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Uncoupling protein 2 (UCP2) is a member of the mitochondrial proton transport family that uncouples proton entry to the mitochondria from ATP synthesis. UCP2 expression levels have been linked to predisposition to diabetes and obesity. In addition, UCP2 prevents neuronal death and injury. Here we show that the common -866G/A promoter polymorphism i...
Citations
... 11 Conversely, rs659366 SNP has also been associated with increased UCP2 expression in adipose cells, pancreatic β-cells, inflammatory cell lines, and human blood samples. [12][13][14][15] The differences in effect on mRNA levels might suggest that other factors, either independently or in interaction with the -866 variant, influence the UCP2 mRNA levels. Although the authors successfully demonstrated the association between SIRT3 (rs11246020) SNP, UCP2 (rs659366) SNP, and PAH severity, the contribution of those specific SNPs to PAH etiology in humans remains to be experimentally investigated. ...
... Mitochondrial uncoupling is a condition that uncouples proton entry to the mitochondria from ATP synthesis and attenuates the mitochondrial membrane potential. UCPs are a family of inner mitochondrial membrane proteins that are thought to maintain a balance between the energy supply and cell demand in defending cells against ROS production [33,34]. UCP2-866G (rs659366) was found to have higher efficiency of UCP2 expression and promoter activity than -866A. ...
... UCP2-866G (rs659366) was found to have higher efficiency of UCP2 expression and promoter activity than -866A. UCP2 G-866A has been linked to a predisposition to diabetes, obesity, and inflammation [33,35]. In the present study, the genetic alteration in the UCP2 G-866A allele was shown to significantly influence sperm fertility and motility. ...
Sperm motility is one of the major determinants of male fertility. Since sperm need a great deal of energy to support their fast movement by active metabolism, they are thus extremely vulnerable to oxidative damage by the reactive oxygen species (ROS) and other free radicals generated as byproducts in the electron transport chain. The present study is aimed at understanding the impact of a mitochondrial oxidizing/reducing microenvironment in the etiopathology of male infertility. We detected the mitochondrial DNA (mtDNA) 4,977 bp deletion in human sperm. We examined the gene mutation of ATP synthase 6 (ATPase6 m.T8993G) in ATP generation, the gene polymorphisms of uncoupling protein 2 (UCP2, G-866A) in the uncoupling of oxidative phosphorylation, the role of genes such as manganese superoxide dismutase (MnSOD, C47T) and catalase (CAT, C-262T) in the scavenging system in neutralizing reactive oxygen species, and the role of human 8-oxoguanine DNA glycosylase (hOGG1, C1245G) in 8-hydroxy-2'-deoxyguanosine (8-OHdG) repair. We found that the sperm with higher motility were found to have a higher mitochondrial membrane potential and mitochondrial bioenergetics. The genotype frequencies of UCP2 G-866A, MnSOD C47T, and CAT C-262T were found to be significantly different among the fertile subjects, the infertile subjects with more than 50% motility, and the infertile subjects with less than 50% motility. A higher prevalence of the mtDNA 4,977 bp deletion was found in the subjects with impaired sperm motility and fertility. Furthermore, we found that there were significant differences between the occurrences of the mtDNA 4,977 bp deletion and MnSOD (C47T) and hOGG1 (C1245G). In conclusion, the maintenance of the mitochondrial redox microenvironment and genome integrity is an important issue in sperm motility and fertility.
... For example, in human studies, it was shown that polymorphism of the UCP2 makes different phenotypes. In -866G/A polymorphism for the promoter of UCP2, the G allele is associated with a lower expression of UCP2 when compared to the A allele [38] and this polymorphism modulates the development of diabetes [39]. In another study of Egyptian children and their mothers, GG genotype after AG was the most frequent and the G allele was the most present in mothers who affected with obesity and male children who also have obesity, (statistical signi icance was not observed) [37]. ...
Obesity is rising worldwide, and the inflammatory disease increased in parallel. Many studies demonstrate excess fat mass is an indicator of obesity. As much as lipid increased in the cell, ROS production increased. On the other hand, ROS could enhance lipid storage and increased adiposity. So obesity and inflammation have a reciprocal relationship. Uncoupling protein2 (UCP2) could control the metabolism of energy, adipose tissue, and weight management. Also, UCP2 decreased ROS, oxidative stress, and inflammation. Therefore, as metabolism-related to oxidative stress and inflammatory status, and by considering the modulatory contribution of UCP2 in inflammation; it seems UCP2 could link obesity and inflammation. This study aims to review the studies about the association between UCP2 and obesity focusing on the inflammatory process linked to ROS. In conclusion, as the results contradict the association between UCP2 as the center of metabolism and obesity, obesity-related hormones, and oxidative stress, further studies in human trials are recommended.
... These cells showed enhanced ROS production, confirming that mitochondrial activity is altered in blood leukocytes during MS. Interestingly, a polymorphism in the gene encoding for the mitochondrial protein uncoupling protein 2, which leads to its reduced expression in circulating leukocytes, have been linked to MS susceptibility (Vogler, et al., 2005), further supporting a potential role for immune cell mitochondrial metabolism in MS. ...
Neuroinflammatory and neurodegenerative diseases are characterized by the recruitment of circulating blood‐borne innate and adaptive immune cells into the central nervous system (CNS). These leukocytes sustain the detrimental response in the CNS by releasing pro‐inflammatory mediators that induce activation of local glial cells, blood–brain barrier (BBB) dysfunction, and neural cell death. However, infiltrating peripheral immune cells could also dampen CNS inflammation and support tissue repair. Recent advances in the field of immunometabolism demonstrate the importance of metabolic reprogramming for the activation and functionality of such innate and adaptive immune cell populations. In particular, an increasing body of evidence suggests that the activity of metabolites and metabolic enzymes could influence the pathogenic potential of immune cells during neuroinflammatory and neurodegenerative disorders. In this review, we discuss the role of intracellular metabolic cues in regulating leukocyte‐mediated CNS damage in Alzheimer's and Parkinson's disease, multiple sclerosis and stroke, highlighting the therapeutic potential of drugs targeting metabolic pathways for the treatment of neurological diseases.
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... For instant, the -866 G/A polymorphism in the UCP2 gene has been linked to rheumatoid arthritis and multiple sclerosis. [28] In addition, the A allele was found to have a protective role against chronic inflammatory conditions such as systemic lupus erythematosus. [29] ...
Objectives:
Autoimmune hypothyroidism (AHT) is a common endocrine disorder. Although the exact cause of AHT is not yet understood, genetic factors may play a major role. Uncoupling protein 2 (UCP2) is a member of mitochondrial protein family involved in the regulation of cellular metabolism. An important functional polymorphism in the UCP2 gene, 45-bp insertion/deletion (ins/del) polymorphism, has been linked to certain clinical conditions. However, an association between the 45-bp ins/del polymorphism and AHT has not yet been established.
Methods:
In this study, about 259 blood samples were collected from, patients with AHT and age-matched healthy control subjects. DNA was extracted for UCP2 45-bp ins/del polymorphisms genotyping, using a standard polymerase chain reaction technique. The distribution of different genotypes was determined in both groups and possible association with AHT was also assessed by logistic regression analysis using the Del/Del variant as a reference genotype.
Results:
The frequency of the UCP2 45-bp ins/del polymorphism in the total study population was 49.04%, 40.15%, and 10.81% for Del/Del, Ins/Del, and Ins/Ins genotypes, respectively. The logistic regression analysis showed crude odds ratios (ORs), respectively, with their 95% confidence intervals (CIs) and P-values in codominant (Del/Ins) (OR = 1.53, CI = 0.89-2.60, P = 0.17), codominant (Ins/Ins) (OR = 0.75, CI = 0.34-1.74, P = 0.53), dominant (OR = 1.30, CI = 0.79-2.16, P = 0.37), and recessive (OR = 0.62, CI = 0.29-1.36, P = 0.30) inheritance models tested, where none of which were statistically significant.
Conclusion:
Our data revealed the distribution of the UCP2 45-bp ins/del polymorphisms in Jazan area and confirmed the lack of association between these genetic variants and the development of AHT.
... The single nucleotide polymorphism (SNP) for SIRT3 rs11246020 A allele causes a change of valine to isoleucine at residue 208, which causes a 34% reduction in SIRT3 activity compared to the G allele (137). Similarly, the UCP2 rs659366 G allele is associated with reduced transcription compared to the A allele (92,320). Disrupting SIRT3 and/or UCP2 function inhibits PDH activity by PDK-independent mechanisms (which are thus not amenable to DCA therapy). ...
In lung vascular cells, mitochondria serve a canonical metabolic role, governing energy homeostasis. In addition, mitochondria exist in dynamic networks, which serve noncanonical functions, including regulation of redox signaling, cell cycle, apoptosis, and mitochondrial quality control. Mitochondria in pulmonary artery smooth muscle cells (PASMC) are oxygen sensors and initiate hypoxic pulmonary vasoconstriction. Acquired dysfunction of mitochondrial metabolism and dynamics contribute to a cancer-like phenotype in pulmonary arterial hypertension (PAH). Acquired mitochondrial abnormalities, such as increased pyruvate dehydrogenase kinase (PDK) and pyruvate kinase muscle isoform 2 (PKM2) expression, which increase uncoupled glycolysis (the Warburg phenomenon), are implicated in PAH. Warburg metabolism sustains energy homeostasis by the inhibition of oxidative metabolism that reduces mitochondrial apoptosis, allowing unchecked cell accumulation. Warburg metabolism is initiated by the induction of a pseudohy-poxic state, in which DNA methyltransferase (DNMT)-mediated changes in redox signaling cause normoxic activation of HIF-1α and increase PDK expression. Furthermore, mitochondrial division is coordinated with nuclear division through a process called mitotic fission. Increased mitotic fission in PAH, driven by increased fission and reduced fusion favors rapid cell cycle progression and apoptosis resistance. Downregulation of the mitochondrial calcium uniporter complex (MCUC) occurs in PAH and is one potential unifying mechanism linking Warburg metabolism and mitochondrial fission. Mitochondrial metabolic and dynamic disorders combine to promote the hyperproliferative, apoptosis-resistant, phenotype in PAH PASMC, endothelial cells, and fibroblasts. Understanding the molecular mechanism regulating mitochondrial metabolism and dynamics has permitted identification of new biomarkers, nuclear and CT imaging modalities, and new therapeutic targets for PAH.
... Sullivan et al. reported that neurones from immature rat brains were more resistant to seizures compared to those from mature rat brain and that this was due to higher levels of mitochondrial uncoupling in those cells, associated with a higher expression of UCP2 [36]. Due to this significant functions, UCP variants were assessed often in some diseases including body composition and resting energy expenditure [37], energy metabolism [38], obesity [39], multiple sclerosis [40], diabetic neuropathy [41], and schizophrenia [42]. ...
OBJECTIVE: Substance use disorders (SUD) are among the most important public health problems throughout the world. We investigated whether COMT (Val108/158Met), CNR2 (rs2501432 and rs2229579), UCP2 (rs659366), and IL-17 (rs763780) gene variants were associated with SUD and its clinical parameters in a Turkish population.
METHODS: We conducted a case–control study among 136 subjects with SUD and 100 healthy controls. Six variants were analysed by the PCR-RFLP method.
RESULTS: The CNR2 rs2229579 T/T genotype and T allele increased in SUD groups than controls while the C/C genotype and C allele were more prevalent in the control group compared to the SUD group (p = 0.000 and p = 0.001, respectively). The COMT Val108/158Met Val/Val genotype and Val allele were significantly associated with polysubstance abuse (p < 0.05). There was no significant difference between the SUD group and control group regarding genotype and allele frequencies of COMT (Val108/158Met), CNR2 (rs2501432), UCP2 (rs659366) and IL-17 (rs763780) variants.
CONCLUSIONS: This is the first study that discussed the relation of these variants and SUD patients in the Turkish population. The results of the analysis indicated that the CNR2 rs2229579 variant has an effect on susceptibility to SUD, suggesting that this variant might play a role in the physiopathology of SUD. The COMT Val108/158Met variant might be an important factor affecting polysubstance use.
... This SNP has also been associated with T2DM and obesity in different populations [1,[12][13][14][15], and it is described as being functional since it putatively changes one or more transcription factor binding sites in the UCP2 promoter [2]. Accordingly, the minor A allele has been associated with either increased [16][17][18][19] or decreased UCP2 mRNA expression [20][21][22][23]. However, it is still unclear if the A allele directly affects UCP2 expression in endothelial cells or if it is in linkage disequilibrium with another functional SNP in the UCP2 gene. ...
... Hence, the UCP2 -866A allele seems to upregulate UCP2 promoter activity in INS-1E cells derived from rat beta-cells [17,18]. Data on human cells and tissues have been conflicting, showing that the -866A allele might lead to either increased [16,19] or decreased [20][21][22][23] UCP2 expression. A plausible explanation for these contradictory results is that this SNP is located in putative binding sites for specific transcription factors, such as PAX6, ARNT/HIF-1α, CREB1, and IPF1 [16,17,21]. ...
The mitochondrial uncoupling protein 2 (UCP2) decreases reactive oxygen species (ROS) formation by mitochondria. Our group previously showed that the UCP2 -866A allele was associated with risk of diabetic retinopathy (DR), which is caused by hyperglycemia-induced oxidative stress. To date, it is still unclear if the -866A allele directly affects UCP2 expression in endothelial cells. Thus, we investigated the effect of the A allele on UCP2 promoter activity in HUVECs treated with high glucose (HG) or hydrogen peroxide (H2O2). To quantify UCP2 promoter activity, HUVECs were transfected with pGL3 plasmids containing the UCP2 promoter and the firefly luciferase coding sequence. Experimental groups were: (1) pGL3-866G-transfected cells and (2) pGL3-866A cells, both under normal (4 mM) or HG (25 mM) concentrations for 24 h and 48 h or incubated with H2O2 (0.1 mM) for 1 h. UCP2 promoter activity was monitored by Luminescent Dual-luciferase Assay. HG induced an upregulation of UCP2 promoter activity in PGL3-866G cells after 24 h of treatment (P = 0.027), but not after 48 h. Compared to pGL3-866G cells, pGL3-866A cells seems to have reduced UCP2 promoter activity following 24 h and 48 h of normal glucose treatment (P = 0.087 and P = 0.022). After HG treatment, pGL3-866A cells had more marked UCP2 downregulation (24 h: − 3.2-folds, P < 0.001; and 48 h: − 2.5-folds, P < 0.001 vs. G cells). Both pGL3-866G and pGL3-866A cells treated with H2O2 showed a ≅ 4-fold increase in UCP2 promoter activity (both P < 0.001). The -866A allele modifies UCP2 promoter activity in HUVECs under HG treatment but not in the H2O2 condition.
... The UCP2 −866G allele was correlated with lower levels of UCP2 expression in vitro and in vivo. Thus, UCP2 may contribute to MS susceptibility by regulating the level of UCP2 protein in the CNS and/or in the immune system (17). Defects in mtDNA have been associated with late-onset MS. ...
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system (CNS) and is characterized by a high degree of heterogeneity in progression and treatment response. Mitochondrial dysfunction is increasingly recognized as an important feature of MS pathology and may be relevant for clinical disease progression. This paper systematically reviews published evidence concerning the role of mitochondrial abnormalities with MS. Literature searched using the Web of Science, PMC/Medline via PubMed and Scopus databases up to May 2017 with no time and language limitation. After quality assessment, 9 articles were included in the study. All data extraction was conducted by two reviewers independently. Based on the results of the studies, it seems that mitochondrial DNA abnormality and mitochondrial dysfunction may be due to primary inflammation in MS or may be occurred itself before any inflammation, but definitely contributes to axonal degeneration and disease progression. Mitochondrial abnormality contributes to axonal degeneration in MS and disease progression.
... Des polymorphismes de gènes nucléaires codant des protéines mitochondriales ont aussi été impliqués dans l'émergence de pathologies inflammatoires telles que celles dans le gène UCP2 qui ont été reliées à la susceptibilité à la sclérose en plaques chez l'homme (Vogler et al., 2005) et à l'encéphalite auto-immune expérimentale chez la souris (Vogler et al., 2006). ...
Les myopathies inflammatoires sont des maladies auto-immunes rares dont le dénominateur commun est la faiblesse musculaire et l'inflammation. Leur origine n’est pas connue et les traitements sont conventionnels partiellement efficaces. Par une approche épidémiologique, nous avons montré que l’étude de l’incidence et de la prévalence est un outil utile pour mettre en évidence des déterminants des myopathies inflammatoires. Une meilleure identification et une meilleure classification des patients atteints de ces maladies sont cependant nécessaires pour préciser l’épidémiologie des myopathies inflammatoires.Par une approche translationnelle, nous avons montré que, par rapport aux autres myopathies inflammatoires, des dysfonctions mitochondriales périfasciculaires sont une caractéristique des dermatomyosites, qui jouent un rôle dans l’intolérance à l’effort et le maintien de l’inflammation. Ces résultats ouvrent des nouvelles voies pour mieux comprendre et traités les myopathies inflammatoires.
