UCP2 is a mitochondrial transporter with an unusual very short half‐life

Rousset, S.; Mozo, Julien; Dujardin, Geneviève; Emre, Yalin; Masscheleyn, Sandrine; Ricquier, Daniel; Cassard-Doulcier, Anne-Marie

doi:10.1016/j.febslet.2007.01.010

Cited by 83 publications

(71 citation statements)

References 32 publications

(47 reference statements)

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“…UCP2 is a member of the inner mitochondrial membrane anion carrier superfamily (Ricqier & Bouillaud 2000, Rousset et al 2007. Proton leak activity of UCP2 has an important role in negative regulation of insulin secretion via its inhibition of ATP synthesis in b-cells (Jezek 2002).…”

Section: Introductionmentioning

confidence: 99%

Uncoupling protein 2 negatively regulates glucose-induced glucagon-like peptide 1 secretion

Zhang

Li²,

Liang³

et al. 2012

Journal of Molecular Endocrinology

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It is known that endogenous levels of the incretin hormone glucagon-like peptide 1 (GLP1) can be enhanced by various secretagogues, but the mechanism underlying GLP1 secretion is still not fully understood. We assessed the possible effect of uncoupling protein 2 (UCP2) on GLP1 secretion in mouse intestinal tract and NCI-H716 cells, a wellcharacterized human enteroendocrine L cell model. Localization of UCP2 and GLP1 in the gastrointestinal tract was assessed by immunofluorescence staining. Ucp2 mRNA levels in gut were analyzed by quantitative RT-PCR. Human NCI-H716 cells were transiently transfected with siRNAs targeting UCP2. The plasma and ileum tissue levels of GLP1 (7-36) amide were measured using an ELISA kit. UCP2 was primarily expressed in the mucosal layer and colocalized with GLP1 in gastrointestinal mucosa. L cells secreting GLP1 also expressed UCP2. After glucose administration, UCP2-deficient mice showed increased glucose-induced GLP1 secretion compared with wild-type littermates. GLP1 secretion increased after NCI-H716 cells were transfected with siRNAs targeting UCP2. UCP2 was markedly upregulated in ileum tissue from ob/ob mice, and GLP1 secretion decreased compared with normal mice. Furthermore, GLP1 secretion increased after administration of genipin by oral gavage. Taken together, these results reveal an inhibitory role of UCP2 in glucose-induced GLP1 secretion.

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Section: Introductionmentioning

confidence: 99%

Uncoupling protein 2 negatively regulates glucose-induced glucagon-like peptide 1 secretion

Zhang

Li²,

Liang³

et al. 2012

Journal of Molecular Endocrinology

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“…The turnover rate of proteins can vary from minutes to years, often conforming to their biological functions (3,4). The constant renewal of the protein population is an energy-intensive process, yet it allows the cell to rapidly modulate protein levels in response to changes in the environment (5,6).…”

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confidence: 99%

Analysis of proteome dynamics in the mouse brain

Price

Guan²,

Burlingame³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

335

447

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Fig. 2. (A)Interaction web of top-down and bottom-up effects in the eelgrass study system. The top predator is the sea otter (E. lutris), the mesopredators are crabs (Cancer spp. and Pugettia producta), the epiphyte mesograzers are primarily an isopod (I. resecata) and a sea slug (P. taylori), and algal epiphyte competitors of eelgrass primarily consist of chain-forming diatoms, and the red alga Smithora naiadum. Solid arrows indicate direct effects, dashed arrows indicate indirect effects, and the plus and minus symbols indicate positive and/or negative effects on trophic guilds and eelgrass condition. C, competitive interaction; T, trophic interaction. (Original artwork by A. C. Hughes.) (B-E) Survey results testing for the effects of sea otter density on eelgrass bed community properties (Tables S2 and S3). Elkhorn Slough (sea otters present and high nutrients) eelgrass beds (n = 4) are coded in red, and the Tomales Bay reference site (no sea otters, low nutrients) beds (n = 4) are coded in blue. (B) Crab biomass and size structure of two species of Cancer crabs; (C) grazer biomass per shoot and large grazer density; (D) algal epiphyte loading; and (E) aboveground and belowground eelgrass biomass. DW, dry weight; FW, fresh weight.

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“…Although the uncoupling activity of uncoupling proteins may be dependent on acute regulation by endogenous activators such as protonmotive force, fatty acids and reactive alkenals [17,18,20], it is not known whether, or how, such activation is acutely reversed [35]. A plausible mechanism of deactivation of any postulated function of UCP2 is by protein degradation: in ovarian and granulosa cell lines and in macrophages, UCP2 is turned over remarkably rapidly, with a half-life of about 1 h [36,37]. The same is true in INS-1E cells, where the half-life is constant at about 60 min, regardless of the glucose concentration and putative activation state [12].…”

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confidence: 99%

Mitochondrial uncoupling protein 2 in pancreatic β‐cells

Brand

Parker

Affourtit

et al. 2010

Diabetes Obesity Metabolism

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Pancreatic β-cells have remarkable bioenergetics in which increased glucose supply upregulates the cytosolic ATP/ADP ratio and increases insulin secretion. This arrangement allows glucose-stimulated insulin secretion (GSIS) to be regulated by the coupling efficiency of oxidative phosphorylation. Uncoupling protein 2 (UCP2) modulates coupling efficiency and may regulate GSIS. Initial measurements of GSIS and glucose tolerance in Ucp2 −/− mice supported this model, but recent studies show confounding effects of genetic background. Importantly, however, the enhancement of GSIS is robustly recapitulated with acute UCP2 knockdown in INS-1E insulinoma cells. UCP2 protein level in these cells is dynamically regulated, over at least a fourfold concentration range, by rapid proteolysis (half-life less than 1 h) opposing regulated gene transcription and mRNA translation. Degradation is catalysed by the cytosolic proteasome in an unprecedented pathway that is currently known to act only on UCP2 and UCP3. Evidence for proteasomal turnover of UCP2 includes sensitivity of degradation to classic proteasome inhibitors in cells, and reconstitution of degradation in vitro in mitochondria incubated with ubiquitin and the cytosolic 26S proteasome. These dynamic changes in UCP2 content may provide a fine level of control over GSIS in β-cells. Keywords: glucose-stimulated insulin secretion, INS-1E cells, mitochondria, proteasome, protein degradation, turnover, UCP2, UCP3 Date submitted 25 March 2010; date of final acceptance 24 April 2010 IntroductionThe energy metabolism of pancreatic β-cells is extraordinary. Nearly all other mammalian cells rigorously regulate their bioenergetics using internal cues, and only take up fuels when they need them for oxidation and energy release or for storage. Pancreatic β-cells work the other way round, and use fuel supply to regulate their ATP production and cytosolic ATP/ADP ratio.A skeletal muscle cell, for example, will take up glucose from the bloodstream through a plasma membrane glucose transporter, glucose transporter type 4 (GLUT4), when insulin is high and glucose is abundant, otherwise it will use fatty acids as fuel [1]. It will store glucose as glycogen when insulin and ATP are high and calcium (the trigger for muscle contraction and energy demand) is low. Even after glucose enters the cytoplasm, a muscle cell will allow it to enter glycolysis only when that cell requires energy. Glucose 6-phosphate is a non-competitive inhibitor of muscle hexokinase, so when ATP is sufficiently high, glycolysis stalls, glucose 6-phosphate builds up, hexokinase activity is inhibited and glucose metabolism slows. When more ATP is needed because of internal ATP demand, phosphofructokinase and pyruvate kinase are activated, glucose 6-phosphate levels fall and hexokinase channels glucose into glycolysis and to the mitochondria. The mitochondrial electron transport chain pumps protons across the mitochondrial inner membrane, restoring a high protonmotive force and ATP production, until ATP rises and oxidativ...

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UCP2 is a mitochondrial transporter with an unusual very short half‐life

Cited by 83 publications

References 32 publications

Uncoupling protein 2 negatively regulates glucose-induced glucagon-like peptide 1 secretion

Uncoupling protein 2 negatively regulates glucose-induced glucagon-like peptide 1 secretion

Analysis of proteome dynamics in the mouse brain

Mitochondrial uncoupling protein 2 in pancreatic β‐cells

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