2.A.29.3.4
Human UCP2; implicated in a variety of physiological and pathological processes including protection from oxidative stress, negative regulation of glucose sensing systems and the adaptation of fatty acid oxidation capacity to starvation. It is not involved in thermogenesis as is UCP1 (Azzu and Brand, 2009). Leucine zipper EF hand-containing transmembrane protein 1 (LetM1; 2.A.97) and uncoupling proteins 2 and 3 (UCP2/3) contribute to two distinct mitochondrial Ca²⁺ uptake pathways (Waldeck-Weiermair et al., 2011).  UCP2 transports protons and chloride ions, is activated by fatty acids and inhibited by purine nucleotides (Hoang et al. 2012).  It reduces mitochondrial Ca²⁺ uptake in response to intracellular Ca²⁺ release in pancreatic beta cells (Alam et al. 2012).  Arginine residues in TMS2 are important for chloride transport without affecting fatty acid-dependent proton transport (Hoang et al. 2015). UCP2 is impermeable to water and has a fatty acid binding site related to H⁺ transport (Škulj et al. 2021). A biphasic proton transport mechanism for uncoupling proteins, with a focus on UCP2, has been proposed (Ardalan et al. 2021). Klotho (TC# 8.A.49) inhibits H₂O₂-induced oxidative stress and apoptosis in periodontal ligament stem cells by regulating UCP2 expression (Zhu et al. 2021). TMS2 functions in the formation of a stable ion channel due to the presence of arginine residues, in particular Arg88, which is a key residue for the movement of Cl^- ions. An atomic-level description of the Cl^- ion transport mechanism has been provided (Naz and Moin 2022). Oxaloacetic acid induces muscle energy substrate depletion and fatigue by JNK-mediated mitochondrial uncoupling using UCP2 (Yin et al. 2024).