Show simple item record

dc.contributor.authorWang, Hua
dc.contributor.authorNi, Hong-Min
dc.contributor.authorChao, Xiaojuan
dc.contributor.authorMa, Xiaowen
dc.contributor.authorRodriguez, Yssa Ann
dc.contributor.authorChavan, Hemantkumar
dc.contributor.authorWang, Shaogui
dc.contributor.authorKrishnamurthy, Partha
dc.contributor.authorDobrowsky, Rick
dc.contributor.authorXu, De-Xiang
dc.contributor.authorJaeschke, Hartmut
dc.contributor.authorDing, Wen-Xing
dc.identifier.citationWang, 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.
dc.descriptionThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.en_US
dc.description.abstractMitochondria 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.en_US
dc.description.sponsorshipNIH R01 AA 020518en_US
dc.description.sponsorshipNIH R01 DK 102142en_US
dc.description.sponsorshipNIH U01 AA 024733en_US
dc.description.sponsorshipNIH P20 GM 103549en_US
dc.description.sponsorshipNIH P30 GM 118247en_US
dc.description.sponsorshipNIH COBRE grant 9P20GM104936en_US
dc.description.sponsorshipNIH S10RR027564en_US
dc.rights© 2019 The Authors. Published by Elsevier B.V.en_US
dc.subjectCell deathen_US
dc.titleDouble deletion of PINK1 and Parkin impairs hepatic mitophagy and exacerbates acetaminophen-induced liver injury in miceen_US
kusw.kuauthorRodriguez, Yssa Ann
kusw.kuauthorDobrowsky, Rick
kusw.kudepartmentPharmacology and Toxicologyen_US
kusw.oaversionScholarly/refereed, publisher versionen_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US

Files in this item


This item appears in the following Collection(s)

Show simple item record

© 2019 The Authors. Published by Elsevier B.V.
Except where otherwise noted, this item's license is described as: © 2019 The Authors. Published by Elsevier B.V.