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Further Support to the Uncoupling-to-Survive Theory: The Genetic Variation of Human UCP Genes Is Associated with Longevity  [PDF]
Giuseppina Rose, Paolina Crocco, Francesco De Rango, Alberto Montesanto, Giuseppe Passarino
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0029650
Abstract: In humans Uncoupling Proteins (UCPs) are a group of five mitochondrial inner membrane transporters with variable tissue expression, which seem to function as regulators of energy homeostasis and antioxidants. In particular, these proteins uncouple respiration from ATP production, allowing stored energy to be released as heat. Data from experimental models have previously suggested that UCPs may play an important role on aging rate and lifespan. We analyzed the genetic variability of human UCPs in cohorts of subjects ranging between 64 and 105 years of age (for a total of 598 subjects), to determine whether specific UCP variability affects human longevity. Indeed, we found that the genetic variability of UCP2, UCP3 and UCP4 do affect the individual's chances of surviving up to a very old age. This confirms the importance of energy storage, energy use and modulation of ROS production in the aging process. In addition, given the different localization of these UCPs (UCP2 is expressed in various tissues including brain, hearth and adipose tissue, while UCP3 is expressed in muscles and Brown Adipose Tissue and UCP4 is expressed in neuronal cells), our results may suggest that the uncoupling process plays an important role in modulating aging especially in muscular and nervous tissues, which are indeed very responsive to metabolic alterations and are very important in estimating health status and survival in the elderly.
Genetic Variance in Uncoupling Protein 2 in Relation to Obesity, Type 2 Diabetes, and Related Metabolic Traits: Focus on the Functional ?866G>A Promoter Variant (rs659366)  [PDF]
Louise T. Dalgaard
Journal of Obesity , 2011, DOI: 10.1155/2011/340241
Abstract: Uncoupling proteins (UCPs) are mitochondrial proteins able to dissipate the proton gradient of the inner mitochondrial membrane when activated. This decreases ATP-generation through oxidation of fuels and may theoretically decrease energy expenditure leading to obesity. Evidence from Ucp(?/?) mice revealed a role of UCP2 in the pancreatic β-cell, because β-cells without UCP2 had increased glucose-stimulated insulin secretion. Thus, from being a candidate gene for obesity UCP2 became a valid candidate gene for type 2 diabetes mellitus. This prompted a series of studies of the human UCP2 and UCP3 genes with respect to obesity and diabetes. Of special interest was a promoter variant of UCP2 situated 866bp upstream of transcription initiation (?866G>A, rs659366). This variant changes promoter activity and has been associated with obesity and/or type 2 diabetes in several, although not all, studies. The aim of the current paper is to summarize current evidence of association of UCP2 genetic variation with obesity and type 2 diabetes, with focus on the ?866G>A polymorphism. 1. Introduction Uncoupling protein 2 (UCP2) and uncoupling protein 3 (UCP3) belong to a large family of mitochondrial transmembrane carriers. UCP2 was identified in 1997 based on its homology to the brown fat uncoupling protein (UCP, then renamed UCP1) [1, 2]. Shortly thereafter, UCP3 was cloned also based on homology to UCP1 and UCP2 [3, 4]. Later, more distantly related proteins were identified and named UCP4 and UCP5 (BMCP1) [5–7]. The physiological role of UCP1 is well established; it is responsible for nonshivering thermogenesis in brown fat, in which it induces proton leak across the inner mitochondrial membrane [8, 9]. Now 14 years later, the physiological functions of UCP2 and UCP3 are still under debate, as is the role of genetic variation in these. The aim of this paper is to recapitulate the currently published literature on human genetic variation in the UCP2 genomic region concerning development of obesity, type 2 diabetes, and related metabolic disorders with focus on the ?866G>A promoter polymorphism (rs659366). 2. Physiological Functions of UCP2 and UCP3 UCP2 is ubiquitously expressed [1, 2] whereas UCP3 is found predominantly in skeletal muscle and brown adipose tissue [3, 4, 10], and their expression is both induced by fasting, and peroxisome proliferators as well as hyperglycemia, which indicates a role connected with the availability of fuel substrates [11–14]. However, the upregulation in response to thyroid hormone, cold, β3-adrenergic agonists, and high fat diets
Acetoacetate reduces growth and ATP concentration in cancer cell lines which over-express uncoupling protein 2
Eugene J Fine, Anna Miller, Edward V Quadros, Jeffrey M Sequeira, Richard D Feinman
Cancer Cell International , 2009, DOI: 10.1186/1475-2867-9-14
Abstract: Seven aggressive human cancer cell lines, and three control fibroblast lines were grown in vitro in either 10 mM glucose medium (GM), or in glucose plus 10 mM acetoacetate [G+AcA]. The cells were assayed for cell growth, ATP production and expression of UCP2.There was a high correlation of cell growth with ATP concentration (r = 0.948) in a continuum across all cell lines. Controls demonstrated normal cell growth and ATP with the lowest density of mitochondrial UCP2 staining while all cancer lines demonstrated proportionally inhibited growth and ATP, and over-expression of UCP2 (p < 0.05).Seven human cancer cell lines grown in glucose plus acetoacetate medium showed tightly coupled reduction of growth and ATP concentration. The findings were not observed in control fibroblasts. The observed over-expression of UCP2 in cancer lines, but not in controls, provides a plausible molecular mechanism by which acetoacetate spares normal cells but suppresses growth in cancer lines. The results bear on the hypothesized potential for ketogenic diets as therapeutic strategies.Otto Warburg observed that many cancers lose their capacity for mitochondrial respiration, limiting ATP production to anaerobic glycolytic pathways [1]. The phenomenon is particularly prevalent in aggressive malignancies, most of which are also hypoxic. Hypoxia induces a stochastic imbalance between the number of reduced mitochondrial species vs. available oxygen, resulting in increased reactive oxygen species (ROS) whose toxicity can lead to apoptotic cell death. One mitochondrial adaptation to increased ROS is over-expression of uncoupling protein 2 (UCP2) which has been reported in a number of human cancer cell lines [2-4]. Horimoto et al. [3] demonstrated UCP2 over-expression in most of the 120 colon cancer lines tested, the extent correlating with the degree of tumor aggressiveness. Increased UCP2 expression was also associated with reduction in ATP production in malignant oxyphilic thyroid tumors [2],
Uncoupling Protein 2 and 4 Expression Pattern during Stem Cell Differentiation Provides New Insight into Their Putative Function  [PDF]
Anne Rupprecht, Dana Sittner, Alina Smorodchenko, Karolina E. Hilse, Justus Goyn, Rudolf Moldzio, Andrea E. M. Seiler, Anja U. Br?uer, Elena E. Pohl
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0088474
Abstract: Apart from the first family member, uncoupling protein 1 (UCP1), the functions of other UCPs (UCP2-UCP5) are still unknown. In analyzing our own results and those previously published by others, we have assumed that UCP's cellular expression pattern coincides with a specific cell metabolism and changes if the latter is altered. To verify this hypothesis, we analyzed the expression of UCP1-5 in mouse embryonic stem cells before and after their differentiation to neurons. We have shown that only UCP2 is present in undifferentiated stem cells and it disappears simultaneously with the initiation of neuronal differentiation. In contrast, UCP4 is simultaneously up-regulated together with typical neuronal marker proteins TUJ-1 and NeuN during mESC differentiation in vitro as well as during murine brain development in vivo. Notably, several tested cell lines express UCP2, but not UCP4. In line with this finding, neuroblastoma cells that display metabolic features of tumor cells express UCP2, but not UCP4. UCP2's occurrence in cancer, immunological and stem cells indicates that UCP2 is present in cells with highly proliferative potential, which have a glycolytic type of metabolism as a common feature, whereas UCP4 is strongly associated with non-proliferative highly differentiated neuronal cells.
Acute Knockdown of Uncoupling Protein-2 Increases Uncoupling via the Adenine Nucleotide Transporter and Decreases Oxidative Stress in Diabetic Kidneys  [PDF]
Malou Friederich-Persson, Shakil Aslam, Lina Nordquist, William J. Welch, Christopher S. Wilcox, Fredrik Palm
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0039635
Abstract: Increased O2 metabolism resulting in chronic hypoxia is common in models of endstage renal disease. Mitochondrial uncoupling increases O2 consumption but the ensuing reduction in mitochondrial membrane potential may limit excessive oxidative stress. The present study addressed the hypothesis that mitochondrial uncoupling regulates mitochondria function and oxidative stress in the diabetic kidney. Isolated mitochondria from kidney cortex of control and streptozotocin-induced diabetic rats were studied before and after siRNA knockdown of uncoupling protein-2 (UCP-2). Diabetes resulted in increased UCP-2 protein expression and UCP-2-mediated uncoupling, but normal mitochondria membrane potential. This uncoupling was inhibited by GDP, which also increased the membrane potential. siRNA reduced UCP-2 protein expression in controls and diabetics (?30–50%), but paradoxically further increased uncoupling and markedly reduced the membrane potential. This siRNA mediated uncoupling was unaffected by GDP but was blocked by ADP and carboxyatractylate (CAT). Mitochondria membrane potential after UCP-2 siRNA was unaffected by GDP but increased by CAT. This demonstrated that further increased mitochondria uncoupling after siRNA towards UCP-2 is mediated through the adenine nucleotide transporter (ANT). The increased oxidative stress in the diabetic kidney, manifested as increased thiobarbituric acids, was reduced by knocking down UCP-2 whereas whole-body oxidative stress, manifested as increased circulating malondialdehyde, remained unaffected. All parameters investigated were unaffected by scrambled siRNA. In conclusion, mitochondrial uncoupling via UCP-2 regulates mitochondria membrane potential in diabetes. However, blockade of the diabetes-induced upregulation of UCP- 2 results in excessive uncoupling and reduced oxidative stress in the kidney via activation of ANT.
The essential oils component p-cymene induces proton leak through Fo-ATP synthase and uncoupling of mitochondrial respiration
Custódio JBA, Ribeiro MV, Silva FSG, Machado M, Sousa MC
Journal of Experimental Pharmacology , 2011, DOI: http://dx.doi.org/10.2147/JEP.S16387
Abstract: sential oils component p-cymene induces proton leak through Fo-ATP synthase and uncoupling of mitochondrial respiration Original Research (2630) Total Article Views Authors: Custódio JBA, Ribeiro MV, Silva FSG, Machado M, Sousa MC Published Date August 2011 Volume 2011:3 Pages 69 - 76 DOI: http://dx.doi.org/10.2147/JEP.S16387 José BA Custódio1,2, Mariana V Ribeiro1,2, Filomena SG Silva1,2, Marisa Machado3,4, M Céu Sousa3,4 1Center for Neuroscience and Cell Biology, 2Laboratory of Biochemistry, Faculty of Pharmacy, 3Center of Pharmaceutical Studies, 4Laboratory of Microbiology, Faculty of Pharmacy, University of Coimbra, Portugal Abstract: Essential oils can be used as antimicrobial, antioxidant, and anticarcinogenic agents or to preserve and give flavors to foods. The activity of phenolic-rich essential oils has been observed in fractions containing thymol and carvacrol which show synergistic effects with their precursor p-cymene. Their mode of action is related to several targets in the cell but specific mechanisms of activity and cytotoxic effects remain poorly characterized. Given the importance of mitochondria for cellular functions and their critical role in a vast number of diseases, this work evaluated the effects of p-cymene on mitochondrial functions. It was observed that p-cymene did not change the oxygen consumption by respiratory chain (state 2 respiration). However, p-cymene decreased the mitochondrial membrane potential (Δψ), depressed the rate of ADP phosphorylation (state 3), and stimulated the oxygen consumption after phosphorylation of ADP (state 4). The respiratory control ratio (state 3/state 4) was decreased as a consequence of the inhibition of state 3 and stimulation of state 4 respiration but the ADP/O index remained unaltered as well as the mitochondrial Ca2+ fluxes. Moreover, p-cymene did not induce mitochondrial membrane disruption but depressed the Δψ, and the stimulatory effect observed on state 4, similar to the effect observed on state 2 respiration plus ATP, was inhibited by oligomycin. These effects suggest that p-cymene allows a proton leak through the Fo fraction of the phosphorylative system, changing the mitochondrial proton motive force and ATP synthesis capacity. Therefore, these data suggest mitochondria as a target for p-cymene toxicity action mechanisms.
The essential oils component p-cymene induces proton leak through Fo-ATP synthase and uncoupling of mitochondrial respiration  [cached]
Custódio JBA,Ribeiro MV,Silva FSG,Machado M
Journal of Experimental Pharmacology , 2011,
Abstract: José BA Custódio1,2, Mariana V Ribeiro1,2, Filomena SG Silva1,2, Marisa Machado3,4, M Céu Sousa3,4 1Center for Neuroscience and Cell Biology, 2Laboratory of Biochemistry, Faculty of Pharmacy, 3Center of Pharmaceutical Studies, 4Laboratory of Microbiology, Faculty of Pharmacy, University of Coimbra, Portugal Abstract: Essential oils can be used as antimicrobial, antioxidant, and anticarcinogenic agents or to preserve and give flavors to foods. The activity of phenolic-rich essential oils has been observed in fractions containing thymol and carvacrol which show synergistic effects with their precursor p-cymene. Their mode of action is related to several targets in the cell but specific mechanisms of activity and cytotoxic effects remain poorly characterized. Given the importance of mitochondria for cellular functions and their critical role in a vast number of diseases, this work evaluated the effects of p-cymene on mitochondrial functions. It was observed that p-cymene did not change the oxygen consumption by respiratory chain (state 2 respiration). However, p-cymene decreased the mitochondrial membrane potential (Δψ), depressed the rate of ADP phosphorylation (state 3), and stimulated the oxygen consumption after phosphorylation of ADP (state 4). The respiratory control ratio (state 3/state 4) was decreased as a consequence of the inhibition of state 3 and stimulation of state 4 respiration but the ADP/O index remained unaltered as well as the mitochondrial Ca2+ fluxes. Moreover, p-cymene did not induce mitochondrial membrane disruption but depressed the Δψ, and the stimulatory effect observed on state 4, similar to the effect observed on state 2 respiration plus ATP, was inhibited by oligomycin. These effects suggest that p-cymene allows a proton leak through the Fo fraction of the phosphorylative system, changing the mitochondrial proton motive force and ATP synthesis capacity. Therefore, these data suggest mitochondria as a target for p-cymene toxicity action mechanisms. Keywords: antimicrobial, proton leak, ATP synthase, p-cymene, essential oils, food additive, mitochondrial respiration, uncoupling
Metabolic Flux Analysis of Mitochondrial Uncoupling in 3T3-L1 Adipocytes  [PDF]
Yaguang Si, Hai Shi, Kyongbum Lee
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0007000
Abstract: Background Increasing energy expenditure at the cellular level offers an attractive option to limit adiposity and improve whole body energy balance. In vivo and in vitro observations have correlated mitochondrial uncoupling protein-1 (UCP1) expression with reduced white adipose tissue triglyceride (TG) content. The metabolic basis for this correlation remains unclear. Methodology/Principal Findings This study tested the hypothesis that mitochondrial uncoupling requires the cell to compensate for the decreased oxidation phosphorylation efficiency by up-regulating lactate production, thus redirecting carbon flux away from TG synthesis. Metabolic flux analysis was used to characterize the effects of non-lethal, long-term mitochondrial uncoupling (up to 18 days) on the pathways of intermediary metabolism in differentiating 3T3-L1 adipocytes. Uncoupling was induced by forced expression of UCP1 and chemical (FCCP) treatment. Chemical uncoupling significantly decreased TG content by ca. 35%. A reduction in the ATP level suggested diminished oxidative phosphorylation efficiency in the uncoupled adipocytes. Flux analysis estimated significant up-regulation of glycolysis and down-regulation of fatty acid synthesis, with chemical uncoupling exerting quantitatively larger effects. Conclusions/Significance The results of this study support our hypothesis regarding uncoupling-induced redirection of carbon flux into glycolysis and lactate production, and suggest mitochondrial proton translocation as a potential target for controlling adipocyte lipid metabolism.
Muscle Mitochondrial Uncoupling Dismantles Neuromuscular Junction and Triggers Distal Degeneration of Motor Neurons  [PDF]
Luc Dupuis, Jose-Luis Gonzalez de Aguilar, Andoni Echaniz-Laguna, Judith Eschbach, Frédérique Rene, Hugues Oudart, Benoit Halter, Caroline Huze, Laurent Schaeffer, Frédéric Bouillaud, Jean-Philippe Loeffler
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0005390
Abstract: Background Amyotrophic lateral sclerosis (ALS), the most frequent adult onset motor neuron disease, is associated with hypermetabolism linked to defects in muscle mitochondrial energy metabolism such as ATP depletion and increased oxygen consumption. It remains unknown whether muscle abnormalities in energy metabolism are causally involved in the destruction of neuromuscular junction (NMJ) and subsequent motor neuron degeneration during ALS. Methodology/Principal Findings We studied transgenic mice with muscular overexpression of uncoupling protein 1 (UCP1), a potent mitochondrial uncoupler, as a model of muscle restricted hypermetabolism. These animals displayed age-dependent deterioration of the NMJ that correlated with progressive signs of denervation and a mild late-onset motor neuron pathology. NMJ regeneration and functional recovery were profoundly delayed following injury of the sciatic nerve and muscle mitochondrial uncoupling exacerbated the pathology of an ALS animal model. Conclusions/Significance These findings provide the proof of principle that a muscle restricted mitochondrial defect is sufficient to generate motor neuron degeneration and suggest that therapeutic strategies targeted at muscle metabolism might prove useful for motor neuron diseases.
Uncoupling Protein 1 of Brown Adipocytes, the Only Uncoupler: A Historical Perspective  [PDF]
Daniel Ricquier
Frontiers in Endocrinology , 2011, DOI: 10.3389/fendo.2011.00085
Abstract: Uncoupling protein 1 (UCP1), is a unique mitochondrial membranous protein devoted to adaptive thermogenesis, a specialized function performed by brown adipocytes. Whereas the family of mitochondrial metabolite carriers comprises ~40 members, UCP1 is the only memberable to translocate protons through the inner membrane of brown adipocyte mitochondria. By this process, UCP1 uncouples respiration from ATP synthesis and therefore provokes energy dissipation in the form of heat while, also stimulating high levels of fatty acid oxidation. UCP1 homologs were identified but they are biochemically and physiologically different from UCP1. Thirty five years after its identification, UCP1 still appears as a fascinating component. The recent renewal of the interest in human brown adipose tissue makes UCP1 as a potential target for strategies of treatment of metabolic disorders.
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