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Deficiency in E3 Ubiquitin Ligase Parkin Exacerbates Chronic Alcohol Intake-Induced Cardiomyopathy through an Ambra1-Dependent Mechanism
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  • Mingjie Yang,
  • Shuyi Wang,
  • Ne Wu,
  • Xihui Xu,
  • Yingmei Zhang,
  • Jun Ren
Mingjie Yang
Zhongshan Hospital Fudan University
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Shuyi Wang
University of Wyoming
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Ne Wu
Zhongshan Hospital Fudan University
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Xihui Xu
University of Wyoming
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Yingmei Zhang
Zhongshan Hospital Fudan University
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Jun Ren
University of Wyoming College of Health Sciences
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Abstract

Background and purpose: Chronic alcohol intake provoked unfavorable geometric and functional changes in the heart along with altered autophagy. Parkin, a cytosolic E3 ubiquitin ligase encoded by PARK2 gene, governs mitochondrial homeostasis and mitophagy although its role in alcoholic cardiomyopathy remains unclear. Experimental approach: This study was designed to examine the role of Parkin in alcohol-induced cardiomyopathy. Adult male wild-type (WT) and PARKIN2 knockout (Parkin-/-) mice were placed on alcohol (4%) or control diet for 8 weeks. Echocardiographic and cardiomyocyte mechanical properties, myocardial and mitochondrial morphology, autophagy and mitophagy were evaluated. GFP-LC3 puncta was employed to assess autophagosome formation. Key results: Our results revealed that alcohol intake led to unfavorable geometric and contractile changes (enlarged left ventricular chamber; decreased fractional shortening, ejection fraction, peak shortening and velocity of shortening/relengthening, prolonged relengthening duration), enlarged cardiomyocyte size and interstitial fibrosis, as well as mitochondrial swelling with cristae disarrangement and mitochondrial depolarization, the effects of which were exacerbated by Parkin deficiency. Alcohol consumption promoted autophagy and PINK1-Parkin-mediated mitophagy, the effects of which were cancelled off by Parkin knockout. Co-immunoprecipitation noted a tight interaction between Parkin and Ambra1 (autophagy and beclin1 regulator 1). In vitro study using neonatal rat cardiomyocytes revealed that Parkin transfection ameliorated ethanol-induced changes in autophagy. However, Ambra1 silencing negated Parkin-induced protection against ethanol-induced autophagy. Conclusions and implications: Taken together, these data suggest an integral role for Parkin in the face of alcoholic challenge possibly through its interaction with Ambra1 to promote autophagy and maintain mitochondrial homeostasis.

Peer review status:ACCEPTED

18 Feb 2020Submitted to British Journal of Pharmacology
20 Feb 2020Submission Checks Completed
20 Feb 2020Assigned to Editor
25 Feb 2020Reviewer(s) Assigned
01 Apr 2020Editorial Decision: Revise Minor
06 Jun 20201st Revision Received
13 Jul 2020Assigned to Editor
13 Jul 2020Submission Checks Completed
16 Jul 2020Reviewer(s) Assigned
29 Jul 2020Review(s) Completed, Editorial Evaluation Pending
14 Aug 2020Editorial Decision: Revise Minor
17 Aug 20202nd Revision Received
19 Aug 2020Submission Checks Completed
19 Aug 2020Assigned to Editor
25 Aug 2020Review(s) Completed, Editorial Evaluation Pending
01 Sep 2020Editorial Decision: Accept