Julia Chalker - June 23

The Role of Glutaredoxin-2 in Regulating Superoxide/Hydrogen Peroxide Formation from Liver and Cardiac Tissue.

S-glutathionylation is vital for controlling metabolism, solute transport and other processes in mitochondria in response to redox changes. S-glutathionylation has also been found to control the production of reactive oxygen species (ROS), particularly from complex I of the electron transport chain and the pyruvate and 2-oxoglutarate dehydrogenase complexes. The importance of Grx2 in physiology is underscored by the consequences associated with its absence or deregulation. Grx2 deficiency is associated with heart disease, neurological deficits, and cataracts, which have all been linked to increased ROS production. However, the overall mechanism of how Grx2 contributes to the control of ROS production from mitochondria in different bioenergetics sites, metabolizing different substrates, has not yet been examined. Using Grx2+/- and Grx2-/- mice, we have shown that Grx2 controls the emission of superoxide (O2●-) /hydrogen peroxide (H2O2) from liver and cardiac mitochondria in a tissue and substrate dependant manner. In cardiac tissue, Grx2+/- and Grx2-/- mitochondria display increased ROS production when metabolizing succinate. However, no differences were observed when pyruvate and 2-oxoglutarate was the oxidation substrate. In liver tissue, mitochondria isolated from Grx2-/- mice show a significant decrease in O2●-/H2O2 emission when metabolizing pyruvate and 2-oxoglutarate, but only the Grx2+/- show decreases when supplemented with succinate. Also, noted in this study was a significant difference in ROS production from liver and cardiac mitochondria from C57BL/6N mice when metabolizing different substrates. Succinate was a more a significant source of ROS in cardiac mitochondria compared to pyruvate and 2-oxoglutate, while the opposite effect was observed in liver mitochondria. Our results show that Grx2 plays an important role in controlling mitochondrial ROS production in different tissues. In addition, it has different targets for regulation which may be dependent on tissue specific differences in substrate preference for ROS formation.

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