Specific Sequence Motifs of Mitochondrial Uncoupling Proteins

Ježek, Petr; Urbánková, Eva

doi:10.1080/713803586

Cited by 41 publications

(40 citation statements)

References 21 publications

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“…Substitution of Phe‐267 by Tyr in the supposed PN binding site of UCP1 led to a decrease of its affinity to GDP [32]. However, UCP2–4 and At PUMP1–2 have a tyrosine at this position [33,34]. Nevertheless, all UCPs have the residues that were previously indicated to be essential for PN binding to UCP1 [34].…”

Section: Discussionmentioning

confidence: 96%

Functional reconstitution of Arabidopsis thaliana plant uncoupling mitochondrial protein (AtPUMP1) expressed in Escherichia coli

et al. 2001

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The Arabidopsis thaliana uncoupling protein (UCP) gene was expressed in Escherichia coli and isolated protein reconstituted into liposomes. Linoleic acid-induced H+ fluxes were sensitive to purine nucleotide inhibition with an apparent K(i) (in mM) of 0.8 (GDP), 0.85 (ATP), 0.98 (GTP), and 1.41 (ADP); the inhibition was pH-dependent. Kinetics of AtPUMP1-mediated H+ fluxes were determined for lauric, myristic, palmitic, oleic, linoleic, and linolenic acids. Properties of recombinant AtPUMP1 indicate that it represents a plant counterpart of animal UCP2 or UCP3. This work brings the functional and genetic approaches together for the first time, providing strong support that AtPUMP1 is truly an UCP.

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Section: Discussionmentioning

confidence: 96%

Functional reconstitution of Arabidopsis thaliana plant uncoupling mitochondrial protein (AtPUMP1) expressed in Escherichia coli

et al. 2001

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“…UCP3 shares 57% amino acid homology with UCP1, has the same predicted tertiary structure, and like UCP1, possesses a nucleotide binding domain (2,3). UCP3 protein is most abundant in skeletal muscle and is present to a lesser extent in brown adipose tissue and heart (4).…”

Section: Uncoupling Protein-3 (Ucp3)mentioning

confidence: 99%

Essential Role for Uncoupling Protein-3 in Mitochondrial Adaptation to Fasting but Not in Fatty Acid Oxidation or Fatty Acid Anion Export

Seifert¹,

Bézaire²,

Estey

et al. 2008

Journal of Biological Chemistry

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Uncoupling protein-3 (UCP3) is a mitochondrial inner membrane protein expressed most abundantly in skeletal muscle and to a lesser extent in heart and brown adipose tissue. Evidence supports a role for UCP3 in fatty acid oxidation (FAO); however, the underlying mechanism has not been explored. In 2001 we proposed a role for UCP3 in fatty acid export, leading to higher FAO rates (Himms-Hagen, J., and Uncoupling protein-3 (UCP3)3 is a member of the family of mitochondrial inner membrane anion carrier proteins which includes uncoupling protein-1 (UCP1), expressed exclusively in brown adipose tissue where it mediates adaptive thermogenesis via an inducible proton leak (1). UCP3 shares 57% amino acid homology with UCP1, has the same predicted tertiary structure, and like UCP1, possesses a nucleotide binding domain (2, 3). UCP3 protein is most abundant in skeletal muscle and is present to a lesser extent in brown adipose tissue and heart (4). In contrast to UCP1, the physiological role and underlying mechanism of action of UCP3 are as yet unresolved. A proposed function for UCP3 is in lipid metabolism (5, 6) and supportive evidence has accrued. In Gullah African-Americans an exon 6 splice junction polymorphism resulting in a truncated form of UCP3 was associated with lower fatty acid oxidation (FAO) as assessed by indirect calorimetry (7); similar results were found in Ucp3 Ϫ/Ϫ mice (8). Early overexpression studies in mice and human muscle cells reported increased FAO (9, 10); however, these results may be confounded by nonspecifically increased basal proton leak due to supraphysiological UCP3 overexpression (11,12). Physiological overexpression is associated with greater FAO in L6 myotubes (13) and elevated maximal activity of carnitine palmitoyl transferase-1, ␤-hydroxyacyl dehydrogenase, and citrate synthase and lower lipid storage in mouse skeletal muscle (14,15). Although these studies functionally link UCP3 and increased FAO, the underlying mechanism remains unexplored, including whether the association between UCP3 and FAO may be related to reduced oxidative stress (13, 16 -19).Two hypotheses of UCP3-mediated fatty acid handling propose that UCP3 transports fatty acid anions from the mitochondrial matrix (20,21). Schrauwen et al. (21) suggest the physiological outcome to be reduced matrix lipotoxicity. We, on the other hand, proposed a UCP3 export function that leads to increased FAO (20). Specifically, when fatty acyl supply is high, UCP3 would act in concert with mitochondrial thioesterase-1 (MTE-1), which cleaves long chain acyl-CoA into fatty acid anions and CoA (22, 23). Fatty acid anions, which cannot be reactivated in the matrix, would be exported by UCP3 to the cytosol to be reactivated then oxidized or esterified (Fig. 1). * This work was supported by the Canadian Institutes of Health Research(Institute of Nutrition, Metabolism, and Diabetes) (to M.-E. H.), the Canadian Diabetes Association (to E. L. S.), and the Natural Sciences and Engineering Research Council (to V. B.). The costs of publication ...

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“…Uncoupling proteins (UCPs) are mitochondrial carrier proteins that can dissipate the proton gradient to prevent the pmf from becoming excessive when there is nutrient overload, which can reduce reactive oxygen species (ROS) produced by electron transport (11). There are five mitochondrial UCP homologues in mammals (12). The closely related UCPs are UCP1-3.…”

mentioning

confidence: 99%

UCP2 is highly expressed in pancreatic α-cells and influences secretion and survival

Diao

Allister

Koshkin

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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In pancreatic ␤-cells, uncoupling protein 2 (UCP2) influences mitochondrial oxidative phosphorylation and insulin secretion. Here, we show that ␣-cells express significantly higher levels of UCP2 than do ␤-cells. Greater mitochondrial UCP2-related uncoupling was observed in ␣-cells compared with ␤-cells and was accompanied by a lower oxidative phosphorylation efficiency (ATP/O). Conversely, reducing UCP2 activity in ␣-cells was associated with higher mitochondrial membrane potential generated by glucose oxidation and with increased ATP synthesis, indicating more efficient metabolic coupling. In vitro, the suppression of UCP2 activity led to reduced glucagon secretion in response to low glucose; however, in vivo, fasting glucagon levels were normal in UCP2 ؊/؊ mice. In addition to its effects on secretion, UCP2 played a cytoprotective role in islets, with UCP2 ؊/؊ ␣-cells being more sensitive to specific death stimuli. In summary, we demonstrate a direct role for UCP2 in maintaining ␣-cell function at the level of glucose metabolism, glucagon secretion, and cytoprotection.lood-glucose levels are tightly regulated by the islet hormones insulin and glucagon. Insulin is secreted from ␤-cells when glucose levels are high to increase glucose utilization, whereas glucagon is secreted from ␣-cells when glucose levels are low to elevate blood glucose. It is well established that ␤-cell dysfunction, resulting in a lack of insulin secretion, is a key event in the development of hyperglycemia that is associated with both type 1 and 2 diabetes (1, 2). In type 2 diabetes, ␤-cell dysfunction can in part be explained by the loss of proper glucose sensing, leading to abnormal insulin secretion. However, in both forms of diabetes, glucagon secretion can be dysregulated during hyper-and hypoglycemia (3, 4), suggesting that glucose sensing by the ␣-cell is also impaired. For this reason, it is important to understand mechanistically how glucagon is regulated by glucose in normal and diseased states.High plasma levels of glucose inhibit glucagon secretion; however, it is still unclear whether this in vivo response is mediated directly via glucose sensing or indirectly by neuronal modulation and/or paracrine/endocrine effects (5-8). Pancreatic ␣-cells, like ␤-cells, possess ATP-dependent K ϩ (K ATP ) channels; however, the metabolism/oxidation of glucose resulting in closure of the K ATP channels causes inhibition of glucagon secretion (9, 10). It is suggested that N-type Ca 2ϩ channels modulate this alternate excitability downstream of K ATP -channel closure (10). Glucose metabolism in ␣-cells generates a proton-motive force (pmf) in the inner mitochondria that drives the synthesis of ATP via ATP synthase. Uncoupling proteins (UCPs) are mitochondrial carrier proteins that can dissipate the proton gradient to prevent the pmf from becoming excessive when there is nutrient overload, which can reduce reactive oxygen species (ROS) produced by electron transport (11). There are five mitochondrial UCP homologues in mammals (12). The closel...

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Specific Sequence Motifs of Mitochondrial Uncoupling Proteins

Abstract: SummaryWe have searched for the exclusivity of common sequence motifs of the mitochondrial uncoupling proteins (UCP1, UCP2, UCP3,

Cited by 41 publications

References 21 publications

Functional reconstitution of Arabidopsis thaliana plant uncoupling mitochondrial protein (AtPUMP1) expressed in Escherichia coli

Functional reconstitution of Arabidopsis thaliana plant uncoupling mitochondrial protein (AtPUMP1) expressed in Escherichia coli

Essential Role for Uncoupling Protein-3 in Mitochondrial Adaptation to Fasting but Not in Fatty Acid Oxidation or Fatty Acid Anion Export

UCP2 is highly expressed in pancreatic α-cells and influences secretion and survival

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