A Mechanistic Review of Mitophagy and Its Role in Protection against Alcoholic Liver Disease.

Jessica Williams,Wen-Xing Ding

doi:10.3390/biom5042619

Abstract

Alcoholic liver disease (ALD) is a major health problem worldwide, and alcohol is well-known to cause mitochondrial damage, which exacerbates alcohol-induced liver injury and steatosis. No successful treatments are currently available for treating ALD. Therefore, a better understanding of mechanisms involved in regulation of mitochondrial homeostasis in the liver and how these mechanisms may protect against alcohol-induced liver disease is needed for future development of better therapeutic options for ALD. Mitophagy is a key mechanism for maintaining mitochondrial homeostasis by removing damaged mitochondria, and mitophagy protects against alcohol-induced liver injury. Parkin, an E3 ubiquitin ligase, is well-known to induce mitophagy in in vitro models although Parkin-independent mechanisms for mitophagy induction also exist. In this review, we discuss the roles of Parkin and mitophagy in protection against alcohol-induced liver injury and steatosis. We also discuss Parkin-independent mechanisms for mitophagy induction, which have not yet been evaluated in the liver but may also potentially have a protective role against ALD. In addition to mitophagy, mitochondrial spheroid formation may also provide a novel mechanism of protection against ALD, but the role of mitochondrial spheroids in protection against ALD progression needs to be further explored. Targeting removal of damaged mitochondria by mitophagy or inducing formation of mitochondrial spheroids may be promising therapeutic options for treatment of ALD.

Highlights

Alcoholic liver disease (ALD) is a global health problem that is caused by heavy alcohol consumption in addition to other environmental, lifestyle, and genetic factors
The most studied mechanism of mitophagy induction is Parkin-induced mitophagy, and Parkin protects against development of alcohol-induced liver injury and steatosis via initiation of mitophagy and maintenance of mitochondrial function [39]
Mitophagy still occurs, to a lesser extent compared to WT mice, in Parkin KO mice after alcohol and acetaminophen treatments [39,138], suggesting that adaptive compensatory mechanisms for mitophagy induction exist in the liver during chronic loss of Parkin

Summary

Introduction

Alcoholic liver disease (ALD) is a global health problem that is caused by heavy alcohol consumption in addition to other environmental, lifestyle, and genetic factors. We and others have shown that autophagy protects against alcohol-induced liver injury [13,18,19], and protection is due to selective removal of damaged mitochondria and lipid droplets by mitophagy and lipophagy, respectively [13,18]. Mitochondria are the major sites of ATP production and are involved in heme synthesis, fatty acid oxidation, maintenance of calcium levels, and initiation of cell death [27], and mitochondrial dysfunction leads to progression of ALD [28,29,30] Mitochondria maintain their homeostasis by various mechanisms. Mitophagy degrades damaged mitochondria in the lysosome [20,21,22,38], which is an important mechanism for protection against alcohol-induced liver injury and steatosis [13,18,39]. Mitophagy and formation of mitochondrial spheroids as protective mechanisms against alcohol-induced liver injury and steatosis are discussed in this review

Alcohol Metabolism

ALD Pathogenesis

Parkin-Dependent Mitophagy

Parkin-Independent Mitophagy

Findings

Concluding Remarks