UCP2
Description
The UCP2 (uncoupling protein 2) is a protein-coding gene located on chromosome 11.
Mitochondrial uncoupling protein 2 is a protein that in humans is encoded by the UCP2 gene. Mitochondrial uncoupling proteins (UCP) are members of the larger family of mitochondrial anion carrier proteins (MACP). UCPs separate, or uncouple, oxidative phosphorylation from ATP synthesis by dissipating the mitochondrial membrane potential as heat, also referred to as the mitochondrial proton leak. UCPs facilitate the transfer of anions from the inner to the outer mitochondrial membrane and the return transfer of protons from the outer to the inner mitochondrial membrane. They also reduce the mitochondrial membrane potential in mammalian cells, which reduces production of reactive oxygen species (ROS). In contrast to UCP1 and UCP3, which are primarily expressed in adipose and smooth muscle, UCP2 is expressed on many different tissues including the kidney, liver, GI tract, brain, and skeletal muscle. The exact mechanisms of anion transfer by UCPs are not known. UCPs contain the three homologous protein domains of MACPs. Although it was originally thought to play a role in non-shivering thermogenesis, obesity, diabetes and atherosclerosis, it now appears that the main function of UCP2 is the control of mitochondria-derived reactive oxygen species. Chromosomal order is 5'-UCP3-UCP2-3'.
UCP2 is an antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner mitochondrial membrane. This process is driven by the mitochondrial membrane potential, and it impacts glycolysis, glutaminolysis, and glutathione-dependent redox balance. Continuous export of oxaloacetate and related four-carbon dicarboxylates from the mitochondrial matrix into the cytosol negatively regulates the oxidation of acetyl-CoA substrates via the Krebs cycle, lowering the ATP/ADP ratio and ROS production. There is debate on whether UCP2 facilitates proton re-entry into the mitochondrial matrix. If it does, this process may affect ATP turnover and serve as a protective mechanism against oxidative stress. Proton re-entry might be linked to metabolite transport to allow for proton flux switching and optimized ATP turnover. UCP2 regulates glucose utilization as an energy source. It is essential for glucose-induced DRP1-dependent mitochondrial fission and neuron activation in the ventromedial nucleus of the hypothalamus (VMH). This mitochondrial adaptation mechanism modulates the VMH pool of glucose-excited neurons, influencing systemic glucose homeostasis. UCP2 regulates ROS levels and metabolic reprogramming of macrophages during the resolution of inflammation. It attenuates ROS production in response to IL33 to preserve the integrity of the Krebs cycle, which is essential for persistent production of itaconate and subsequent GATA3-dependent differentiation of inflammation-resolving alternatively activated macrophages. UCP2 can unidirectionally transport anions, including L-malate, L-aspartate, phosphate, and chloride ions. It does not mediate adaptive thermogenesis.
UCP2 is also known as BMIQ4, SLC25A8, UCPH.
