Glutamate contributes to alcohol hepatotoxicity by enhancing oxidative stress in mitochondria

• Published in: Journal of bioenergetics and biomembranes Vol. 49; no. 3; pp. 253 - 264
• Main Authors: Teplova, Vera V., Kruglov, Alexey G., Kovalyov, Leonid I., Nikiforova, Anna B., Fedotcheva, Nadezhda I., Lemasters, John J.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-06-2017; Springer Nature B.V
• Subjects: Alcohol; Alcoholic beverages; Alcoholism - enzymology; Alcoholism - pathology; Alcohols; Animal Anatomy; Animal Biochemistry; Animals; Biochemistry; Bioorganic Chemistry; Catalase; Chemical and Drug Induced Liver Injury - etiology; Chemistry; Chemistry and Materials Science; Electron transport; Electron transport chain; Ethanol; Ethanol - toxicity; Exposure; Glutamate dehydrogenase; Glutamic acid; Glutamic Acid - pharmacology; Hepatotoxicity; Histology; Hydrogen peroxide; Intoxication; Liver; Mitochondria; Mitochondria, Liver - enzymology; Mitochondria, Liver - metabolism; Morphology; NAD; Organelles; Organic Chemistry; Oxidation; Oxidative stress; Oxidative Stress - drug effects; Oxygen; Proteomics - methods; Rats; Rats, Wistar; Reactive oxygen species; Reactive Oxygen Species - metabolism; Rodents; Substrates; Superoxide; Glutamate dehydrogenase; Chronic alcohol intoxication; Oxidative stress; Reactive oxygen species; Liver mitochondria
• ISSN: 0145-479X; 1573-6881
• DOI: 10.1007/s10863-017-9713-0

Chronic alcohol intoxication is associated with increased oxidative stress. However, the mechanisms by which ethanol triggers an increase in the production of reactive oxygen species (ROS) and the role of mitochondria in the development of oxidative stress has been insufficiently studied. The biochemical and proteomic data obtained in the present work suggest that one of the main causes of an increase in ROS generation is enhanced oxidation of glutamate in response to long-term alcohol exposure. In the course of glutamate oxidation, liver mitochondria from alcoholic rats generated more superoxide anion and H
2
O
2
than in the presence of other substrates and more than control organelles. In mitochondria from alcoholic rats, rates of H
2
O
2
production and NAD reduction in the presence of glutamate were almost twice higher than in the control. The proteomic study revealed a higher content of glutamate dehydrogenase in liver mitochondria of rats subjected to chronic alcohol exposure. Simultaneously, the content of mitochondrial catalase decreased compared to control. Each of these factors stimulates the production of ROS in addition to ROS generated by the respiratory chain complex I. The results are consistent with the conclusion that glutamate contributes to alcohol hepatotoxicity by enhancing oxidative stress in mitochondria.