Regulation of UCP3 expression and function in response to hypoxia and oxidative stress in mouse cardiomyocytes

Mitochondrial uncoupling proteins (UCPs) are able to increase the mitochondrial inner membrane proton conductance and consequently decrease the electrochemical proton gradient, thus diminishing the efficiency of oxidative phosphorylation. UCP3 is expressed abundantly in skeletal muscle and to a lesser extent in brow adipose tissue (BAT) and heart. Unlike UCP3, that mediates non-shivering thermogenesis in BAT, the main function of UCP3 is not heat production. Instead, it plays important roles in fatty acid oxidation and in the attenuation of superoxide production by the electron transport chain. UCP3 is activated by superoxide and the lipid peroxidation product 4-hydroxy-2-nonenal (HNE), thus providing a negative feedback loop for mitochondrial reactive oxygen species production. We have shown that the treatment with hydrogen peroxide or HNE upregulate UCP3 in mouse cardiomyocytes. Likewise, exposure of these cells to low oxygen concentrations increases UCP3 expression. We have also studied the signaling pathways involved and the consequences of UCP3 upregulation for cell viability. These results have important implications for pathological situations associated with increased oxidative stress and limited oxygen availability such as ischemia-reperfusion injury and stroke.