| Mitochondrial dysfunction is a determinant factor in the pathogenesis of neurological disorders. Reactive oxygen species -induced oxidative damage contributes to mitochondrial dysfunction. Therefore, opposing oxidative stress is a useful strategy in the development of neuroprotective treatments. Uncoupling of mitochondrial respiration from ATP production decreases endogenous ROS production. Accordingly, uncoupling proteins (UCPs) are expected to have ROS-lowering properties. However, it appears that UCPs are not equally involved in ROS regulation. UCP1 is mostly thermogenic, and the roles of UCP2 and 3 in neuroprotection are controversial. Here, we hypothesize that UCP4, a brain-specific uncoupling protein, protects neuronal cells from ROS-induced damage by preserving mitochondrial integrity and function. In our preliminary studies, we silenced UCP4 in neuronal PC12 cells. This decreased cell viability (77.3% of control) and increased ROS production under basal conditions. In addition, treatment with H 2O2 or diamide potentiated oxidative stress. Moreover, mitochondrial and cellular GSH were significantly depleted in cells that had reduced UCP4 function (52% and 67% of control, respectively). Interestingly, in PC12 cells overexpressing human UCP4, levels of mitochondrial and cellular GSH increased (156% and 131% increase, respectively). These findings suggest that UCP4 decreases ROS, and regulates the mitochondrial pool of GSH. |
