Mitochondrial proticity and ROS signaling: lessons from the uncoupling proteins

Glutathionylation State of Uncoupling Protein-2 and the Control of Glucose-stimulated Insulin Secretion

“…UCP2 is expressed in many tissues and has been linked to a number of cell signaling functions (10,49). In previous studies, we provided novel evidence that UCP2 is controlled by glutathionylation (6).…”

Glutaredoxin-2 Is Required to Control Proton Leak through Uncoupling Protein-3

“…Previously, we showed that purified UCP3 can be glutathionylated by Grx1 in vitro (22). Furthermore, we were able to show that reversible glutathionylation of UCP3 is required to modulate mitochondrial ROS production that can have profound signaling effects (15). We and others have shown that UCP3 mitigates obesity and promotes fasting-induced fatty acid oxidation (54,55).…”

“…Ϫ/Ϫ Muscle Mitochondria-In our previous work, we showed that glutathionylation of UCP3 inhibits leak and that this can be reversed by ROS (15). The increase in ANT-independent proton leak in Grx2 Ϫ/Ϫ skeletal muscle mitochondria prompted us to determine whether these differences in leak were associated with UCP3 and its glutathionylation state.…”

“…However, several mechanisms have been described for how UCP3 limits mitochondrial ROS. The prevailing hypothesis is that UCP3 controls ROS by inducing the mild leak of protons back into the mitochondrial matrix (15,16). However, other studies have shown that UCP3 functions as a lipid hydroperoxide transporter or calcium uniporter (17,18).…”

“…Thus, the mechanism through which UCP3 regulates cell ROS remains enthusiastically debated. In an effort to provide further clarity on this issue, our group recently explored potential redox regulatory mechanisms involved in controlling UCP3 and UCP2 function (15). By manipulating the redox environment, we showed that covalent attachment of glutathione to UCP3 and UCP2 inhibits proton leak and that the inhibition is reversed by small increases in mitochondrial * This work was supported by grants from the Canadian Institutes of Health Tables S1 and S2, and additional references.…”