A role for uncoupling protein‐2 as a regulator of mitochondrial hydrogen peroxide generation

Nègre‐Salvayre, Anne; Hirtz, Christophe; Carrera, G.; Cazenave, Rémy; Troly, Muriel; Salvayre, Robert; Pénicaud, Luc; Casteilla, Louis

doi:10.1096/fasebj.11.10.9271366

Cited by 710 publications

(516 citation statements)

References 28 publications

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“…A strong link between decreased levels of UCP2 and Gpx1 overexpression is supported by the response of the WT islets to GPX1 mimic, ebselen, and the resistance of OE islets to H 2 O 2 -suppressed GSIS. However, the UCP2 decrease may not be simply attributable to the diminished intracellular ROS because of a possible two-way feedback mechanism for the interaction of UCP2 and H 2 O 2 [49]. While expression and function of UCP2 are activated by ROS [21], mitochondrial H 2 O 2 generation can be decreased by UCP2 [49].…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms for hyperinsulinaemia induced by overproduction of selenium-dependent glutathione peroxidase-1 in mice

et al. 2008

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Aims/hypothesis We previously observed hyperglycaemia, hyperinsulinaemia, insulin resistance and obesity in Gpx1-overexpressing mice (OE). Here we determined whether these phenotypes were eliminated by diet restriction, subsequently testing whether hyperinsulinaemia was a primary effect of Gpx1 overexpression and caused by dysregulation of pancreatic duodenal homeobox 1 (PDX1) and uncoupling protein-2 (UCP2) in islets. Methods First, 24 male OE and wild-type (WT) mice (2 months old) were given 3 g (diet-restricted) or 5 g (fullfed) feed per day for 4 months to compare their glucose metabolism. Thereafter, several mechanistic experiments were conducted with pancreas and islets of the two genotypes (2 or 6 months old) to assay for beta cell mass, reactive oxygen species (ROS) levels, mitochondrial membrane potential (Δ= m ) and expression profiles of regulatory proteins. A functional assay of islets was also performed. Results Diet restriction eliminated obesity but not hyperinsulinaemia in OE mice. These mice had greater pancreatic beta cell mass (more than twofold) and pancreatic insulin content (40%) than the WT, along with an enhanced Δ= m and glucose-stimulated insulin secretion in islets. With diminished ROS production, the OE islets displayed hyperacetylation of H3 and H4 histone in the Pdx1 promoter, elevated PDX1 and decreased UCP2. Conclusions/interpretation Overproduction of the major antioxidant enzyme, glutathione peroxidase 1, caused seemingly beneficial changes in pancreatic PDX1 and UCP2, but eventually led to chronic hyperinsulinaemia by dysregulating islet insulin production and secretion.

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Section: Discussionmentioning

confidence: 99%

Molecular mechanisms for hyperinsulinaemia induced by overproduction of selenium-dependent glutathione peroxidase-1 in mice

et al. 2008

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“…Therefore, mechanisms that reduce membrane potential could lower superoxide production. A negative regulation of the mitochondrial ROS production by UCPs was first suggested in 1997 [9]; Skulachev in 1998 [10] also suggested that superoxide production may be reduced by factors that decrease mitochondrial membrane potential. Thus, as superoxide production can be Abbreviations: 3HADH, 3-hydroxyacyl CoA dehydrogenase; ANT, adenine nucleotide translocator; CPT-I, carnitine-palmitoyl-transferase-I; CPT-II, carnitine-palmitoyl-transferase-II; CS, citrate synthase; FA, fatty acid; HNE, 4-hydroxynonenal; LCAD, long-chain acyl CoA dehydrogenase; LDCL, lucigenin-derived chemiluminescence; MACP, mitochondrial anion carrier protein; NEFA, non-esterified fatty acid; ROS, reactive oxygen species; SS, subsarcolemmal; UCP, uncoupling protein decreased by mild uncoupling [10,11], mitochondrial anion carrier proteins (MACPs) including uncoupling protein (UCP) and adenine nucleotide translocator (ANT) may have an inhibitory action on the overproduction of mitochondrial superoxide.…”

Section: Introductionmentioning

confidence: 99%

Sequential changes in superoxide production, anion carriers and substrate oxidation in skeletal muscle mitochondria of heat‐stressed chickens

et al. 2007

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We have shown that heat-stressed birds exhibit increased superoxide production in skeletal muscle mitochondria.To determine the precise mechanism for this effect, here we studied not only progressive, but also sequential changes in superoxide production, anion carriers and substrate oxidation in mitochondria of heat-stressed chickens. Exposure to acute heat stress (34°C for 6, 12 and 18 h) stimulated pectoralis muscle mitochondrial superoxide production. Heat stress-induced downregulations of avUCP gene transcripts and mitochondrial avUCP protein content were time-dependent: avUCP gene transcript was decreased after 6 h, while avUCP protein content was only downregulated after 12 h of heat stress. Avian adenine nucleotide translocator (avANT) gene transcripts were not changed on exposure to heat stress, suggesting that avANT may not be involved in the regulation of superoxide production in the muscle mitochondria of heat-stressed chickens. During the initial stage of acute heat stress b-oxidation enzymes gene transcripts and activity were upregulated, with elevated plasma non-esterified fatty acid levels and increased expression of mitochondrial fatty acid transport genes. This sudden surge in mitochondrial substrate oxidation resulted in higher superoxide production: the avUCP expression at 6 h after heat stress might have not been large enough to alleviate the overproduction of reactive oxygen species (ROS) even though a small amount of endogenous FFA, a potential uncoupler, might have been present in the mitochondria. Thereafter, avUCP content was downregulated while substrate oxidation returned to control levels. This downregulation of avUCP may have caused increased mitochondrial superoxide production, keeping the superoxide production high in the later stages of heat stress. These results suggest that overproduction of mitochondrial ROS in chicken skeletal muscle under the heat stress might result from enhanced substrate oxidation and downregulation of avUCP in a time-dependent manner.

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“…Based on their similarity of sequence, UCP2 and UCP3 were first suggested to play a role in regulated thermogenesis [2]. Later studies demonstrated that this may not be the case [3] and now evidence is accumulating in favour of a role in reducing the production of reactive oxygen species (ROS) by the mitochondria [4,5].…”

Section: Introductionmentioning

confidence: 99%

Increasing uncoupling protein-2 in pancreatic beta cells does not alter glucose-induced insulin secretion but decreases production of reactive oxygen species

Produit-Zengaffinen¹,

Davis-Lameloise²,

Perreten³

et al. 2006

Diabetologia

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Aims/hypothesis Levels of uncoupling protein-2 (UCP2) are regulated in the pancreatic beta cells and an increase in the protein level has been associated with mitochondrial uncoupling and alteration in glucose-stimulated insulin secretion. However, it is not clear whether an increase in uncoupling protein-2 per se induces mitochondrial uncoupling and affects ATP generation and insulin secretion. Materials and methods Transgenic mice with beta cell-specific overexpression of the human UCP2 gene and INS-1 cells with doxycycline-inducible overproduction of the protein were generated and the consequences of increased levels of UCP2 on glucose-induced insulin secretion and on parameters reflecting mitochondrial uncoupling were determined.Results In transgenic mice, an increase in beta cell UCP2 protein concentration did not significantly modify plasma glucose and insulin levels. Glucose-induced insulin secretion and elevation in the ATP/ADP ratio were unaltered by an increase in UCP2 level. In INS-1 cells, a similar increase in UCP2 level did not modify glucose-induced insulin secretion, cytosolic ATP and ATP/ADP ratio, or glucose oxidation. Increased levels of UCP2 did not modify the mitochondrial membrane potential and oxygen consumption. Increased UCP2 levels decreased cytokine-induced production of reactive oxygen species. Conclusion/interpretation The results obtained in transgenic mice and in the beta cell line do not support the hypothesis that an increase in UCP2 protein per se uncouples the mitochondria and decreases glucose-induced insulin secretion. In contrast, the observation that increased UCP2 levels decrease cytokine-induced production of reactive oxygen species indicates a potential protective effect of the protein on beta cells, as observed in other cell types.

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A role for uncoupling protein‐2 as a regulator of mitochondrial hydrogen peroxide generation

Cited by 710 publications

References 28 publications

Molecular mechanisms for hyperinsulinaemia induced by overproduction of selenium-dependent glutathione peroxidase-1 in mice

Molecular mechanisms for hyperinsulinaemia induced by overproduction of selenium-dependent glutathione peroxidase-1 in mice

Sequential changes in superoxide production, anion carriers and substrate oxidation in skeletal muscle mitochondria of heat‐stressed chickens

Increasing uncoupling protein-2 in pancreatic beta cells does not alter glucose-induced insulin secretion but decreases production of reactive oxygen species

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