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Increased nitroxidative stress promotes mitochondrial dysfunction in alcoholic and nonalcoholic fatty liver disease.

Song BJ, Abdelmegeed MA, Henderson LE, Yoo SH, Wan J, Purohit V, Hardwick JP, Moon KH - Oxid Med Cell Longev (2013)

Bottom Line: Increased nitroxidative stress causes mitochondrial dysfunctions through oxidative modifications of mitochondrial DNA, lipids, and proteins.Many mitochondrial proteins including the enzymes involved in fat oxidation and energy supply could be oxidatively modified (including S-nitrosylation/nitration) under increased nitroxidative stress and thus inactivated, leading to increased fat accumulation and ATP depletion.To demonstrate the underlying mechanism(s) of mitochondrial dysfunction, we employed a redox proteomics approach using biotin-N-maleimide (biotin-NM) as a sensitive biotin-switch probe to identify oxidized Cys residues of mitochondrial proteins in the experimental models of alcoholic and acute liver disease.

View Article: PubMed Central - PubMed

Affiliation: Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD 20892, USA. bj.song@nih.gov

ABSTRACT
Increased nitroxidative stress causes mitochondrial dysfunctions through oxidative modifications of mitochondrial DNA, lipids, and proteins. Persistent mitochondrial dysfunction sensitizes the target cells/organs to other pathological risk factors and thus ultimately contributes to the development of more severe disease states in alcoholic and nonalcoholic fatty liver disease. The incidences of nonalcoholic fatty liver disease continuously increase due to high prevalence of metabolic syndrome including hyperlipidemia, hypercholesterolemia, obesity, insulin resistance, and diabetes. Many mitochondrial proteins including the enzymes involved in fat oxidation and energy supply could be oxidatively modified (including S-nitrosylation/nitration) under increased nitroxidative stress and thus inactivated, leading to increased fat accumulation and ATP depletion. To demonstrate the underlying mechanism(s) of mitochondrial dysfunction, we employed a redox proteomics approach using biotin-N-maleimide (biotin-NM) as a sensitive biotin-switch probe to identify oxidized Cys residues of mitochondrial proteins in the experimental models of alcoholic and acute liver disease. The aims of this paper are to briefly describe the mechanisms, functional consequences, and detection methods of mitochondrial dysfunction. We also describe advantages and limitations of the Cys-targeted redox proteomics method with alternative approaches. Finally, we discuss various applications of this method in studying oxidatively modified mitochondrial proteins in extrahepatic tissues or different subcellular organelles and translational research.

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Summary of oxidatively modified mitochondrial proteins in alcohol-exposed rat livers. Oxidized mitochondrial proteins were purified from alcohol-exposed rats and dextrose-exposed pair-fed controls, identified by mass spectral analysis, and then grouped under different functions, as adapted from [67].
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fig2: Summary of oxidatively modified mitochondrial proteins in alcohol-exposed rat livers. Oxidized mitochondrial proteins were purified from alcohol-exposed rats and dextrose-exposed pair-fed controls, identified by mass spectral analysis, and then grouped under different functions, as adapted from [67].

Mentions: In addition to ALDH isozymes, many other mitochondrial proteins were oxidatively modified and inactivated in alcohol-exposed rat livers [67] (Figure 2). We also observed similar patterns of oxidatively modified mitochondrial proteins in the animal models of acute liver disease from hepatic I/R injury [70] or MDMA exposure [14, 91], or during fasting-related oxidative stress [92]. We expect that similar patterns of oxidative modifications of many mitochondrial proteins would be identified in experimental models of nonalcoholic fatty liver disease caused by high fat diets [76] or methionine/choline-deficient diets [10, 45], based on increased oxidative stress and similar courses of disease progress between alcoholic and nonalcoholic fatty liver diseases [9].


Increased nitroxidative stress promotes mitochondrial dysfunction in alcoholic and nonalcoholic fatty liver disease.

Song BJ, Abdelmegeed MA, Henderson LE, Yoo SH, Wan J, Purohit V, Hardwick JP, Moon KH - Oxid Med Cell Longev (2013)

Summary of oxidatively modified mitochondrial proteins in alcohol-exposed rat livers. Oxidized mitochondrial proteins were purified from alcohol-exposed rats and dextrose-exposed pair-fed controls, identified by mass spectral analysis, and then grouped under different functions, as adapted from [67].
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3649774&req=5

fig2: Summary of oxidatively modified mitochondrial proteins in alcohol-exposed rat livers. Oxidized mitochondrial proteins were purified from alcohol-exposed rats and dextrose-exposed pair-fed controls, identified by mass spectral analysis, and then grouped under different functions, as adapted from [67].
Mentions: In addition to ALDH isozymes, many other mitochondrial proteins were oxidatively modified and inactivated in alcohol-exposed rat livers [67] (Figure 2). We also observed similar patterns of oxidatively modified mitochondrial proteins in the animal models of acute liver disease from hepatic I/R injury [70] or MDMA exposure [14, 91], or during fasting-related oxidative stress [92]. We expect that similar patterns of oxidative modifications of many mitochondrial proteins would be identified in experimental models of nonalcoholic fatty liver disease caused by high fat diets [76] or methionine/choline-deficient diets [10, 45], based on increased oxidative stress and similar courses of disease progress between alcoholic and nonalcoholic fatty liver diseases [9].

Bottom Line: Increased nitroxidative stress causes mitochondrial dysfunctions through oxidative modifications of mitochondrial DNA, lipids, and proteins.Many mitochondrial proteins including the enzymes involved in fat oxidation and energy supply could be oxidatively modified (including S-nitrosylation/nitration) under increased nitroxidative stress and thus inactivated, leading to increased fat accumulation and ATP depletion.To demonstrate the underlying mechanism(s) of mitochondrial dysfunction, we employed a redox proteomics approach using biotin-N-maleimide (biotin-NM) as a sensitive biotin-switch probe to identify oxidized Cys residues of mitochondrial proteins in the experimental models of alcoholic and acute liver disease.

View Article: PubMed Central - PubMed

Affiliation: Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD 20892, USA. bj.song@nih.gov

ABSTRACT
Increased nitroxidative stress causes mitochondrial dysfunctions through oxidative modifications of mitochondrial DNA, lipids, and proteins. Persistent mitochondrial dysfunction sensitizes the target cells/organs to other pathological risk factors and thus ultimately contributes to the development of more severe disease states in alcoholic and nonalcoholic fatty liver disease. The incidences of nonalcoholic fatty liver disease continuously increase due to high prevalence of metabolic syndrome including hyperlipidemia, hypercholesterolemia, obesity, insulin resistance, and diabetes. Many mitochondrial proteins including the enzymes involved in fat oxidation and energy supply could be oxidatively modified (including S-nitrosylation/nitration) under increased nitroxidative stress and thus inactivated, leading to increased fat accumulation and ATP depletion. To demonstrate the underlying mechanism(s) of mitochondrial dysfunction, we employed a redox proteomics approach using biotin-N-maleimide (biotin-NM) as a sensitive biotin-switch probe to identify oxidized Cys residues of mitochondrial proteins in the experimental models of alcoholic and acute liver disease. The aims of this paper are to briefly describe the mechanisms, functional consequences, and detection methods of mitochondrial dysfunction. We also describe advantages and limitations of the Cys-targeted redox proteomics method with alternative approaches. Finally, we discuss various applications of this method in studying oxidatively modified mitochondrial proteins in extrahepatic tissues or different subcellular organelles and translational research.

Show MeSH
Related in: MedlinePlus