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Glutamate contributes to alcohol hepatotoxicity by enhancing oxidative stress in mitochondria

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Abstract

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 H2O2 than in the presence of other substrates and more than control organelles. In mitochondria from alcoholic rats, rates of H2O2 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.

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Acknowledgements

This work was supported by grant from the Ministry of Education and Science of the Russian Federation, Agreement № 14.Z50.31.0028 and grant from the Russian Foundation for Basic Research (project № 14-04-01664a).

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Authors and Affiliations

  1. Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, Pushchino, Moscow Region, 142290, Russia

    Vera V. Teplova, Alexey G. Kruglov, Anna B. Nikiforova, Nadezhda I. Fedotcheva & John J. Lemasters

  2. A. N. Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Leninsky prospekt, 33, Moscow, 119071, Russia

    Leonid I. Kovalyov

  3. Center for Cell Death, Injury & Regeneration, Department of Drug Discovery & Biomedical Sciences and Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC, 29425, USA

    John J. Lemasters

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  1. Vera V. Teplova
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Correspondence to Alexey G. Kruglov.

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Teplova, V.V., Kruglov, A.G., Kovalyov, L.I. et al. Glutamate contributes to alcohol hepatotoxicity by enhancing oxidative stress in mitochondria. J Bioenerg Biomembr 49, 253–264 (2017). https://doi.org/10.1007/s10863-017-9713-0

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