Mini-review
The mitochondrial uncoupling protein-2: current status

https://doi.org/10.1016/S1357-2725(99)00049-7Get rights and content

Abstract

In eukaryotic cells ATP is generated by oxidative phosphorylation, an energetic coupling at the mitochondrial level. The oxidative reactions occurring in the respiratory chain generate an electrochemical proton gradient on both sides of the inner membrane. This gradient is used by the ATPsynthase to phosphorylate ADP into ATP. The coupling between respiration and ADP phosphorylation is only partial in brown adipose tissue (BAT) mitochondria, where the uncoupling protein UCP1 causes a reentry of protons into the matrix and abolishes the electrochemical proton gradient. The liberated energy is then dissipated as heat and ATP synthesis is reduced. This property was for a long time considered as an exception and specific to the non-shivering thermogenesis found in BAT. The recent cloning of new UCPs expressed in other tissues revealed the importance of this kind of regulation of respiratory control in metabolism and energy expenditure. The newly characterised UCPs are potential targets for obesity treatment drugs which could favour energy expenditure and diminish the metabolic efficiency.

In 1997, we cloned UCP2 and proposed a role for this new uncoupling protein in diet-induced thermogenesis, obesity, hyperinsulinemia, fever and resting metabolic rate. Currently, an abundant literature deals with UCP2, but its biochemical and physiological functions and regulation remain unclear. The present review reports the status of our knowledge of this mitochondrial carrier in terms of sequence, activity, tissue distribution and regulation of expression. The putative physiological roles of UCP2 will be introduced and discussed.

Section snippets

UCP2: a new member of the mitochondrial carriers

Mitchell's chemio-osmotic theory requires a coupling between electron transport by the respiratory chain (respiration) and ATP synthesis (phosphorylation) at the mitochondrial level. However, the mitochondrial coupling of oxygen consumption to ADP phosphorylation is only partial in most cells. The impermeability of protons to the inner mitochondrial membrane appears to be an essential component of the coupling (Fig. 1). Nevertheless the mechanisms involved in modifying proton conductance of the

Tissue distribution in human and rodents

In contrast to the specific localisation of UCP1 in BAT, and UCP3 in skeletal muscle, heart and BAT, UCP2 has a nearly ubiquitous pattern of expression [29], [31]. Fig. 6 shows the pattern of mRNA expression of the different members of the UCP family in rodents.

Regulation of UCP2 expression (see Table 1)

Unlike UCP1, no reliable specific anti-UCP2 antibody is currently available and all the studies of regulation of UCP2 expression are based on the measurement of mRNA levels. Several molecules and various physiological situations involved in the control of energy balance, have been studied for their influence on UCP2 expression.

UCP2 in obesity and diabetes

Since UCP2 may play a role in energy dissipation, several groups have studied its regulation in mouse and human obesity and diabetes, situations with altered energy homeostasis. That UCP2 regulation may be relevant to the physiology of obesity was first suggested by the observation that message levels increased in several mice strains fed on a high fat diet [29]. In several models of animal obesity, the level of UCP2 mRNA is increased in comparison with lean controls [31], but this is not

Directions for future research

A role for UCP2 in the fever response to infection seems plausible and could allow a better understanding of the molecular mechanisms controlling fever. Indeed, Faggioni et al. [28] administered lipopolysaccharids (LPS) to mice and observed an increase of body temperature (fever) and of the UCP2 mRNA level in liver. Indomethacin, an antipyretic drug reversed these effects. This field of investigation seems attractive and a putative role of UCP2 in the cells of the immune system, especially in

Acknowledgements

CF was supported by a Ph.D. thesis fellowship of the Direction des Recherches, Etudes et Techniques and by Institut Danone, DS is owner of a ‘Human Mobility Program’ grant from the European Union Research. The laboratory was supported by the Centre National de la Recherche Scientifique, the Association pour la Recherche contre le Cancer, AFM and Laboratoires Servier. We thank Dr Daniel Ricquier, Dr Bruno Miroux, Dr Ian Colison and Dr Roger Karess for reading the manuscript and Dr Marta Llovera

References (99)

  • F. Denjean et al.

    Differential regulation of uncoupling protein 1, 2 and 3 gene expression by sympathetic innervation in brown adipose tissue of thermoneutral or cold-exposed rats

    FEBS Lett.

    (1999)
  • V. Emilsson et al.

    The effects of the beta3-adrenoceptor agonist BRL 35135 on UCP isoform mRNA expression

    Biochem. Biophys. Res. Commun.

    (1998)
  • R. Faggioni et al.

    Induction of UCP2 gene expression by LPS: a potential mechanism for increased thermogenesis during infection

    Biochem. Biophys. Res. Commun.

    (1998)
  • K.D. Garlid et al.

    The mechanism of proton transport mediated by mitochondrial uncoupling proteins

    FEBS Lett.

    (1998)
  • D.W. Gong et al.

    Uncoupling protein-3 is a mediator of thermogenesis regulated by thyroid hormone, 3-adrenergic agonists, and leptin

    J. Biol. Chem.

    (1997)
  • D.W. Gong et al.

    Genomic organization and regulation by dietary fat of the uncoupling protein 3 and 2 genes

    Biochim. Biophys. Res. Commun.

    (1999)
  • M.M. Gonzalez-Barroso et al.

    The uncoupling protein UCP1 does not increase the proton conductance of the inner mitochondrial membrane by functioning as a fatty acid anion transporter

    J. Biol. Chem.

    (1998)
  • S. Hidaka et al.

    Molecular cloning of rat uncoupling protein 2 cDNA and its expression in genetically obese Zucker fatty (fa/fa) rats

    Biochim. Biophys. Acta

    (1998)
  • Z. Hodny et al.

    High expression of uncoupling protein 2 in foetal liver

    FEBS Lett.

    (1998)
  • P. Jezek et al.

    Fatty acid cycling mechanism and mitochondrial uncoupling proteins

    Biochim. Biophys. Acta

    (1998)
  • H. Kageyama et al.

    Increased uncoupling protein-2 and -3 gene expressions in skeletal muscle of STZ-induced diabetic rats

    FEBS Lett.

    (1998)
  • A. Lanni et al.

    Induction of UCP2 mRNA by thyroid hormones in rat heart

    FEBS Lett.

    (1997)
  • D. Larrouy et al.

    Kupffer cells are a dominant site of uncoupling protein 2 expression in rat liver

    Biochim. Biophys. Res. Commun.

    (1997)
  • I.G. Maia et al.

    AtPUMP: an Arabidopsis gene encoding a plant uncoupling mitochondrial protein

    FEBS Lett.

    (1998)
  • T. Masaki et al.

    Enhanced expression of uncoupling protein 2 gene in rat WAT and skeletal muscle following chronic treatment with thyroidhormone

    FEBS Lett.

    (1997)
  • J. Matsuda et al.

    Cloning of rat uncoupling-3 and uncoupling protein-2 cDNAs: their gene expression in rats fed high-fat diet

    FEBS Lett.

    (1997)
  • C. Nobes et al.

    Non-ohmic proton conductance of the mitochondrial inner membrane in hepatocytes

    J. Biol. Chem.

    (1990)
  • C. Pecqueur et al.

    Functional organization of the human uncoupling protein-2 gene, and juxtaposition to the uncoupling protein-3 gene

    Biochim. Biophys. Res. Commun.

    (1999)
  • D. Sanchis et al.

    Skeletal muscle UCP2 and UCP3 gene expression in a rat cancer cachexia model

    FEBS Lett.

    (1998)
  • D. Sanchis et al.

    BMCP1, a novel mitochondrial carrier with high expression in the central nervous system of humans and rodents, and respiration uncoupling activity in recombinant yeast

    J. Biol. Chem.

    (1998)
  • M. Shimabukuro et al.

    Induction of uncoupling protein-2 mRNA by troglytazone in the pancreatic islets of Zucker diabetic fatty rat

    Biochem. Biophys. Res. Commun.

    (1997)
  • T. Shimokawa et al.

    In vivo effects of Pioglitazone on uncoupling protein-2 and -3 mRNA levels in skeletal muscle of hyperglycemic KK mice

    Biochim. Biophys. Res. Commun.

    (1998)
  • R.A. Simonyan et al.

    Thermoregulatory uncoupling in heart muscle mitochondria: involvement of the ATP/ADP antiporter and uncoupling protein

    FEBS Lett.

    (1998)
  • V.P. Skulachev

    Uncoupling: new approaches to an old problem of bioenergetics

    Biochim. Biophys. Acta

    (1998)
  • N. Tsuboyama-Kasaoka et al.

    Up-regulation of uncoupling protein 3 (UCP3) mRNA by exercise training and down-regulation of UCP3 by denervation in skeletal muscles

    Biochim. Biophys. Res. Commun.

    (1998)
  • A. Vidal-Puig et al.

    UCP3: an uncoupling protein homologue expressed preferentially and abundantly in skeletal muscle and brown adipose tissue

    Biochim. Biophys. Res. Commun.

    (1997)
  • M. Yamada et al.

    Genomic organization and promoter function of the mouse uncoupling protein 2 (UCP2) gene

    FEBS Lett.

    (1998)
  • H. Yoshitomi et al.

    Differential regulation of mouse uncoupling proteins among brown adipose tissue, WAT, and skeletal muscle in chronic beta 3 adrenergic receptor agonist treatment

    Biochim. Biophys. Res. Commun.

    (1998)
  • S. Bao et al.

    Expression of mRNAs encoding uncoupling proteins in human skeletal muscle: effects of obesity and diabetes

    Diabetes

    (1997)
  • L. Baozhen et al.

    Bidirectional regulation of uncoupling protein-3 and GLUT-4 mRNA in skeletal muscle by cold

    Am. J. Physiol.

    (1998)
  • P. Barbe et al.

    Uncoupling protein-2 messenger ribonucleic acid expression during very-low-calorie diet in obese premenopausal women

    J. Clin. Endocrinol. Metab.

    (1998)
  • O. Boss et al.

    Effect of endurance training on mRNA expression of uncoupling proteins 1, 2 and 3 in the rat

    FASEB J.

    (1998)
  • C. Bouchard et al.

    Linkage between markers in the vicinity of the uncoupling protein 2 gene and resting metabolic rate in humans

    Hum. Mol. Genet.

    (1997)
  • F. Bouillaud et al.

    A sequence related to a DNA recognition element is essential for the inhibition by nucleotides of proton transport through the mitochondrial uncoupling protein

    EMBO J.

    (1994)
  • R.P. Brun et al.

    Differential activation of adipogenesis by multiple PPAR isoforms

    Genet. & Dev.

    (1996)
  • F. Buttgereit et al.

    A hierarchy of ATP consuming processes in mammalian cells

    Biochem. J.

    (1995)
  • A. Camirand et al.

    Thiazolidinediones stimulate uncoupling protein-2 expression in cell lines representing white and Brown adipose tissue and skeletal muscle

    Endocrinology

    (1998)
  • T.P. Combatsiaris et al.

    Downregulation of uncoupling protein 2 mRNA in WAT and uncoupling protein 3 mRNA in skeletal muscle during the early stages of leptin treatment

    Diabetes

    (1999)
  • N. Cortright et al.

    Regulation of skeletal muscle UCP2 and UCP3 gene expression by exercise and denervation

    Am. J. Physiol.

    (1999)
  • Cited by (83)

    • AMPK activation by pterostilbene contributes to suppression of hepatic gluconeogenic gene expression and glucose production in H4IIE cells

      2018, Biochemical and Biophysical Research Communications
      Citation Excerpt :

      Since PPARα activation plays an important role in promoting the oxidation of activated acyl-CoA esters, through activation of medium acyl-coenzyme A dehydrogenase, ACO, and CPT-1 in mitochondria [20,21], our findings that pterostilbene activates gene expression of ACO, CPT-1, and UCP2 in H4IIE cells are consistent with its role of an activator of PPARα [9]. UCP2 plays a role in adaptive thermogenesis, lipid metabolism, and in the development of non-alcoholic fatty liver disease [22]. Further, UCP2 is an antioxidant mitochondrial protein leading to a downregulation of reactive oxygen species production [23].

    • Cranberry extract attenuates hepatic inflammation in high-fat-fed obese mice

      2016, Journal of Nutritional Biochemistry
      Citation Excerpt :

      This could imply that macrophage recruitment is decreased by CBE supplementation and macrophage polarization or inflammatory response by hepatocytes may be altered. Uncoupling protein 2 (UCP2) is embedded in the inner membrane of mitochondria in all tissues and is thought to have a role in regulating reactive oxygen species (ROS) [34]. UCP2 has also been suggested to have a role in promoting the pathogenesis of NASH and its expression is increased in response to increased plasma free fatty acids and hepatic steatosis.

    • Role of mitochondrial uncoupling protein 2 in cancer cell resistance to gemcitabine

      2012, Biochimica et Biophysica Acta - Molecular Cell Research
    • New aspects of melanocortin signaling: A role for PRCP in α-MSH degradation

      2011, Frontiers in Neuroendocrinology
      Citation Excerpt :

      The signaling modality by which T3 affects arcuate neurons seems to involve a thyroid hormone regulated mitochondrial protein, uncoupling protein 2 (UCP2; Fig. 1) [41,119]. UCP2, a protein belonging to a family of mitochondrial anion carrier, is located in the inner membrane of the mitochondria and its primary function is thought to leak hydrogen protons from the intermembrane space to the matrix of the mitochondria [16,71]. Through this process, UCP2 may affect ATP and superoxide production, and decrease the entry of calcium to the mitochondrial matrix [153].

    View all citing articles on Scopus
    View full text