Mitochondrial Protein UCP2 Controls Pancreas Development

Abstract

The mitochondrial carrier uncoupling protein (UCP) 2 belongs to the family of the UCPs. Despite its name, it is now accepted that UCP2 is rather a metabolite transporter than a UCP. UCP2 can regulate oxidative stress and/or energetic metabolism. In rodents, UCP2 is involved in the control of α- and β-cell mass as well as insulin and glucagon secretion. Our aim was to determine whether the effects of UCP2 observed on β-cell mass have an embryonic origin. Thus, we used knockout mice. We found an increased size of the pancreas in fetuses at embryonic day 16.5, associated with a higher number of α- and β-cells. This phenotype was caused by an increase of PDX1 progenitor cells. Perinatally, an increase in the proliferation of endocrine cells also participates in their expansion. Next, we analyzed the oxidative stress in the pancreata. We quantified an increased nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2) in the mutant, suggesting an increased production of reactive oxygen species (ROS). Phosphorylation of AKT, an ROS target, was also activated in the pancreata. Finally, administration of the antioxidant -acetyl-l-cysteine to pregnant mice alleviated the effect of knocking out UCP2 on pancreas development. Together, these data demonstrate that UCP2 controls pancreas development through the ROS-AKT signaling pathway.

Development of the duct system during exocrine pancreas differentiation in the grass snake Natrix natrix (Lepidosauria, Serpentes)

“…This increase may be correlated with the energy demand during the differentiation of the duct cells, lumen formation, and tubulogenesis. Mitochondria are important systems producing energy in all vertebrate cells (Chan, ) and it is suggested that they play a significant role in pancreas morphogenesis (Broche et al, ).…”

Mitochondrial dysfunction and pancreatic islet β‑cell failure (Review)

“…Uncoupling proteins (UCPs) are closely associated with IMM potential (44,45). Complexes I-IV in the ETC pump protons from the mitochondrial matrix into the IMM and the intermembranous space to establish a H + gradient, whilst UCPs (particularly UCP-1) in the IMM facilitate proton leakage to reduce the IMM potential, uncoupling the respiratory process from ADP phosphorylation (42,46). During this process, UCPs render the final products derived from electron transport to be heat instead of ATP ( Fig.…”

“…The potential role of UCPs in the modulation of insulin secretion in response to glucose has been the focus of research attention. UCP-2 is a negative regulator during pancreatic development (46) and silences glucose oxidation in β-cells, which is the initial process of GSIS (94). Previous studies have demonstrated that upregulated UCP-2 and downregulated UCP-3 under chronic high glucose conditions impaired GSIS in β-cells (43,95).…”

Klotho inhibits H 2 O 2 -induced oxidative stress and apoptosis in periodontal ligament stem cells by regulating UCP2 expression

“…Uncoupling protein 2 (UCP2), a member of mitochondrial transporters family, has been reported to be involved in metabolic reprogramming [17,18]. The ability of UCP2 to regulate glucose is strongly associated with cellular proliferation and apoptosis [19].…”