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Thioredoxin Reductase-2 Is Essential for Keeping Low Levels of H2O2 Emission from Isolated Heart Mitochondria

Stanley, B. A., Sivakumaran, V., Shi, S., McDonald, Iain, Lloyd, David, Watson, W. H., Aon, M. A. and Paolocci, N. 2011. Thioredoxin Reductase-2 Is Essential for Keeping Low Levels of H2O2 Emission from Isolated Heart Mitochondria. The Journal of Biological Chemistry 286 (38) , pp. 33669-33677. 10.1074/jbc.M111.284612

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Abstract

Respiring mitochondria produce H2O2 continuously. When production exceeds scavenging, H2O2 emission occurs, endangering cell functions. The mitochondrial peroxidase peroxiredoxin-3 reduces H2O2 to water using reducing equivalents from NADPH supplied by thioredoxin-2 (Trx2) and, ultimately, thioredoxin reductase-2 (TrxR2). Here, the contribution of this mitochondrial thioredoxin system to the control of H2O2 emission was studied in isolated mitochondria and cardiomyocytes from mouse or guinea pig heart. Energization of mitochondria by the addition of glutamate/malate resulted in a 10-fold decrease in the ratio of oxidized to reduced Trx2. This shift in redox state was accompanied by an increase in NAD(P)H and was dependent on TrxR2 activity. Inhibition of TrxR2 in isolated mitochondria by auranofin resulted in increased H2O2 emission, an effect that was seen under both forward and reverse electron transport. This effect was independent of changes in NAD(P)H or membrane potential. The effects of auranofin were reproduced in cardiomyocytes; superoxide and H2O2 levels increased, but similarly, there was no effect on NAD(P)H or membrane potential. These data show that energization of mitochondria increases the antioxidant potential of the TrxR2/Trx2 system and that inhibition of TrxR2 results in increased H2O2 emission through a mechanism that is independent of changes in other redox couples.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Earth and Ocean Sciences
Subjects: Q Science > QP Physiology
Uncontrolled Keywords: Glutathione; Mitochondria; Reactive Oxygen Species (ROS); Thioredoxin; Thioredoxin Reductase; NAD(P)H; Auranofin; Cardiomyocytes; Forward and Reverse Electron Transport; Mitochondrial Membrane Potential
Publisher: American Society for Biochemistry and Molecular Biology
ISSN: 0021-9258
Last Modified: 04 Jun 2017 03:00
URI: http://orca.cf.ac.uk/id/eprint/15169

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