UCP2, a metabolic sensor coupling glucose oxidation to mitochondrial metabolism?

Pecqueur, Claire; Alves-Guerra, Marie-Clotilde; Ricquier, Daniel; Bouillaud, Frédéric

doi:10.1002/iub.188

Cited by 80 publications

(71 citation statements)

References 58 publications

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“…Taken together these data suggest that the loss of UCP2 promotes preferential usage of glucose as energy source in DM mice. Indeed, UCP2 has previously been shown to promote mitochondrial FAO while limiting mitochondrial catabolism of pyruvate originating from glucose [16]. In agreement with this, mtDNA mutator mice failed to increase circulating free fatty acid (FFA) levels at 40 weeks of age probably owing to exhaustion of lipid stores as a result of increased FAO enabled by high UCP2 upregulation (Figure 2B).…”

Section: Resultssupporting

confidence: 75%

“…There are also strong arguments against the role of UCP2 in proton conductance. Unlike UCP1-deficient mice, UCP2 KO mice are resistant to cold exposure and they are not prone to obesity, even when fed a high fat diet, arguing against a role of UCP2 in energy expenditure [16]. Furthermore, depletion of UCP2 in tissues such as spleen or lung that express high levels of the protein does not change the uncoupling state of these cells [13].…”

Section: Discussionmentioning

confidence: 99%

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Loss of UCP2 Attenuates Mitochondrial Dysfunction without Altering ROS Production and Uncoupling Activity

et al. 2014

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Although mitochondrial dysfunction is often accompanied by excessive reactive oxygen species (ROS) production, we previously showed that an increase in random somatic mtDNA mutations does not result in increased oxidative stress. Normal levels of ROS and oxidative stress could also be a result of an active compensatory mechanism such as a mild increase in proton leak. Uncoupling protein 2 (UCP2) was proposed to play such a role in many physiological situations. However, we show that upregulation of UCP2 in mtDNA mutator mice is not associated with altered proton leak kinetics or ROS production, challenging the current view on the role of UCP2 in energy metabolism. Instead, our results argue that high UCP2 levels allow better utilization of fatty acid oxidation resulting in a beneficial effect on mitochondrial function in heart, postponing systemic lactic acidosis and resulting in longer lifespan in these mice. This study proposes a novel mechanism for an adaptive response to mitochondrial cardiomyopathy that links changes in metabolism to amelioration of respiratory chain deficiency and longer lifespan.

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Section: Resultssupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Loss of UCP2 Attenuates Mitochondrial Dysfunction without Altering ROS Production and Uncoupling Activity

et al. 2014

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“…UCP2 has previously been associated with obesity (Dalgaard 2011;Dalgaard and Pedersen 2001). UCP2 is important for uncoupling respiration and promotes mitochondrial fatty acid oxidation (Fisler and Warden 2006), although the physiological significance of its uncoupling activity is discussed (Pecqueur et al 2009). …”

Section: Discussionmentioning

confidence: 99%

Altered expression of genes involved in lipid metabolism in obese subjects with unfavourable phenotype

et al. 2013

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Obesity (BMI C30 kg/m 2 ) increases the risk of developing lifestyle-related diseases. A subgroup of obese individuals has been described as ''metabolically healthy, but obese'' (MHO). In contrast to at-risk obese (ARO), the MHO phenotype is defined by a favourable lipid profile and a normal or only slightly affected insulin sensitivity, despite the same amount of body fat. The objective was to characterize the metabolic phenotype of MHO subjects. We screened a variety of genes involved in lipid metabolism and inflammation in peripheral blood mononuclear cells (PBMC). Obese subjects (men and women; 18-70 years) with BMI C30 kg/m 2 were characterized as MHO (n = 9) or as ARO (n = 10). In addition, eleven healthy, normal weight subjects characterized as healthy by the same criteria as described for the MHO subjects were included. We found that with similar weight, total fat mass and fat mass distribution, the ARO subjects have increased plasma levels of gamma-glutamyl transpeptidase and free fatty acids. This group also has altered expression levels of a number of genes linked to lipid metabolism in PBMC with reduced gene expression levels of uncoupling protein 2, hormone-sensitive lipase and peroxisome proliferatoractivated receptor d compared with MHO subjects. The present metabolic differences between subgroups of obese subjects may contribute to explain some of the underlying mechanisms causing the increased risk of disease among ARO subjects compared with MHO subjects.

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“…The extent of the KB effect on growth and ATP levels in cancer cells directly correlates with the levels of expression of the mitochondrial uncoupling protein, UCP-2 and this protein has recently been proposed to function as a metabolic sensor coupling glucose oxidation to mitochondrial metabolism (Pecqueur et al, 2008(Pecqueur et al, , 2009. Primary mouse embryonic fibroblasts (MEFs) with heterozygous deletions of UCP-2 growing in high glucose media without KB grew faster even in low (3%) oxygen and knocking down UCP-2 (UCP À/À ) was associated with a metabolic shift to dependency on glucose with increased glycolytic and mitochondrial respiration rates and reduced b-oxidation, ATP/ADP ratios and NADH levels.…”

Section: Uncoupling Proteinmentioning

confidence: 99%

Bioenergetic pathways in tumor mitochondria as targets for cancer therapy and the importance of the ROS-induced apoptotic trigger

Ralph

Rodrı́guez-Enrı́quez

Neužil

et al. 2010

Molecular Aspects of Medicine

143

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Mitochondria are emerging as idealized targets for anti-cancer drugs. One reason for this is that although these organelles are inherent to all cells, drugs are being developed that selectively target the mitochondria of malignant cells without adversely affecting those of normal cells. Such anti-cancer drugs destabilize cancer cell mitochondria and these compounds are referred to as mitocans, classified into several groups according to their mode of action and the location or nature of their specific drug targets. Many mitocans selectively interfere with the bioenergetic functions of cancer cell mitochondria, causing major disruptions often associated with ensuing overloads in ROS production leading to the induction of the intrinsic apoptotic pathway. This in-depth review describes the bases for the bioenergetic differences found between normal and cancer cell mitochondria, focussing on those essential changes occurring during malignancy that clinically may provide the most effective targets for mitocan development. A common theme emerging is that mitochondrially mediated ROS activation as a trigger for apoptosis offers a powerful basis for cancer therapy. Continued research in this area is likely to identify increasing numbers of novel agents that should prove highly effective against a variety of cancers with preferential toxicity towards malignant tissue, circumventing tumor resistance to the other more established therapeutic anti-cancer approaches.

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UCP2, a metabolic sensor coupling glucose oxidation to mitochondrial metabolism?

Cited by 80 publications

References 58 publications

Loss of UCP2 Attenuates Mitochondrial Dysfunction without Altering ROS Production and Uncoupling Activity

Loss of UCP2 Attenuates Mitochondrial Dysfunction without Altering ROS Production and Uncoupling Activity

Altered expression of genes involved in lipid metabolism in obese subjects with unfavourable phenotype

Bioenergetic pathways in tumor mitochondria as targets for cancer therapy and the importance of the ROS-induced apoptotic trigger

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