The Emerging Functions of UCP2 in Health, Disease, and Therapeutics

Abstract

The uncoupling proteins (UCPs) are attracting an increased interest as potential therapeutic targets in a number of important diseases. UCP2 is expressed in several tissues, but its physiological functions as well as potential therapeutic applications are still unclear. Unlike UCP1, UCP2 does not seem to be important to thermogenesis or weight control, but appears to have an important role in the regulation of production of reactive oxygen species, inhibition of inflammation, and inhibition of cell death. These are central features in, for example, neurodegenerative and cardiovascular disease, and experimental evidence suggests that an increased expression and activity of UCP2 in models of these diseases has a beneficial effect on disease progression, implicating a potential therapeutic role for UCP2. UCP2 has an important role in the pathogenesis of type 2 diabetes by inhibiting insulin secretion in islet beta cells. At the same time, type 2 diabetes is associated with increased risk of cardiovascular disease and atherosclerosis where an increased expression of UCP2 appears to be beneficial. This illustrates that therapeutic applications involving UCP2 likely will have to regulate expression and activity in a tissue-specific manner.

Role of uncoupling protein UCP2 in cell-mediated immunity: How macrophage-mediated insulitis is accelerated in a model of autoimmune diabetes

“…Because UCP2 seems to control the mitochondrial ROS production, UCP2 was shown to promote or inhibit cell death depending on the cell type and stimulus (8,37,38). However, classically performed cytokine-induced NO production and cell death experiments showed no difference between Ucp2-KO and Ucp2-WT islets in vitro.…”

A carbon monoxide-releasing molecule (CORM-3) uncouples mitochondrial respiration and modulates the production of reactive oxygen species

“…Mitochondrial uncoupling essentially drives an energy-dissipating proton cycle across the mitochondrial inner membrane resulting in a compensatory increase in O 2 consumption that is not accompanied by production of ATP [19]. This can be achieved through various mechanisms including activation of adenine nucleotide transporters (ANT) and uncoupling proteins (UCPs), which have been shown to be crucial for cell survival and homeostasis in various disease states [20][21][22][23][24]. Here we report that low micromolar concentrations of CO, delivered to isolated heart mitochondria by a water-soluble CO-RM, uncouple mitochondrial respiration consequently modulating both ROS production and bioenergetic parameters.…”

Downregulation of uncoupling protein-2 by genipin exacerbates diabetes-induced kidney proximal tubular cells apoptosis

“…Recently, the mitochondrion has emerged as a major source of reactive ROS and UCP2, a mitochondrial membrane protein, has been reported to participate in the regulation of ROS generation. 7,8 UCP2 belongs to the UCP family, which are mitochondrial transporters that are capable of dissipating the proton gradient and increasing thermogenesis while reducing the efficiency of ATP synthesis. Furthermore, several other physiological roles of UCPs have recently become a great concern, including regulation of fatty acid, glucose oxidation, and reduction of mitochondrial ROS generation.…”