Uncoupling Protein 2

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Martin D Brand - One of the best experts on this subject based on the ideXlab platform.

  • Uncoupling Protein 2 attenuates glucose stimulated insulin secretion in ins 1e insulinoma cells by lowering mitochondrial reactive oxygen species
    Free Radical Biology and Medicine, 2011
    Co-Authors: Martin D Brand, Charles Affourtit, Martin Jastroch
    Abstract:

    Glucose-stimulated insulin secretion (GSIS) by pancreatic β cells is regulated by mitochondrial Uncoupling Protein-2 (UCP2), but opposing phenotypes, GSIS improvement and impairment, have been reported for different Ucp2-ablated mouse models. By measuring mitochondrial bioenergetics in attached INS-1E insulinoma cells with and without UCP2, we show that UCP2 contributes to proton leak and attenuates glucose-induced rises in both respiratory activity and the coupling efficiency of oxidative phosphorylation. Strikingly, the GSIS improvement seen upon UCP2 knockdown in INS-1E cells is annulled completely by the cell-permeative antioxidant MnTMPyP. Consistent with this observation, UCP2 lowers mitochondrial reactive oxygen species at high glucose levels. We conclude that UCP2 plays both regulatory and protective roles in β cells by acutely lowering GSIS and chronically preventing oxidative stress. Our findings thus provide a mechanistic explanation for the apparently discrepant findings in the field.

  • dysregulation of glucose homeostasis in nicotinamide nucleotide transhydrogenase knockout mice is independent of Uncoupling Protein 2
    Biochimica et Biophysica Acta, 2009
    Co-Authors: Nadeene Parker, Antonio Vidalpuig, Vian Azzu, Martin D Brand
    Abstract:

    Glucose intolerance in C57Bl/6 mice has been associated with mutations in the nicotinamide nucleotide transhydrogenase (Nnt) gene. It has been proposed that the absence of NNT from mitochondria leads to increased mitochondrial reactive oxygen species production and subsequent activation of Uncoupling Protein 2 (UCP2). Activation of UCP2 has been suggested to uncouple electron transport from ATP synthesis in pancreatic beta cell mitochondria thereby decreasing glucose tolerance due to decreased insulin secretion through lower ATP/ADP ratios. The hypothesis tested in this paper is that UCP2 function is required for the dysregulation of glucose homeostasis observed in NNT ablated mice. Single and double Nnt and Ucp2 knockout mouse lines were used to measure glucose tolerance, whole animal energy balance and biochemical characteristics of mitochondrial Uncoupling. As expected, glucose tolerance was diminished in mice lacking NNT. This was independent of UCP2 as it was observed either in the presence or absence of UCP2. The range of metabolic parameters examined in the mice and the proton conductance of isolated mitochondria remained unaltered in this double NNT and UCP2 knockout model. Ablation of UCP2 did not itself affect glucose tolerance and therefore previous observations of increased glucose tolerance of mice lacking UCP2 were not confirmed. We conclude that the decreased glucose tolerance in Nnt knockout mice observed in our experiments does not require UCP2.

  • Uncoupling Protein 2 contributes significantly to high mitochondrial proton leak in ins 1e insulinoma cells and attenuates glucose stimulated insulin secretion
    Biochemical Journal, 2008
    Co-Authors: Charles Affourtit, Martin D Brand
    Abstract:

    Proton leak exerts stronger control over ATP/ADP in mitochondria from clonal pancreatic beta-cells (INS-1E) than in those from rat skeletal muscle, due to the higher proton conductance of INS-1E mitochondria [Affourtit and Brand (2006) Biochem. J. 393, 151-159]. In the present study, we demonstrate that high proton leak manifests itself at the cellular level too: the leak rate (measured as myxothiazol-sensitive, oligomycin-resistant respiration) was nearly four times higher in INS-1E cells than in myoblasts. This relatively high leak activity was decreased more than 30% upon knock-down of UCP2 (Uncoupling Protein-2) by RNAi (RNA interference). The high contribution of UCP2 to leak suggests that proton conductance through UCP2 accounts for approx. 20% of INS-1E respiration. UCP2 knock-down enhanced GSIS (glucose-stimulated insulin secretion), consistent with a role for UCP2 in beta-cell physiology. We propose that the high mitochondrial proton leak in beta-cells is a mechanism which amplifies the effect of physiological UCP2 regulators on cytoplasmic ATP/ADP and hence on insulin secretion.

  • Uncoupling Protein 2 contributes significantly to high mitochondrial proton leak in ins 1e insulinoma cells and attenuates glucose stimulated insulin secretion
    Biochemical Journal, 2008
    Co-Authors: Charles Affourtit, Martin D Brand
    Abstract:

    Proton leak exerts stronger control over ATP/ADP in mitochondria from clonal pancreatic β-cells (INS-1E) than in those from rat skeletal muscle, due to the higher proton conductance of INS-1E mitochondria [Affourtit and Brand (2006) Biochem. J. 393 , 151–159]. In the present study, we demonstrate that high proton leak manifests itself at the cellular level too: the leak rate (measured as myxothiazol-sensitive, oligomycin-resistant respiration) was nearly four times higher in INS-1E cells than in myoblasts. This relatively high leak activity was decreased more than 30% upon knock-down of UCP2 (Uncoupling Protein-2) by RNAi (RNA interference). The high contribution of UCP2 to leak suggests that proton conductance through UCP2 accounts for approx. 20% of INS-1E respiration. UCP2 knock-down enhanced GSIS (glucose-stimulated insulin secretion), consistent with a role for UCP2 in β-cell physiology. We propose that the high mitochondrial proton leak in β-cells is a mechanism which amplifies the effect of physiological UCP2 regulators on cytoplasmic ATP/ADP and hence on insulin secretion. Abbreviations: Δψ, mitochondrial membrane potential; FCS, foetal calf serum; GSIS, glucose-stimulated insulin secretion; KRBH, Krebs–Ringer bicarbonate Hepes buffer; RNAi, RNA interference; siRNA, small interfering RNA; UCP, Uncoupling Protein

  • physiological levels of mammalian Uncoupling Protein 2 do not uncouple yeast mitochondria
    Journal of Biological Chemistry, 2001
    Co-Authors: James A Harper, Jeffrey A Stuart, Kevin M Brindle, Mika B Jekabsons, Martin D Brand
    Abstract:

    We assessed the ability of human Uncoupling Protein 2 (UCP2) to uncouple mitochondrial oxidative phosphorylation when expressed in yeast at physiological and supraphysiological levels. We used three different inducible UCP2 expression constructs to achieve mitochondrial UCP2 expression levels in yeast of 33, 283, and 4100 ng of UCP2/mg of mitochondrial Protein. Yeast mitochondria expressing UCP2 at 33 or 283 ng/mg showed no increase in proton conductance, even in the presence of various putative effectors, including palmitate and all-trans-retinoic acid. Only when UCP2 expression in yeast mitochondria was increased to 4 microg/mg, more than an order of magnitude greater than the highest known physiological concentration, was proton conductance increased. This increased proton conductance was not abolished by GDP. At this high level of UCP2 expression, an inhibition of substrate oxidation was observed, which cannot be readily explained by an Uncoupling activity of UCP2. Quantitatively, even the Uncoupling seen at 4 microgram/mg was insufficient to account for the basal proton conductance of mammalian mitochondria. These observations suggest that Uncoupling of yeast mitochondria by UCP2 is an overexpression artifact leading to compromised mitochondrial integrity.

Michael B Wheeler - One of the best experts on this subject based on the ideXlab platform.

  • glutathionylation state of Uncoupling Protein 2 and the control of glucose stimulated insulin secretion
    Journal of Biological Chemistry, 2012
    Co-Authors: Ryan J Mailloux, Michael B Wheeler, Christine A Robsondoucette, Emma M Allister, Robert A Screaton, Mary-ellen Harper
    Abstract:

    Abstract The role of reactive oxygen species (ROS) in glucose-stimulated insulin release remains controversial since ROS have been shown to both amplify and impede insulin release. In regard to preventing insulin release, ROS activates Uncoupling Protein-2 (UCP2), a mitochondrial inner membrane Protein that negatively regulates glucose-stimulated insulin secretion (GSIS) by Uncoupling oxidative phosphorylation. With our recent discovery that UCP2-mediated proton leak is modulated by reversible glutathionylation, a process responsive to small changes in ROS levels, we resolved to determine if glutathionylation is required for UCP2 regulation of GSIS. Using Min6 cells and pancreatic islets, we demonstrate that induction of glutathionylation not only deactivates UCP2-mediated proton leak but also enhances GSIS. Conversely, an increase in mitochondrial matrix ROS was found to deglutathionylate and activate UCP2 leak and impede GSIS. Glucose metabolism also decreased the total amount of cellular glutathionylated Proteins and increased the cellular glutathione redox ratio (GSH/GSSG). Intriguingly, the provision of extracellular ROS (H2O2, 10μM) amplified GSIS and also activated UCP2. Collectively our findings indicate that the glutathionylation status of UCP2 contributes to the regulation of GSIS and that different cellular sites and inducers of ROS can have opposing effects on GSIS, perhaps explaining some of the controversy surrounding the role of ROS in GSIS.

  • glutathionylation state of Uncoupling Protein 2 and the control of glucose stimulated insulin secretion
    Journal of Biological Chemistry, 2012
    Co-Authors: Ryan J Mailloux, Michael B Wheeler, Christine A Robsondoucette, Emma M Allister, Robert A Screaton, Mary-ellen Harper
    Abstract:

    The role of reactive oxygen species (ROS) in glucose-stimulated insulin release remains controversial because ROS have been shown to both amplify and impede insulin release. In regard to preventing insulin release, ROS activates Uncoupling Protein-2 (UCP2), a mitochondrial inner membrane Protein that negatively regulates glucose-stimulated insulin secretion (GSIS) by Uncoupling oxidative phosphorylation. With our recent discovery that the UCP2-mediated proton leak is modulated by reversible glutathionylation, a process responsive to small changes in ROS levels, we resolved to determine whether glutathionylation is required for UCP2 regulation of GSIS. Using Min6 cells and pancreatic islets, we demonstrate that induction of glutathionylation not only deactivates UCP2-mediated proton leak but also enhances GSIS. Conversely, an increase in mitochondrial matrix ROS was found to deglutathionylate and activate UCP2 leak and impede GSIS. Glucose metabolism also decreased the total amount of cellular glutathionylated Proteins and increased the cellular glutathione redox ratio (GSH/GSSG). Intriguingly, the provision of extracellular ROS (H2O2, 10 μm) amplified GSIS and also activated UCP2. Collectively, our findings indicate that the glutathionylation status of UCP2 contributes to the regulation of GSIS, and different cellular sites and inducers of ROS can have opposing effects on GSIS, perhaps explaining some of the controversy surrounding the role of ROS in GSIS.

  • β cell Uncoupling Protein 2 regulates reactive oxygen species production which influences both insulin and glucagon secretion
    Diabetes, 2011
    Co-Authors: Christine A Robsondoucette, Vasilij Koshkin, Sobia Sultan, Emma M Allister, Jakob D Wikstrom, Alpana Bhatacharjee, Kacey J Prentice, Samuel B Sereda, Orian S Shirihai, Michael B Wheeler
    Abstract:

    OBJECTIVE-The role of Uncoupling Protein 2 (UCP2) in pancreatic beta-cells is highly debated, partly because of the broad tissue distribution of UCP2 and thus limitations of whole-body UCP2 knockou ...

  • Uncoupling Protein 2 regulates reactive oxygen species formation in islets and influences susceptibility to diabetogenic action of streptozotocin
    Journal of Endocrinology, 2009
    Co-Authors: Simon C Lee, Christine A Robsondoucette, Michael B Wheeler
    Abstract:

    Currently, the physiological function of Uncoupling Protein-2 (UCP2) in pancreatic islets and its role in the development of diabetes is a matter of great debate. To further investigate the impact of UCP2 on diabetes development, we used streptozotocin (STZ) to experimentally generate diabetes in both wild-type (WT) and UCP2-knockout (UCP2KO) mice. While multiple low-dose STZ injections led to hyperglycemia development over a 14-day period in both WT and UCP2KO mice, we found the development of hyperglycemia to be significantly less severe in the UCP2KO mice. Measurement of insulin and glucagon secretion (in vitro), as well as their plasma concentrations (in vivo), indicated that UCP2-deficiency showed enhanced insulin secretion but impaired alpha-cell function. Glucagon secretion was attenuated, despite reduced insulin secretion after exposure to STZ, which together contributed to less severe hyperglycemia development in UCP2KO mice. Further experimentation revealed that UCP2-deficient alpha- and beta-cells had chronically higher cellular reactive oxygen species (ROS) levels than the WT prior to STZ application, which correlated with increased basal beta- and alpha-cell mass. Overall, we suggest that increased chronic ROS signaling as a result of UCP2-deficiency contributes to enhanced beta-cell function and impairment of alpha-cell function, leading to an attenuation of STZ-induced hyperglycemia development.

  • Uncoupling Protein 2 knockout mice have enhanced insulin secretory capacity after a high fat diet
    Diabetes, 2002
    Co-Authors: Jamie W Joseph, Vasilij Koshkin, Chenyu Zhang, Bradford B Lowell, Catherine B Chan, Jing Wang, Michael B Wheeler
    Abstract:

    Uncoupling Protein 2 (UCP2) may act as an important regulator of insulin secretion. In this study, β-cell function in UCP2-deficient mice was examined after a 45% high-fat diet (HFD) to assess its role during the development of diet-induced type 2 diabetes. HFD-fed UCP2 (−/−) mice have lower fasting blood glucose and elevated insulin levels when compared with wild-type (WT) mice. UCP2 (−/−) mice also have enhanced β-cell glucose sensitivity compared with WT mice after HFD, a result that is due in part to the deterioration of glucose responsiveness in WT mice. HFD-fed UCP2 (−/−) mice have increased insulin secretory capacity as a result of increased pancreatic β-cell mass and insulin content per islet. Islets from WT mice exposed to 0.5 mmol/l palmitate for 48 h have significantly reduced mitochondrial membrane potential, ATP concentrations, and glucose responsiveness compared with UCP2 (−/−) islets, suggesting that elevated UCP2 in WT mice increases proton leak and decreases mitochondrial ATP production. Highly increased carnitine palmitoyl transferase-1 gene expression in UCP2 (−/−) mice is suggestive of enhanced fatty acid oxidizing capacity, particularly after HFD stress. These results further establish UCP2 as a component in glucose sensing and suggest a possible new aspect of UCP2 function during the progression of type 2 diabetes.

Bruno Miroux - One of the best experts on this subject based on the ideXlab platform.

  • Uncoupling Protein 2 controls proliferation by promoting fatty acid oxidation and limiting glycolysis derived pyruvate utilization
    The FASEB Journal, 2008
    Co-Authors: Claire Pecqueur, Bruno Miroux, Daniel Ricquier, Thi Bui, C Gelly, Julie Hauchard, Celine Barbot, Frederic Bouillaud, Craig B Thompson
    Abstract:

    Uncoupling Protein-2 (UCP2) belongs to the mitochondrial carrier family and has been thought to be involved in suppressing mitochondrial ROS production through Uncoupling mitochondrial respiration from ATP synthesis. However, we show here that loss of function of UCP2 does not result in a significant increase in ROS production or an increased propensity for cells to undergo senescence in culture. Instead, Ucp2−/− cells display enhanced proliferation associated with a metabolic switch from fatty acid oxidation to glucose metabolism. This metabolic switch requires the unrestricted availability of glucose, and Ucp2−/− cells more readily activate autophagy than wild-type cells when deprived of glucose. Altogether, these results suggest that UCP2 promotes mitochondrial fatty acid oxidation while limiting mitochondrial catabolism of pyruvate. The persistence of fatty acid catabolism in Ucp2+/+ cells during a proliferative response correlates with reduced cell proliferation and enhances resistance to glucose sta...

  • Uncoupling Protein-2 controls proliferation by promoting fatty acid oxidation and limiting glycolysis-derived pyruvate utilization
    FASEB Journal, 2008
    Co-Authors: Claire Pecqueur, Bruno Miroux, Daniel Ricquier, Thi Bui, C Gelly, Julie Hauchard, Celine Barbot, Frederic Bouillaud, Craig Thompson
    Abstract:

    Uncoupling Protein-2 (UCP2) belongs to the mitochondrial carrier family and has been thought to be involved in suppressing mitochondrial ROS production through Uncoupling mitochondrial respiration from ATP synthesis. However, we show here that loss of function of UCP2 does not result in a significant increase in ROS production or an increased propensity for cells to undergo senescence in culture. Instead, Ucp2-/- cells display enhanced proliferation associated with a metabolic switch from fatty acid oxidation to glucose metabolism. This metabolic switch requires the unrestricted availability of glucose, and Ucp2-/- cells more readily activate autophagy than wild-type cells when deprived of glucose. Altogether, these results suggest that UCP2 promotes mitochondrial fatty acid oxidation while limiting mitochondrial catabolism of pyruvate. The persistence of fatty acid catabolism in Ucp2-/- cells during a proliferative response correlates with reduced cell proliferation and enhances resistance to glucose starvation-induced autophagy.

  • Uncoupling Protein 2 controls adiponectin gene expression in adipose tissue through the modulation of reactive oxygen species production
    Diabetes, 2007
    Co-Authors: Emmanuel Chevillotte, Bruno Miroux, Daniel Ricquier, Marta Giralt, Francesc Villarroya
    Abstract:

    Uncoupling Protein-2 (UCP2) is a mitochondrial membrane transporter expressed in white adipose tissue. We observed that circulating adiponectin levels and adiponectin gene expression in adipose tissue are reduced in UCP2-null mice. We studied whether mitochondrial activity and its control by UCP2 may regulate adiponectin gene expression. In 3T3-L1 cells, increasing UCP2 mitochondrial levels by adenoviral-mediated gene transfer induced adiponectin gene expression, whereas oligomycin and antimycin A, inhibitors of ATP synthesis and mitochondrial respiration, led to a downregulation. Reactive oxygen species (ROS) scavengers alleviated the repression of adiponectin gene expression caused by oligomycin or antimycin A. The action of ROS involves the transcription factor CHOP-10, the abundance of which was reduced in response to UCP2 and was induced by oligomycin. CHOP-10 inhibited adiponectin gene expression by interfering with the −117/−73 CCAAT/enhancer binding Protein–binding region in the adiponectin gene promoter. Moreover, CHOP-10 levels were increased in adipose tissue from UCP2-null mice. Results indicate that the modulation of ROS levels by mitochondrial activity, and specifically as a consequence of the action of UCP2, controls adiponectin gene expression. This provides a physiological mechanism by which the adipose tissue energetic status may determine the extent of adiponectin release and influence systemic insulin sensitivity.

  • Uncoupling Protein 2 has protective function during experimental autoimmune encephalomyelitis.
    American Journal of Pathology, 2006
    Co-Authors: Susanne Vogler, Bruno Miroux, Sophie Rousset, Jens Pahnke, Daniel Ricquier, Holger Moch, Saleh M Ibrahim
    Abstract:

    Uncoupling Protein 2 (UCP2) is a member of the mitochondrial transporter superfamily that is expressed in many tissues, including immune cells. UCP2 prevents oxidative stress by reducing reactive oxygen species. Using UCP2-deficient mice, it was shown that UCP2 is involved in the regulation of insulin secretion, in the resistance to infection, and in atherosclerosis. Here, we investigated the role of UCP2 in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis. Immunized C57BL/6J UCP2-deficient mice showed a slightly delayed onset during experimental autoimmune encephalomyelitis (13.0 +/- 0.6 versus 11.5 +/- 0.8 in wild-type controls) and developed significantly higher disease scores than littermate controls (maximum disease score of 2.9 +/- 0.2 versus 1.7 +/- 0.2, P = 0.001). Higher levels of infiltrating T cells into the spinal cord meninges and parenchyma were observed. The T-cell proliferative response to the specific antigen was increased in UCP2-deficient mice compared with littermate controls, and CD4 cells of UCP2 knockout mice produced significantly higher levels of pro-inflammatory cytokines, eg, tumor necrosis factor-alpha and interleukin-2, resulting from a Th1 response. Mice lacking UCP2 also developed a higher B-cell response. Concomitantly, CD4 and CD8 cells of the UCP2-deficient mice showed increased production of reactive oxygen species. These results suggest a protective function of UCP2 in chronic inflammatory diseases such as multiple sclerosis.

  • protective role of Uncoupling Protein 2 in atherosclerosis
    Circulation, 2003
    Co-Authors: Jeanjacques Blanc, Bruno Miroux, Marieclotilde Alvesguerra, Bruno Esposito, Sophie Rousset, Pierre Gourdy, Alain Tedgui, Ziad Mallat
    Abstract:

    Background— Uncoupling Protein 2 (UCP2) regulates the production of reactive oxygen species in macrophages. However, its role in atherosclerosis is unknown. Methods and Results— Irradiated low-density lipoProtein receptor deficient mice (LDLR-/-) were transplanted with bone marrow from either UCP2 deficient mice (Ucp2-/-) or wild type mice (Ucp2+/+). Mice were fed an atherogenic diet for 7 weeks. Engraftment of bone marrow cells was confirmed by the presence of UCP2 Protein expression in spleen cell mitochondria of Ucp2+/+ transplanted mice and its absence in Ucp2-/- transplanted mice. Leukocyte counts and plasma cholesterol levels were comparable in both groups. We found a marked increase in atherosclerotic lesion size in the thoracic aorta of Ucp2-/- transplanted mice compared with control Ucp2+/+ transplanted mice (8.3±0.9% versus 4.3±0.4%, respectively; P<0.005), as well as in the aortic sinus (150 066±12 388 μm2 versus 105 689±9 727 μm2, respectively; P<0.05). This was associated with increased nitro...

Charles Affourtit - One of the best experts on this subject based on the ideXlab platform.

  • Uncoupling Protein 2 attenuates glucose stimulated insulin secretion in ins 1e insulinoma cells by lowering mitochondrial reactive oxygen species
    Free Radical Biology and Medicine, 2011
    Co-Authors: Martin D Brand, Charles Affourtit, Martin Jastroch
    Abstract:

    Glucose-stimulated insulin secretion (GSIS) by pancreatic β cells is regulated by mitochondrial Uncoupling Protein-2 (UCP2), but opposing phenotypes, GSIS improvement and impairment, have been reported for different Ucp2-ablated mouse models. By measuring mitochondrial bioenergetics in attached INS-1E insulinoma cells with and without UCP2, we show that UCP2 contributes to proton leak and attenuates glucose-induced rises in both respiratory activity and the coupling efficiency of oxidative phosphorylation. Strikingly, the GSIS improvement seen upon UCP2 knockdown in INS-1E cells is annulled completely by the cell-permeative antioxidant MnTMPyP. Consistent with this observation, UCP2 lowers mitochondrial reactive oxygen species at high glucose levels. We conclude that UCP2 plays both regulatory and protective roles in β cells by acutely lowering GSIS and chronically preventing oxidative stress. Our findings thus provide a mechanistic explanation for the apparently discrepant findings in the field.

  • Uncoupling Protein 2 contributes significantly to high mitochondrial proton leak in ins 1e insulinoma cells and attenuates glucose stimulated insulin secretion
    Biochemical Journal, 2008
    Co-Authors: Charles Affourtit, Martin D Brand
    Abstract:

    Proton leak exerts stronger control over ATP/ADP in mitochondria from clonal pancreatic beta-cells (INS-1E) than in those from rat skeletal muscle, due to the higher proton conductance of INS-1E mitochondria [Affourtit and Brand (2006) Biochem. J. 393, 151-159]. In the present study, we demonstrate that high proton leak manifests itself at the cellular level too: the leak rate (measured as myxothiazol-sensitive, oligomycin-resistant respiration) was nearly four times higher in INS-1E cells than in myoblasts. This relatively high leak activity was decreased more than 30% upon knock-down of UCP2 (Uncoupling Protein-2) by RNAi (RNA interference). The high contribution of UCP2 to leak suggests that proton conductance through UCP2 accounts for approx. 20% of INS-1E respiration. UCP2 knock-down enhanced GSIS (glucose-stimulated insulin secretion), consistent with a role for UCP2 in beta-cell physiology. We propose that the high mitochondrial proton leak in beta-cells is a mechanism which amplifies the effect of physiological UCP2 regulators on cytoplasmic ATP/ADP and hence on insulin secretion.

  • Uncoupling Protein 2 contributes significantly to high mitochondrial proton leak in ins 1e insulinoma cells and attenuates glucose stimulated insulin secretion
    Biochemical Journal, 2008
    Co-Authors: Charles Affourtit, Martin D Brand
    Abstract:

    Proton leak exerts stronger control over ATP/ADP in mitochondria from clonal pancreatic β-cells (INS-1E) than in those from rat skeletal muscle, due to the higher proton conductance of INS-1E mitochondria [Affourtit and Brand (2006) Biochem. J. 393 , 151–159]. In the present study, we demonstrate that high proton leak manifests itself at the cellular level too: the leak rate (measured as myxothiazol-sensitive, oligomycin-resistant respiration) was nearly four times higher in INS-1E cells than in myoblasts. This relatively high leak activity was decreased more than 30% upon knock-down of UCP2 (Uncoupling Protein-2) by RNAi (RNA interference). The high contribution of UCP2 to leak suggests that proton conductance through UCP2 accounts for approx. 20% of INS-1E respiration. UCP2 knock-down enhanced GSIS (glucose-stimulated insulin secretion), consistent with a role for UCP2 in β-cell physiology. We propose that the high mitochondrial proton leak in β-cells is a mechanism which amplifies the effect of physiological UCP2 regulators on cytoplasmic ATP/ADP and hence on insulin secretion. Abbreviations: Δψ, mitochondrial membrane potential; FCS, foetal calf serum; GSIS, glucose-stimulated insulin secretion; KRBH, Krebs–Ringer bicarbonate Hepes buffer; RNAi, RNA interference; siRNA, small interfering RNA; UCP, Uncoupling Protein

Gyorgy Baffy - One of the best experts on this subject based on the ideXlab platform.

  • Uncoupling Protein 2 and cancer
    Mitochondrion, 2010
    Co-Authors: Gyorgy Baffy
    Abstract:

    Cancer cells respond to unfavorable microenvironments such as nutrient limitation, hypoxia, oxidative stress, and host defense by comprehensive metabolic reprogramming. Mitochondria are linked to this complex adaptive response and emerging evidence indicates that Uncoupling Protein-2 (UCP2), a mitochondrial inner membrane anion carrier, may contribute to this process. Effects of UCP2 on mitochondrial bioenergetics, redox homeostasis, and oxidant production in cancer cells may modulate molecular pathways of macromolecular biosynthesis, antioxidant defense, apoptosis, cell growth and proliferation, enhancing robustness and promoting chemoresistance. Elucidation of these interactions may identify novel anti-cancer strategies.

  • the mitochondrial Uncoupling Protein 2 promotes chemoresistance in cancer cells
    Cancer Research, 2008
    Co-Authors: Zoltan Derdak, Nicholas M Mark, Guido Beldi, Simon C Robson, Jack R Wands, Gyorgy Baffy
    Abstract:

    Cancer cells acquire drug resistance as a result of selection pressure dictated by unfavorable microenvironments. This survival process is facilitated through efficient control of oxidative stress originating from mitochondria that typically initiates programmed cell death. We show this critical adaptive response in cancer cells to be linked to Uncoupling Protein-2 (UCP2), a mitochondrial suppressor of reactive oxygen species (ROS). UCP2 is present in drug-resistant lines of various cancer cells and in human colon cancer. Overexpression of UCP2 in HCT116 human colon cancer cells inhibits ROS accumulation and apoptosis after exposure to chemotherapeutic agents. Tumor xenografts of UCP2-overexpressing HCT116 cells retain growth in nude mice receiving chemotherapy. Augmented cancer cell survival is accompanied by altered NH(2)-terminal phosphorylation of the pivotal tumor suppressor p53 and induction of the glycolytic phenotype (Warburg effect). These findings link UCP2 with molecular mechanisms of chemoresistance. Targeting UCP2 may be considered a novel treatment strategy for cancer.

  • expression of Uncoupling Protein 2 in human colon cancer
    Clinical Cancer Research, 2004
    Co-Authors: Masayoshi Horimoto, Jack R Wands, Murray B Resnick, Tamako Konkin, Justin Routhier, Gyorgy Baffy
    Abstract:

    Purpose: Cancer cell survival depends on adaptive mechanisms that include modulation of oxidative stress. One such mechanism may be via up-regulation of Uncoupling Protein-2 (UCP2), a mitochondrial inner membrane anion carrier recently found to provide cytoprotection in nontumor cells by acting as a sensor and negative regulator of reactive oxygen species production. We hypothesized that UCP2 expression may be increased in colon cancer as part of tumor adaptation. Experimental Design: UCP2 expression was characterized by real-time polymerase chain reaction and Western blotting using paired human colon adenocarcinoma and peritumoral specimens. Oxidant production was characterized by tissue malondialdehyde levels. Tissue microarrays constructed of 107 colon adenocarcinomas as well as representative specimens of hyperplastic polyps and tubular adenomas were used for UCP2 immunohistochemistry. Results: UCP2 mRNA and Protein levels were 3- to 4-fold higher in adenocarcinomas, and UCP2 mRNA levels showed significant correlation with increased tumor tissue malondialdehyde contents. Immunohistochemistry on tissue microarrays showed positive staining for UCP2 in most adenocarcinomas (86.0%); positive staining for UCP2 was seen less often in tubular adenomas (58.8%) and rarely seen in hyperplastic polyps (11.1%). Conclusions: UCP2 expression is increased in most human colon cancers, and the level of expression appears to correlate with the degree of neoplastic changes. These findings may foster the idea that UCP2 is part of a novel adaptive response by which oxidative stress is modulated in colon cancer.

  • Uncoupling Protein 2 deficiency promotes oxidant stress and delays liver regeneration in mice
    Hepatology, 2004
    Co-Authors: Masayoshi Horimoto, Jack R Wands, Zoltan Derdak, Peter Fulop, Gyorgy Baffy
    Abstract:

    The control of liver regeneration remains elusive. Because reactive oxygen species (ROS) are able to mediate cell growth arrest and activate Proteins that inhibit the cell cycle, ROS production may have a negative impact on liver regeneration. We examined how liver regeneration is affected by Uncoupling Protein-2 (UCP2), an inner mitochondrial membrane carrier that senses and negatively regulates superoxide production. Liver regeneration was monitored up to 5 days and was found to be significantly delayed in UCP2(-/-) mice after partial hepatectomy. Apoptosis rates in UCP2(+/+) and UCP2(- /-) liver remnants were similar, while parameters of cell proliferation indicated a diminished response in UCP2(- /-) mice with corresponding changes in the expression of key cell cycle regulatory Proteins and prolonged activation of stress-responsive Protein kinase p38. Levels of malondialdehyde, a marker of ROS generation and oxidant stress, were elevated in UCP2(- /-) livers at every examined time point. Liver remnants of UCP2(+ /+) mice 48 hours post-hepatectomy showed a fourfold increase in the expression of UCP2 Protein primarily detected in hepatocytes. In conclusion, our results suggest that absent or insufficient UCP2 function in the regenerating liver results in increased ROS production and negatively modulates the control of cell cycle.

  • Uncoupling Protein 2 negatively regulates insulin secretion and is a major link between obesity β cell dysfunction and type 2 diabetes
    Cell, 2001
    Co-Authors: Chenyu Zhang, Gyorgy Baffy, Antonio Vidalpuig, Stefan Krauss, Pascale Perret, Odile D Peroni, Danica Grujic, Thilo Hagen, Olivier Boss
    Abstract:

    Abstract β cells sense glucose through its metabolism and the resulting increase in ATP, which subsequently stimulates insulin secretion. Uncoupling Protein-2 (UCP2) mediates mitochondrial proton leak, decreasing ATP production. In the present study, we assessed UCP2's role in regulating insulin secretion. UCP2-deficient mice had higher islet ATP levels and increased glucose-stimulated insulin secretion, establishing that UCP2 negatively regulates insulin secretion. Of pathophysiologic significance, UCP2 was markedly upregulated in islets of ob/ob mice, a model of obesity-induced diabetes. Importantly, ob/ob mice lacking UCP2 had restored first-phase insulin secretion, increased serum insulin levels, and greatly decreased levels of glycemia. These results establish UCP2 as a key component of β cell glucose sensing, and as a critical link between obesity, β cell dysfunction, and type 2 diabetes.

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