Contribution of mitochondria to oxidative stress associated with alcoholic liver disease

doi:10.1016/S0891-5849(01)00769-9

Free Radical Biology and Medicine

Volume 32, Issue 1, 1 January 2002, Pages 11-16

https://doi.org/10.1016/S0891-5849(01)00769-9 Get rights and content

Abstract

The importance of oxidative stress in the development of alcoholic liver disease has long been appreciated. The mechanism by which ethanol triggers an increase in reactive oxygen species in the liver is complex, however, recent findings suggest that the mitochondrion may contribute significantly to the overall increase in oxidant levels in hepatocytes exposed to ethanol acutely or chronically. This review is focused on observations which indicate that the ability of ethanol to increase mitochondrial reactive oxygen species production is linked to its metabolism via oxidative processes and/or ethanol-related alterations to the mitochondrial electron transport chain. Furthermore, the capacity of ethanol-elicited increases in reactive oxygen species to oxidatively modify and inactivate mitochondrial proteins is highlighted as a mechanism by which ethanol might further disrupt the structure and function of mitochondria.

Introduction

The mitochondrion is recognized as an important intracellular target for the damaging effects of ethanol in liver. One of the earliest effects of chronic ethanol consumption on liver is an alteration in mitochondria structure in which the organelle is often enlarged and misshapen and contains disrupted cristae. It was recognized several years ago that these structural changes induced by ethanol exposure were also accompanied by depressed mitochondrial function. Specifically, after chronic ethanol consumption there is a decrease in the rate of ATP synthesis via the oxidative phosphorylation system [1], [2] due to chronic ethanol-related lesions in several components of the mitochondrial respiratory chain (see reviews [3], [4]). A brief summary of those ethanol-related alterations that affect the hepatic energy state will follow. Recently, it has been proposed that these chronic ethanol-related disturbances in mitochondrial structure and function might also be responsible for an increase in the production of reactive oxygen species (ROS) by mitochondria. Thus, mitochondria may be an important contributor to oxidative damage observed in liver following exposure to ethanol. This review article will discuss in detail those mechanisms by which acute and chronic ethanol exposures increase mitochondrial generation of ROS in hepatocytes.

Section snippets

Chronic ethanol-induced alterations to the oxidative phosphorylation system

The key change in hepatic mitochondria after chronic ethanol exposure is a decrease in the rate of ATP synthesis via the oxidative phosphorylation system that might be the result of ethanol-related alterations in the concentration and/or function of the individual components of the respiratory chain. There is conclusive evidence that chronic ethanol consumption depresses the activities of all the mitochondrial respiratory chain segments, except complex II [3], [4]. Chronic ethanol consumption

Mitochondria as a source of ROS

Under normal physiological conditions the mitochondrion is the major source of ROS production in the hepatocyte [16]. Approximately 80–90% of the oxygen utilized by hepatocytes is metabolized by mitochondria [17] and it is estimated that 2% of the oxygen consumed is converted to superoxide anions [18] due to the “leakage” of unpaired electrons to molecular oxygen as they are being transported down the respiratory chain. Evidence suggests that production of ROS occurs at both complex I and III

Acute ethanol oxidation and mitochondrial ROS production in hepatocytes

Studies by our laboratory demonstrate that the mitochondrion is a significant source of ROS when hepatocytes are incubated acutely with ethanol [22], [23]. In order to demonstrate that the metabolism of ethanol would stimulate mitochondrial production of ROS in hepatocytes, we used the ROS-sensitive probe 2′,7′-dichlorofluorescin diacetate (DCFH-DA) to quantify ROS levels in which the green fluorescence intensity of 2′,7′-dichlorofluorescein is positively correlated to the steady-state levels

Chronic ethanol consumption and mitochondrial ROS production in hepatocytes

Evidence for increased mitochondrial production of ROS in animals exposed to ethanol chronically comes largely from indirect measurements of lipid peroxidation products in isolated mitochondria. However, measures of ROS production in real time under strictly controlled oxygen tensions were required to determine whether chronic ethanol consumption increases the mitochondrial contribution to oxidative stress in the hepatocyte. Recently, our laboratory [23], [25] observed that chronic ethanol

Consequence of ethanol-elicited increases in mitochondrial ROS: oxidation of mitochondrial proteins

Previous studies have clearly demonstrated that chronic ethanol consumption decreases the viability of hepatocytes [23], [25], [27]. Our findings demonstrating ethanol-related increases in hepatocyte ROS production suggest that chronic ethanol consumption might create an oxidative stress within the hepatocyte, and particularly in the mitochondrion. Furthermore, chronic ethanol-related decreases in mitochondrial antioxidants, namely glutathione peroxidase-1 activity [28], may also lead to

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¹: This article is part of a series of reviews on “Alcohol, Oxidative Stress and Cell Injury”. The full list of papers may be found on the homepage of the journal.

²: Dr. Shannon M. Bailey obtained her Ph.D. in pharmacology from The University of Oklahoma Health Sciences Center (1996) working on mechanisms of hepatic ischemia-reperfusion injury with Dr. Lester A. Reinke. In 1996, she joined the laboratory of Dr. Carol C. Cunningham at Wake Forest University School of Medicine as a postdoctoral fellow. She is currently an Assistant Professor in the Department of Environmental Health Sciences at the University of Alabama at Birmingham and her research focuses on the role of oxidative stress in alcohol-induced mitochondrial injury.

³: Dr. Carol C. Cunningham is Professor of Biochemistry at Wake Forest University School of Medicine. His research is directed toward determining the effects of chronic ethanol consumption on those mechanisms responsible for hepatic ATP synthesis. Current efforts are focused on characterizing ethanol-related lesions in the mitochondrial oxidative phosphorylation system. The effects of ethanol on glycogen metabolism and glycolytic synthesis of ATP are also areas of investigation.

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Serial review: alcohol, oxidative stress and cell injury Guest editor: Arthur CederbaumContribution of mitochondria to oxidative stress associated with alcoholic liver disease1

Abstract

Introduction

Section snippets

Chronic ethanol-induced alterations to the oxidative phosphorylation system

Mitochondria as a source of ROS

Acute ethanol oxidation and mitochondrial ROS production in hepatocytes

Chronic ethanol consumption and mitochondrial ROS production in hepatocytes

Consequence of ethanol-elicited increases in mitochondrial ROS: oxidation of mitochondrial proteins

Biochim. Biophys. Act

Curr. Top. Bioenerg.

J. Biol. Chem.

Biochem. Pharmacol.

Biochem. Biophys. Res. Commun.

Biochim. Biophys. Acta

Biochim. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

J. Hepatol.

Eur. J. Pharmacol.

Biochim. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

Arch. Biochem. Biophys.

Free Radic. Biol. Med.

Toxicol. Lett.

Serial review: alcohol, oxidative stress and cell injury Guest editor: Arthur Cederbaum
Contribution of mitochondria to oxidative stress associated with alcoholic liver disease¹