Uncoupling proteins: A role in protection against reactive oxygen species—or not?

Cannon, Barbara; Shabalina, Irina G.; Kramarova, Tatiana V.; Petrovič, Nataša; Nedergaard, Jan

doi:10.1016/j.bbabio.2006.05.016

Cited by 173 publications

(117 citation statements)

References 67 publications

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“…Our studies of UCP expression in nTg mice are consistent with other mammalian studies that show little or no induction of skeletal muscle UCP-3 (35)(36)(37), whereas the induction of UCP-3 in Tg mice is more reflective of what has been observed in the highly oxidative, high-LPL-expressing muscles of birds. The UCP homolog in hummingbirds (hmUCP), with high homology to UCP-1, UCP-2, and UCP-3 (55, 70, and 72%, respectively), is induced in response to the daily bout of torpor and is thought to facilitate the rewarming phase (38).…”

Section: Discussionsupporting

confidence: 79%

Increased thermoregulation in cold-exposed transgenic mice overexpressing lipoprotein lipase in skeletal muscle: an avian phenotype?

Jensen

Knaub

Konhilas

et al. 2008

Journal of Lipid Research

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LPL is an enzyme involved in the breakdown and uptake of lipoprotein triglycerides. In the present study, we examined how the transgenic (Tg) overexpression of human LPL in mouse skeletal muscle affected tolerance to cold temperatures, cold-induced thermogenesis, and fuel utilization during this response. Tg mice and their nontransgenic controls were placed in an environmental chamber and housed in metabolic chambers that monitored oxygen consumption and carbon dioxide production with calorimetry. When exposed to 4jC, an attenuation in the decline in body temperature in Tg mice was accompanied by an increased metabolic rate (15%; P , 0.001) and a reduction in respiratory quotient (P , 0.05). Activity levels, the expression of uncoupling proteins in brown fat and muscle, and lean mass failed to explain the enhanced cold tolerance and thermogenesis in Tg mice. The more oxidative type IIa fibers were favored over the more glycolytic type IIb fibers (P , 0.001) in the gastrocnemius and quadriceps muscles of Tg mice. These data suggest that Tg overexpression of LPL in skeletal muscle increases cold tolerance by enhancing the capacity for fat oxidation, producing an avian-like phenotype in which skeletal muscle contributes significantly to the thermogenic response to cold temperatures.-Jensen, D. R., L. A. Knaub, J. P. Konhilas, L. A. Leinwand, P. S. MacLean, and R. H. Eckel. Increased thermoregulation in cold-exposed transgenic mice overexpressing lipoprotein lipase in skeletal muscle: an avian phenotype? J. Lipid Res. 2008. 49: 870-879.

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Section: Discussionsupporting

confidence: 79%

Increased thermoregulation in cold-exposed transgenic mice overexpressing lipoprotein lipase in skeletal muscle: an avian phenotype?

Jensen

Knaub

Konhilas

et al. 2008

Journal of Lipid Research

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“…4 However, this should not be surprising because the function of UCP1 is quite divergent from UCP2 and UCP3. Indeed, UCP1 serves a thermogenic purpose, and studies have demonstrated that UCP1 does not control ROS levels (48). Moreover, there is evidence that UCP1 can be phosphorylated (49).…”

Section: Discussionmentioning

confidence: 99%

Glutathionylation Acts as a Control Switch for Uncoupling Proteins UCP2 and UCP3

Mailloux

Seifert

Bouillaud

et al. 2011

Journal of Biological Chemistry

159

149

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The mitochondrial uncoupling proteins 2 and 3 (UCP2 and -3) are known to curtail oxidative stress and participate in a wide array of cellular functions, including insulin secretion and the regulation of satiety. However, the molecular control mechanism(s) governing these proteins remains elusive. Here we reveal that UCP2 and UCP3 contain reactive cysteine residues that can be conjugated to glutathione. We further demonstrate that this modification controls UCP2 and UCP3 function. Both reactive oxygen species and glutathionylation were found to activate and deactivate UCP3-dependent increases in nonphosphorylating respiration. We identified both Cys 25 and Cys 259 as the major glutathionylation sites on UCP3. Additional experiments in thymocytes from wild-type and UCP2 null mice demonstrated that glutathionylation similarly diminishes non-phosphorylating respiration. Our results illustrate that UCP2-and UCP3-mediated state 4 respiration is controlled by reversible glutathionylation. Altogether, these findings advance our understanding of the roles UCP2 and UCP3 play in modulating metabolic efficiency, cell signaling, and oxidative stress processes.UCP2 and -3 belong to the mitochondrial anion carrier family and are ϳ73% homologous to each other, and they are both ϳ58% homologous to the highly thermogenic uncoupling protein, UCP1. Whereas UCP3 is expressed in skeletal muscle and brown adipose tissue (BAT) 3 and to some extent in the heart, UCP2 is found in a wide variety of tissues (1). UCP2 and UCP3 have been shown to diminish oxidative stress by lowering the mitochondrial membrane potential (2, 3). Acute increases in reactive oxygen species (ROS) production increase proton conductance through both UCP2 and UCP3, providing a negative feedback loop to limit further mitochondrial ROS formation (4, 5). Furthermore, UCP2 and UCP3 have also been implicated in many physiologic functions, suggesting that the common underlying mechanism may be ROS-mediated cell signaling.Previous work has reported that UCP3 protects against insulin resistance and obesity (6 -9), whereas UCP2 has been implicated a broad range of functions, including hormone secretion from the pancreas, immune cell function, and feeding behavior (10 -13). For UCP2, most of these functions are linked to ROS level buffering (14 -16). Indeed, UCP2 null mice on various genetic backgrounds exhibit oxidative stress in many tissue types and a decrease in the circulating glutathione (GSH)/glutathione disulfide ratio (2, 12). Increased expression of UCP2 in cancer cells is associated with the acquisition of drug-resistant phenotypes, a phenomenon related to the ROS-quenching function of UCP2 (17, 18). The absence of UCP3 in skeletal muscle increases oxidative damage and perturbs skeletal muscle metabolism (19). Increased UCP3 expression in muscle augments fatty acid metabolism and also curtails ROS production during fatty acid oxidation (20,21). Remarkably, although they have been linked to a plethora of cellular processes, the molecular control of UCP2 and UCP3 ha...

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“…UCP1 has also been detected in the thymus where it has the capacity to regulate metabolic flux and the production of reactive oxygen species (ROS) (Carroll et al 2005). The widespread presence of other UCPs in eukaryotes, nonthermogenic animal tissues (mammals, fish, birds and insects), plants and unicellular organisms implies that these proteins may elicit functions other than thermogenesis (for a review, see Cannon et al 2006;Echtay 2007;Jarmuszkiewicz et al 2010;Sluse et al 2006;Nicholls 2006;Vercesi et al 2006). However, the physiological functions of UCP1 homologues are still under debate.…”

Section: Introductionmentioning

confidence: 99%

“…UCPs catalyze proton leaking into the matrix and dissipate the proton electrochemical gradient built up during electron transport through the mitochondrial respiratory chain (for a review, see Cannon et al 2006;Echtay 2007;Sluse et al 2006;Nicholls 2006). A direct consequence of the UCP activity stimulated by free fatty acids is a decrease in oxidative phosphorylation efficacy (Skulachev 1996).…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of uncoupling protein 4 in fat body and muscle mitochondria from the cockroach Gromphadorhina cocquereliana

Słocińska

Antos-Krzemińska

Rosiński

et al. 2011

J Bioenerg Biomembr

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We have identified and characterized an uncoupling protein in mitochondria isolated from leg muscle and from fat body, an insect analogue tissue of mammalian liver and adipose tissue, of the cockroach Gromphadorhina coquereliana (GcUCP). This is the first functional characterization of UCP activity in isolated insect mitochondria. Bioenergetic studies clearly indicate UCP function in both insect tissues. In resting (non-phosphorylating) mitochondria, cockroach GcUCP activity was stimulated by the addition of micromolar concentrations of palmitic acid and inhibited by the purine nucleotide GTP. Moreover, in phosphorylating mitochondria, GcUCP activity was able to divert energy from oxidative phosphorylation. Functional studies indicate a higher activity of GcUCP-mediated uncoupling in cockroach muscle mitochondria compared to fat body mitochondria. GcUCP activation by palmitic acid resulted in a decrease in superoxide anion production, suggesting that protection against mitochondrial oxidative stress may be a physiological role of UCPs in insects. GcUCP protein was immunodetected using antibodies raised against human UCP4 as a single band of around 36 kDa. GcUCP protein expression in cockroach muscle mitochondria was significantly higher compared to mitochondria isolated from fat body. LC-MS/MS analyses revealed 100% sequence identities for peptides obtained from GcUCP to UCP4 isoforms from D. melanogaster (the highest homology), human, rat or other insect mitochondria. Therefore, it can be proposed that cockroach GcUCP corresponds to the UCP4 isoforms of other animals.

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Uncoupling proteins: A role in protection against reactive oxygen species—or not?

Cited by 173 publications

References 67 publications

Increased thermoregulation in cold-exposed transgenic mice overexpressing lipoprotein lipase in skeletal muscle: an avian phenotype?

Increased thermoregulation in cold-exposed transgenic mice overexpressing lipoprotein lipase in skeletal muscle: an avian phenotype?

Glutathionylation Acts as a Control Switch for Uncoupling Proteins UCP2 and UCP3

Identification and characterization of uncoupling protein 4 in fat body and muscle mitochondria from the cockroach Gromphadorhina cocquereliana

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