO mice after APAP, and improved survival in PINK1 KO and Parkin KO mice could be due to other functions of PINK1 and Parkin independent of mitophagy. In contrast, APAP-induced mitophagy was significantly impaired in PINK1-Parkin DKO mice. PINK1-Parkin DKO mice had further elevated serum levels of ALT and increased mortality after APAP administration. In conclusion, our results demonstrated that PINK1-Parkin signaling pathway plays a critical role in APAP-induced mitophagy and liver injury.
Description
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Collections
- Pharmacy Scholarly Works [288]
Citation
Wang, H., Ni, H. M., Chao, X., Ma, X., Rodriguez, Y. A., Chavan, H., Wang, S., Krishnamurthy, P., Dobrowsky, R., Xu, D. X., Jaeschke, H., & Ding, W. X. (2019). Double deletion of PINK1 and Parkin impairs hepatic mitophagy and exacerbates acetaminophen-induced liver injury in mice. Redox biology, 22, 101148. https://doi.org/10.1016/j.redox.2019.101148
Items in KU ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.
We want to hear from you! Please share your stories about how Open Access to this item benefits YOU.