Mitochondrial Ca2+, the secret behind the function of uncoupling proteins 2 and 3?

The underlying molecular action of the novel uncoupling proteins 2 and 3 (UCP2 and UCP3) is still under debate. The proteins have been implicated in many cell functions, including the regulation of insulin secretion and regulation of reactive oxygen species (ROS) generation. These effects have mainly been explained by suggesting that the proteins establish a proton leak through the inner mitochondrial membrane (IMM). However, accumulating data question this mechanism and suggest that UCP2 and UCP3 may play other roles, including carrying free fatty acids from the matrix towards the intermembrane space, or contributing to the mitochondrial Ca(2+) uniport. Accordingly, in this review we reflect on these actions of UCP2/UCP3 and discuss alternative explanations for the molecular mechanisms by which UCP2/UCP3 might contribute to aspects of cell function. Based on the potential role of UCP2/UCP3 in regulating mitochondrial Ca(2+) uptake, we propose a scheme whereby these proteins integrate Ca(2+)-dependent signal transduction and energy metabolism in order to meet the energy demand of the cell for its continuous response, adaptation, and stimulation to environmental input.