Uncoupling Proteins (UCP)

Author: Gianpiero Pescarmona
Date: 07/03/2010



UCPs are transmembrane proteins that discharge the proton gradient generated in oxidative phosphorylation and are also involved in regulating reactive oxygen species (ROS)

The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP, 2000

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Possible physiological roles of mitochondrial uncoupling proteins--UCPn. 2002
Int J Biochem Cell Biol. 2002 Oct;34(10):1190-206.
Jezek P.

Five mitochondrial uncoupling proteins exist in the human gemone: UCP2, expressed ubiquitously; UCP1, exclusively in brown adipose tissue (BAT); UCP3, predominantly in muscle; UCP4 and BMCP (UCP5), in brain. UCP4 is the ancestral prototype from which the other UCPn diverged. Findings on the level of organism and reconstituted recombinant proteins demonstrated that UCPn exhibit a protonophoric function, documented by overexpression in mice, L6 myotubes, INS1 cells, muscle, and yeast. In a few cases (yeast), this protonophoric function was correlated with elevated fatty acid (FA) levels. Reconstituted UCPn exhibited nucleotide-sensitive FA induced H(+) uniport. Two mechanisms, local buffering or FA cycling were suggested as an explanation. A basic UCPn role with mild uncoupling is to accelerate metabolism and reduce reactive oxygen species. UCP2 (UCP3) roles were inferred from transcriptional up-regulation mediated by FAs via peroxisome proliferator-activated receptors, cytokines, leptin signalling via hypothalamic pathway, and by thyroide and beta2 adrenergic stimulation. The latter indicated a role in catecholamine-induced thermogenesis in skeletal muscle. UCP2 (UCP3) may contribute to body weight regulation, although obesity was not induced in knockout (KO) mice. An obesity reduction in middle-aged humans was associated with the less common allele of -866 G/A polymorphism in the ucp2 gene promoter enhancing the exon 8 insertion: deletion transcript ratio. Up-regulated UCP2 transcription by pyrogenic cytokines (tumour necrosis factor alpha (TNFalpha)) suggested a role in fever. UCP2 could induce type 2 diabetes as developed from obesity due to up-regulated UCP2 transcription by FAs in pancreatic beta-cells. UCPn might be pro-apoptotic as well as anti-apoptotic, depending on transcriptional and biochemical regulation. Copyright 2002 Elsevier Science Ltd.


When relevant for the function

  • Primary structure
  • Secondary structure
  • Tertiary structure
  • Quaternary structure

UCP1brown adipose tissue 4q31
UCP2all tissues, muscle, white adip. t.11q13
UCP3skeletal muscle, heart11q13
UCP4adult and fetal brain"6p11.2-q12":
UCP5brain, pituitary, testisXq24


mRNA synthesis
protein synthesis
post-translational modifications


cellular localization,
biological function

  • Enzymes
  • Cell signaling and Ligand transport
  • Structural proteins


Uncoupling protein 3 and physical activity: the role of uncoupling protein 3 in energy metabolism revisited. 2003

Only a minimal physical activity is required to downregulate UCP3

Involvement of the vitamin D receptor in energy metabolism: regulation of uncoupling proteins.
Am J Physiol Endocrinol Metab. 2009 Apr;296(4):E820-8. Epub 2009 Jan 27.
Wong KE, Szeto FL, Zhang W, Ye H, Kong J, Zhang Z, Sun XJ, Li YC.

Department of Medicine, Committee on Molecular Metabolism and Nutrition, The University of Chicago, MC 4076, 5841 S. Maryland Ave., Chicago, IL 60637, USA.

Recent studies have established that vitamin D plays multiple biological roles beyond calcium metabolism; however, whether vitamin D is involved in energy metabolism is unknown. To address this question, we characterized the metabolic phenotypes of vitamin D receptor (VDR)-null mutant mice. Under a normocalcemic condition, VDR-null mice displayed less body fat mass and lower plasma triglyceride and cholesterol levels compared with wild-type (WT) mice; when placed on a high-fat diet, VDR-null mice showed a slower growth rate and accumulated less fat mass globally than WT mice, even though their food intake and intestinal lipid transport capacity were the same as WT mice. Consistent with the lower adipose mass, plasma leptin levels were lower and white adipocytes were histologically smaller in VDR-null mice than WT mice. The rate of fatty acid beta-oxidation in the white adipose tissue was higher, and the expression of uncoupling protein (UCP) 1, UCP2 and UCP3 was markedly upregulated in VDR-null mice, suggesting a higher energy expenditure in the mutant mice. Experiments using primary brown fat culture confirmed that 1,25-dihydroxyvitamin D3 directly suppressed the expression of the UCPs. Consistently, the energy expenditure, oxygen consumption, and CO2 production in VDR-null mice were markedly higher than in WT mice. These data indicate that vitamin D is involved in energy metabolism and adipocyte biology in vivo in part through regulation of beta-oxidation and UCP expression.


Iron regulatory protein 1 sustains mitochondrial iron loading and function in frataxin deficiency. 2015

Mitochondrial iron accumulation is a hallmark of diseases associated with impaired iron-sulfur cluster (Fe-S) biogenesis, such as Friedreich ataxia linked to frataxin (FXN) deficiency. The pathophysiological relevance of the mitochondrial iron loading and the underlying mechanisms are unknown. Using a mouse model of hepatic FXN deficiency in combination with mice deficient for iron regulatory protein 1 (IRP1), a key regulator of cellular iron metabolism, we show that IRP1 activation in conditions of Fe-S deficiency increases the available cytosolic labile iron pool. Surprisingly, our data indicate that IRP1 activation sustains mitochondrial iron supply and function rather than driving detrimental iron overload. Mitochondrial iron accumulation is shown to depend on mitochondrial dysfunction and heme-dependent upregulation of the mitochondrial iron importer mitoferrin-2. Our results uncover an unexpected protective role of IRP1 in pathological conditions associated with altered Fe-S metabolism.

close friends of UCP2


Identification of distal cis-regulatory elements at mouse mitoferrin loci using zebrafish transgenesis. 2011

Mitoferrin 1 (Mfrn1; Slc25a37) and mitoferrin 2 (Mfrn2; Slc25a28) function as essential mitochondrial iron importers for heme and Fe/S cluster biogenesis. A genetic deficiency of Mfrn1 results in a profound hypochromic anemia in vertebrate species. To map the cis-regulatory modules (CRMs) that control expression of the Mfrn genes, we utilized genome-wide chromatin immunoprecipitation (ChIP) datasets for the major erythroid transcription factor GATA-1.

Sustained expression of heme oxygenase-1 alters iron homeostasis in nonerythroid cells. 2012

Sustained HO-1 activity increased the expression of both the mitochondrial iron importer mitoferrin-2 and the rate-limiting enzyme in heme synthesis, aminolevulinate synthase-1, and it augmented the mitochondrial content of heme.

Monitoring changes in gene expression in renal ischemia-reperfusion in the rat. 2002
Nine genes were up-regulated (ADAM2, HO-1, UCP-2, and thymosin beta4 in the early phase and clusterin, vanin1, fibronectin, heat-responsive protein 12 and FK506 binding protein in the established phase), whereas another nine were down-regulated (glutamine synthetase, cytochrome p450 IId6, and cyp 2d9 in the early phase and cyp 4a14, Xist gene, PPARgamma, alpha-albumin, uromodulin, and ADH B2 in the established phase).

Postprandial cell defense system responses to meal formulations: stratification through gene expression profiling. 2014
SIRT 1, UCP2, HO1, GSS, PTGS2, TP53, CDKN2A, PPIA, SOCS3, and APE1 expression profiles revealed distinct stratified subgroups associated with plasma HDLs, TNF-α and postprandial responses of SOCS3, and PPIA.

Ucp2 and phagocytosis - Results from Quetzal® linguistic biomedical search

bafilomycin respiratory chain - Results from Quetzal® linguistic biomedical search

Endoplasmic reticulum-mitochondria crosstalk in NIX-mediated murine

erythropoiesis ucp - Results from Quetzal® linguistic biomedical search

Iron uptake and ferritin synthesis in human erythroblasts.

Enrichment of erythroblasts from human bone marrow using complement-mediated lysis: measurement of ferritin.

erythroblasts ferritin - Results from Quetzal® linguistic biomedical search

Molecular evolution of UCP1 and the evolutionary history of mammalian

non-shivering thermogenesis. - PubMed - NCBI

Tabella UCP diverse specie

Dietary modification dampens liver inflammation and fibrosis in obesity-related fatty liver disease. - PubMed - NCBI

Mitochondrial uncoupling: role of uncoupling protein anion carriers and relationship to thermogenesis and weight control the benefits of losing co... - PubMed - NCBI

Calcitriol and energy metabolism. - PubMed - NCBI

Expression of uncoupling protein 2 on macrophages and its relation to interleukin-10/interferon ratio in patients with unexplained recurrent spont.

macrophages ucp - Results from Quetzal® linguistic biomedical search

macrophages lysosomes v-atpase - Cerca con Google

Regulation of uncoupling protein 2 expression by long-chain fatty acids and hormones in bovine mammary epithelial cells. 2008

Although mammary epithelial cells are known to synthesize and accumulate triacylglycerol (TAG) in order to produce milk lipid in the cytosol, lipid and energy metabolism is still not fully understood. In this study, we assessed the effects of long-chain fatty acid (LCFA) on the accumulation of cytosolic TAG and uncoupling protein (UCP) 2 in cloned bovine mammary epithelial cells (bMEC). LCFAs significantly raised the expression of UCP2 mRNA and the accumulation of TAG. We observed the rapid elevation in UCP2 shown at 6h after LCFA treatment. Insulin (5-50 ng/ml) or dexamethasone (500 nM) significantly suppressed the expression of UCP2 mRNA. These results suggest that UCP2 play an important role of lipid and energy metabolism in mammary epithelial cells.

UCP2 and hormone

Uncoupling protein 2 and 4 expression pattern during stem cell differentiation provides new insight into their putative function. 2014

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.


The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP, 2000

Mitochondrial uncoupling proteins in human physiology and disease. 2002

2016-09-13T21:40:53 - Gianpiero Pescarmona



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