Skip to main content
SpringerLink
Log in

UCP2, a mitochondrial protein regulated at multiple levels

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

An ever-increasing number of studies highlight the role of uncoupling protein 2 (UCP2) in a broad range of physiological and pathological processes. The knowledge of the molecular mechanisms of UCP2 regulation is becoming fundamental in both the comprehension of UCP2-related physiological events and the identification of novel therapeutic strategies based on UCP2 modulation. The study of UCP2 regulation is a fast-moving field. Recently, several research groups have made a great effort to thoroughly understand the various molecular mechanisms at the basis of UCP2 regulation. In this review, we describe novel findings concerning events that can occur in a concerted manner at various levels: Ucp2 gene mutation (single nucleotide polymorphisms), UCP2 mRNA and protein expression (transcriptional, translational, and protein turn-over regulation), UCP2 proton conductance (ligands and post-transcriptional modifications), and nutritional and pharmacological regulation of UCP2.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Brand MD, Brindle KM, Buckingham JA, Harper JA, Rolfe DF, Stuart JA (1999) The significance and mechanism of mitochondrial proton conductance. Int J Obes Relat Metab Disord 23(Suppl 6):S4–S11

    CAS  PubMed  Google Scholar 

  2. Klingenberg M (1999) Uncoupling protein—a useful energy dissipator. J Bioenergy Biomembr 31:419–430

    CAS  Google Scholar 

  3. Jezek P, Urbankova E (2000) Specific sequence of motifs of mitochondrial uncoupling proteins. IUBMB Life 49:63–70

    CAS  PubMed  Google Scholar 

  4. Andrews ZB, Diano S, Horvath TL (2005) Mitochondrial uncoupling proteins in the CNS: in support of function and survival. Nat Rev Neurosci 6:829–840

    CAS  PubMed  Google Scholar 

  5. Arsenijevic D, Onuma H, Pecqueur C, Raimbault S, Manning BS, Miroux B, Couplan E, Alves-Guerra MC, Goubern M, Surwit R et al (2000) Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat Genet 26:435–439

    CAS  PubMed  Google Scholar 

  6. Kong D, Vong L, Parton LE, Ye C, Tong Q, Hu X, Choi B, Bruning JC, Lowell BB (2010) Glucose stimulation of hypothalamic MCH neurons involves K(ATP) channels, is modulated by UCP2, and regulates peripheral glucose homeostasis. Cell Metab 12:545–552

    CAS  PubMed  Google Scholar 

  7. Krauss S, Zhang CY, Lowell BB (2005) The mitochondrial uncoupling-protein homologues. Nat Rev Mol Cell Biol 6:248–261

    CAS  PubMed  Google Scholar 

  8. Ledesma A, de Lacoba MG, Rial E (2002) The mitochondrial uncoupling proteins. Genome Biol 3:REVIEWS3015

    PubMed Central  PubMed  Google Scholar 

  9. Simon-Areces J, Dietrich MO, Hermes G, Garcia-Segura LM, Arevalo MA, Horvath TL (2012) UCP2 induced by natural birth regulates neuronal differentiation of the hippocampus and related adult behavior. PLoS ONE 7:e42911

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Yu XX, Barger JL, Boyer BB, Brand MD, Pan G, Adams SH (2000) Impact of endotoxin on UCP homolog mRNA abundance, thermoregulation, and mitochondrial proton leak kinetics. Am J Physiol Endocrinol Metab 279:E433–E446

    CAS  PubMed  Google Scholar 

  11. Berardi MJ, Shih WM, Harrison SC, Chou JJ (2011) Mitochondrial uncoupling protein 2 structure determined by NMR molecular fragment searching. Nature 476:109–113

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Jelokhani-Niaraki M, Ivanova MV, McIntyre BL, Newman CL, McSorley FR, Young EK, Smith MD (2008) A CD study of uncoupling protein-1 and its transmembrane and matrix-loop domains. Biochem J 411:593–603

    CAS  PubMed  Google Scholar 

  13. Echtay KS (2007) Mitochondrial uncoupling proteins—what is their physiological role? Free Radic Biol Med 43:1351–1371

    CAS  PubMed  Google Scholar 

  14. Keller PA, Lehr L, Giacobino JP, Charnay Y, Assimacopoulos-Jeannet F, Giovannini N (2005) Cloning, ontogenesis, and localization of an atypical uncoupling protein 4 in Xenopus laevis. Physiol Genomics 22:339–345

    CAS  PubMed  Google Scholar 

  15. Hanak P, Jezek P (2001) Mitochondrial uncoupling proteins and phylogenesis—UCP4 as the ancestral uncoupling protein. FEBS Lett 495:137–141

    CAS  PubMed  Google Scholar 

  16. Richard D, Picard F (2011) Brown fat biology and thermogenesis. Front Biosci 16:1233–1260

    CAS  Google Scholar 

  17. Garlid KD, Jaburek M, Jezek P, Varecha M (2000) How do uncoupling proteins uncouple? Biochim Biophys Acta 1459:383–389

    CAS  PubMed  Google Scholar 

  18. Diao J, Allister EM, Koshkin V, Lee SC, Bhattacharjee A, Tang C, Giacca A, Chan CB, Wheeler MB (2008) UCP2 is highly expressed in pancreatic alpha-cells and influences secretion and survival. Proc Natl Acad Sci USA 105:12057–12062

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Emre Y, Hurtaud C, Karaca M, Nubel T, Zavala F, Ricquier D (2007) Role of uncoupling protein UCP2 in cell-mediated immunity: how macrophage-mediated insulitis is accelerated in a model of autoimmune diabetes. Proc Natl Acad Sci USA 104:19085–19090

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Klingenberg M, Huang SG (1999) Structure and function of the uncoupling protein from brown adipose tissue. Biochim Biophys Acta 1415:271–296

    CAS  PubMed  Google Scholar 

  21. Hoang T, Smith MD, Jelokhani-Niaraki M (2012) Toward understanding the mechanism of ion transport activity of neuronal uncoupling proteins UCP2, UCP4, and UCP5. Biochemistry 51:4004–4014

    CAS  PubMed  Google Scholar 

  22. Borecky J, Maia IG, Arruda P (2001) Mitochondrial uncoupling proteins in mammals and plants. Biosci Rep 21:201–212

    CAS  PubMed  Google Scholar 

  23. Couplan E, del Mar Gonzalez-Barroso M, Alves-Guerra MC, Ricquier D, Goubern M, Bouillaud F (2002) No evidence for a basal, retinoic, or superoxide-induced uncoupling activity of the uncoupling protein 2 present in spleen or lung mitochondria. J Biol Chem 277:26268–26275

    CAS  PubMed  Google Scholar 

  24. Cadenas S, Buckingham JA, Samec S, Seydoux J, Din N, Dulloo AG, Brand MD (1999) UCP2 and UCP3 rise in starved rat skeletal muscle but mitochondrial proton conductance is unchanged. FEBS Lett 462:257–260

    CAS  PubMed  Google Scholar 

  25. Zhang CY, Baffy G, Perret P, Krauss S, Peroni O, Grujic D, Hagen T, Vidal-Puig AJ, Boss O, Kim YB et al (2001) Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes. Cell 105:745–755

    CAS  PubMed  Google Scholar 

  26. Pecqueur C, Bui T, Gelly C, Hauchard J, Barbot C, Bouillaud F, Ricquier D, Miroux B, Thompson CB (2008) Uncoupling protein-2 controls proliferation by promoting fatty acid oxidation and limiting glycolysis-derived pyruvate utilization. FASEB J 22:9–18

    CAS  PubMed  Google Scholar 

  27. Cannon B, Shabalina IG, Kramarova TV, Petrovic N, Nedergaard J (2006) Uncoupling proteins: a role in protection against reactive oxygen species—or not? Biochim Biophys Acta 1757:449–458

    CAS  PubMed  Google Scholar 

  28. Nedergaard J, Cannon B (2003) The ‘novel’ ‘uncoupling’ proteins UCP2 and UCP3: what do they really do? Pros and cons for suggested functions. Exp Physiol 88:65–84

    CAS  PubMed  Google Scholar 

  29. Nicholls DG (2006) The physiological regulation of uncoupling proteins. Biochim Biophys Acta 1757:459–466

    CAS  PubMed  Google Scholar 

  30. Nubel T, Emre Y, Rabier D, Chadefaux B, Ricquier D, Bouillaud F (2008) Modified glutamine catabolism in macrophages of Ucp2 knock-out mice. Biochim Biophys Acta 1777:48–54

    PubMed  Google Scholar 

  31. Produit-Zengaffinen N, Davis-Lameloise N, Perreten H, Becard D, Gjinovci A, Keller PA, Wollheim CB, Herrera P, Muzzin P, Assimacopoulos-Jeannet F (2007) Increasing uncoupling protein-2 in pancreatic beta cells does not alter glucose-induced insulin secretion but decreases production of reactive oxygen species. Diabetologia 50:84–93

    CAS  PubMed  Google Scholar 

  32. Shabalina IG, Nedergaard J (2011) Mitochondrial (‘mild’) uncoupling and ROS production: physiologically relevant or not? Biochem Soc Trans 39:1305–1309

    CAS  PubMed  Google Scholar 

  33. Blanc J, Alves-Guerra MC, Esposito B, Rousset S, Gourdy P, Ricquier D, Tedgui A, Miroux B, Mallat Z (2003) Protective role of uncoupling protein 2 in atherosclerosis. Circulation 107:388–390

    CAS  PubMed  Google Scholar 

  34. Moukdar F, Robidoux J, Lyght O, Pi J, Daniel KW, Collins S (2009) Reduced antioxidant capacity and diet-induced atherosclerosis in uncoupling protein-2-deficient mice. J Lipid Res 50:59–70

    CAS  PubMed  Google Scholar 

  35. Rousset S, Emre Y, Join-Lambert O, Hurtaud C, Ricquier D, Cassard-Doulcier AM (2006) The uncoupling protein 2 modulates the cytokine balance in innate immunity. Cytokine 35:135–142

    CAS  PubMed  Google Scholar 

  36. Rupprecht A, Brauer AU, Smorodchenko A, Goyn J, Hilse KE, Shabalina IG, Infante-Duarte C, Pohl EE (2012) Quantification of uncoupling protein 2 reveals its main expression in immune cells and selective up-regulation during T-cell proliferation. PLoS ONE 7:e41406

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Diano S, Horvath TL (2012) Mitochondrial uncoupling protein 2 (UCP2) in glucose and lipid metabolism. Trends Mol Med 18:52–58

    CAS  PubMed  Google Scholar 

  38. Derdak Z, Mark NM, Beldi G, Robson SC, Wands JR, Baffy G (2008) The mitochondrial uncoupling protein-2 promotes chemoresistance in cancer cells. Cancer Res 68:2813–2819

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Robbins D, Zhao Y (2011) New aspects of mitochondrial uncoupling proteins (UCPs) and their roles in tumorigenesis. Int J Mol Sci 12:5285–5293

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Su WP, Lo YC, Yan JJ, Liao IC, Tsai PJ, Wang HC, Yeh HH, Lin CC, Chen HH, Lai WW et al (2012) Mitochondrial uncoupling protein 2 regulates the effects of paclitaxel on Stat3 activation and cellular survival in lung cancer cells. Carcinogenesis 33:2065–2075

    CAS  PubMed  Google Scholar 

  41. Zhang K, Shang Y, Liao S, Zhang W, Nian H, Liu Y, Chen Q, Han C (2007) Uncoupling protein 2 protects testicular germ cells from hyperthermia-induced apoptosis. Biochem Biophys Res Commun 360:327–332

    CAS  PubMed  Google Scholar 

  42. Harper ME, Antoniou A, Villalobos-Menuey E, Russo A, Trauger R, Vendemelio M, George A, Bartholomew R, Carlo D, Shaikh A et al (2002) Characterization of a novel metabolic strategy used by drug-resistant tumor cells. FASEB J 16:1550–1557

    CAS  PubMed  Google Scholar 

  43. Derdak Z, Fulop P, Sabo E, Tavares R, Berthiaume EP, Resnick MB, Paragh G, Wands JR, Baffy G (2006) Enhanced colon tumor induction in uncoupling protein-2 deficient mice is associated with NF-kappaB activation and oxidative stress. Carcinogenesis 27:956–961

    CAS  PubMed  Google Scholar 

  44. Kuai XY, Ji ZY, Zhang HJ (2010) Mitochondrial uncoupling protein 2 expression in colon cancer and its clinical significance. World J Gastroenterol 16:5773–5778

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Clemons M, Goss P (2001) Estrogen and the risk of breast cancer. N Engl J Med 344:276–285

    CAS  PubMed  Google Scholar 

  46. Felty Q, Singh KP, Roy D (2005) Estrogen-induced G1/S transition of G0-arrested estrogen-dependent breast cancer cells is regulated by mitochondrial oxidant signaling. Oncogene 24:4883–4893

    CAS  PubMed  Google Scholar 

  47. Sastre-Serra J, Valle A, Company MM, Garau I, Oliver J, Roca P (2010) Estrogen down-regulates uncoupling proteins and increases oxidative stress in breast cancer. Free Radic Biol Med 48:506–512

    CAS  PubMed  Google Scholar 

  48. Ayyasamy V, Owens KM, Desouki MM, Liang P, Bakin A, Thangaraj K, Buchsbaum DJ, LoBuglio AF, Singh KK (2011) Cellular model of Warburg effect identifies tumor promoting function of UCP2 in breast cancer and its suppression by genipin. PLoS ONE 6:e24792

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Sayeed A, Meng Z, Luciani G, Chen LC, Bennington JL, Dairkee SH (2010) Negative regulation of UCP2 by TGFbeta signaling characterizes low and intermediate-grade primary breast cancer. Cell Death Dis 1:e53

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Wang F, Fu X, Chen X, Chen X, Zhao Y (2010) Mitochondrial uncoupling inhibits p53 mitochondrial translocation in TPA-challenged skin epidermal JB6 cells. PLoS ONE 5:e13459

    PubMed Central  PubMed  Google Scholar 

  51. Dalla Pozza E, Fiorini C, Dando I, Menegazzi M, Sgarbossa A, Costanzo C, Palmieri M, Donadelli M (2012) Role of mitochondrial uncoupling protein 2 in cancer cell resistance to gemcitabine. Biochim Biophys Acta 1823:1856–1863

    CAS  PubMed  Google Scholar 

  52. Dando I, Fiorini C, Pozza ED, Padroni C, Costanzo C, Palmieri M, Donadelli M (2013) UCP2 inhibition triggers ROS-dependent nuclear translocation of GAPDH and autophagic cell death in pancreatic adenocarcinoma cells. Biochim Biophys Acta 1833:672–679

    CAS  PubMed  Google Scholar 

  53. Mailloux RJ, Adjeitey CN, Harper ME (2010) Genipin-induced inhibition of uncoupling protein-2 sensitizes drug-resistant cancer cells to cytotoxic agents. PLoS ONE 5:e13289

    PubMed Central  PubMed  Google Scholar 

  54. Warburg O (1956) On the origin of cancer cells. Science 123:309–314

    CAS  PubMed  Google Scholar 

  55. Samudio I, Fiegl M, McQueen T, Clise-Dwyer K, Andreeff M (2008) The Warburg effect in leukemia-stroma cocultures is mediated by mitochondrial uncoupling associated with uncoupling protein 2 activation. Cancer Res 68:5198–5205

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Dalgaard LT (2011) 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). J Obes 2011:340241

    PubMed Central  PubMed  Google Scholar 

  57. Dalgaard LT, Andersen G, Larsen LH, Sorensen TI, Andersen T, Drivsholm T, Borch-Johnsen K, Fleckner J, Hansen T, Din N et al (2003) Mutational analysis of the UCP2 core promoter and relationships of variants with obesity. Obes Res 11:1420–1427

    CAS  PubMed  Google Scholar 

  58. Krempler F, Esterbauer H, Weitgasser R, Ebenbichler C, Patsch JR, Miller K, Xie M, Linnemayr V, Oberkofler H, Patsch W (2002) A functional polymorphism in the promoter of UCP2 enhances obesity risk but reduces type 2 diabetes risk in obese middle-aged humans. Diabetes 51:3331–3335

    CAS  PubMed  Google Scholar 

  59. Lapice E, Pinelli M, Pisu E, Monticelli A, Gambino R, Pagano G, Valsecchi S, Cocozza S, Riccardi G, Vaccaro O (2010) Uncoupling protein 2 G(−866)A polymorphism: a new gene polymorphism associated with C-reactive protein in type 2 diabetic patients. Cardiovasc Diabetol 9:68

    PubMed Central  PubMed  Google Scholar 

  60. Sesti G, Cardellini M, Marini MA, Frontoni S, D’Adamo M, Del Guerra S, Lauro D, De Nicolais P, Sbraccia P, Del Prato S et al (2003) A common polymorphism in the promoter of UCP2 contributes to the variation in insulin secretion in glucose-tolerant subjects. Diabetes 52:1280–1283

    CAS  PubMed  Google Scholar 

  61. Yang M, Huang Q, Wu J, Yin JY, Sun H, Liu HL, Zhou HH, Liu ZQ (2009) Effects of UCP2 −866 G/A and ADRB3 Trp64Arg on rosiglitazone response in Chinese patients with type 2 diabetes. Br J Clin Pharmacol 68:14–22

    PubMed Central  PubMed  Google Scholar 

  62. Srivastava N, Prakash J, Lakhan R, Agarwal CG, Pant DC, Mittal B (2009) A common polymorphism in the promoter of UCP2 is associated with obesity and hyperinsulenemia in northern Indians. Mol Cell Biochem 337:293–298

    PubMed  Google Scholar 

  63. Andersen G, Dalgaard LT, Justesen JM, Anthonsen S, Nielsen T, Thorner LW, Witte D, Jorgensen T, Clausen JO, Lauritzen T et al (2012) The frequent UCP2 −866G>A polymorphism protects against insulin resistance and is associated with obesity: a study of obesity and related metabolic traits among 17,636 Danes. Int J Obes (London) 37:175–181

    Google Scholar 

  64. Hamada T, Kotani K, Fujiwara S, Sano Y, Domichi M, Tsuzaki K, Takahashi K, Sakane N (2008) The UCP2-866 A/A genotype is associated with low density lipoprotein particle sizes in the general population. Med Sci Monit 14:107–111

    Google Scholar 

  65. Tribble DL, Holl LG, Wood PD, Krauss RM (1992) Variations in oxidative susceptibility among six low density lipoprotein subfractions of differing density and particle size. Atherosclerosis 93:189–199

    CAS  PubMed  Google Scholar 

  66. Ehara S, Ueda M, Naruko T, Haze K, Itoh A, Otsuka M, Komatsu R, Matsuo T, Itabe H, Takano T et al (2001) Elevated levels of oxidized low density lipoprotein show a positive relationship with the severity of acute coronary syndromes. Circulation 103:1955–1960

    CAS  PubMed  Google Scholar 

  67. Palmer BR, Devereaux CL, Dhamrait SS, Mocatta TJ, Pilbrow AP, Frampton CM, Skelton L, Yandle TG, Winterbourn CC, Richards AM et al (2009) The common G−866A polymorphism of the UCP2 gene and survival in diabetic patients following myocardial infarction. Cardiovasc Diabetol 8:31

    PubMed Central  PubMed  Google Scholar 

  68. Xu K, Zhang M, Cui D, Fu Y, Qian L, Gu R, Wang M, Shen C, Yu R, Yang T (2011) UCP2 −866G/A and Ala55 Val, and UCP3 −55C/T polymorphisms in association with type 2 diabetes susceptibility: a meta-analysis study. Diabetologia 54:2315–2324

    CAS  PubMed  Google Scholar 

  69. Willig AL, Casazza KR, Divers J, Bigham AW, Gower BA, Hunter GR, Fernandez JR (2009) Uncoupling protein 2 Ala55Val polymorphism is associated with a higher acute insulin response to glucose. Metabolism 58:877–881

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Vimaleswaran KS, Radha V, Ghosh S, Majumder PP, Sathyanarayana Rao MR, Mohan V (2011) Uncoupling protein 2 and 3 gene polymorphisms and their association with type 2 diabetes in Asian Indians. Diabetes Technol Ther 13:19–25

    CAS  PubMed  Google Scholar 

  71. Heidema AG, Wang P, van Rossum CT, Feskens EJ, Boer JM, Bouwman FG, Van’t Veer P, Mariman EC (2010) Sex-specific effects of CNTF, IL6 and UCP2 polymorphisms on weight gain. Physiol Behav 99:1–7

    CAS  PubMed  Google Scholar 

  72. Chen HH, Lee WJ, Wang W, Huang MT, Lee YC, Pan WH (2007) Ala55Val polymorphism on UCP2 gene predicts greater weight loss in morbidly obese patients undergoing gastric banding. Obes Surg 17:926–933

    PubMed  Google Scholar 

  73. Rance KA, Johnstone AM, Murison S, Duncan JS, Wood SG, Speakman JR (2007) Plasma leptin levels are related to body composition, sex, insulin levels and the A55V polymorphism of the UCP2 gene. Int J Obes (London) 31:1311–1318

    CAS  Google Scholar 

  74. Rose G, Crocco P, De Rango F, Montesanto A, Passarino G (2011) Further support to the uncoupling-to-survive theory: the genetic variation of human UCP genes is associated with longevity. PLoS ONE 6:e29650

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Lee HJ, Ryu HJ, Shin HD, Park BL, Kim JY, Cho YM, Park KS, Song J, Oh B (2008) Associations between polymorphisms in the mitochondrial uncoupling proteins (UCPs) with T2DM. Clin Chim Acta 398:27–33

    CAS  PubMed  Google Scholar 

  76. Balakrishnan VS, Rao M (2007) Genetics and reverse epidemiology among patients on chronic hemodialysis. Semin Dial 20:570–576

    PubMed  Google Scholar 

  77. Gonzalez-Barroso MM, Giurgea I, Bouillaud F, Anedda A, Bellanne-Chantelot C, Hubert L, de Keyzer Y, de Lonlay P, Ricquier D (2008) Mutations in UCP2 in congenital hyperinsulinism reveal a role for regulation of insulin secretion. PLoS ONE 3:e3850

    PubMed Central  PubMed  Google Scholar 

  78. Lee YH, Kim W, Yu BC, Park BL, Kim LH, Shin HD (2008) Association of the ins/del polymorphisms of uncoupling protein 2 (UCP2) with BMI in a Korean population. Biochem Biophys Res Commun 371:767–771

    CAS  PubMed  Google Scholar 

  79. Srivastava A, Rock C, Zhang K, Ruan M, Bolander ME, Sarkar G (2006) Expression of a novel alternatively spliced UCP-2 transcript in osteogenic sarcoma. J Orthop Sci 11:51–57

    CAS  PubMed  Google Scholar 

  80. Martinez-Hervas S, Mansego ML, de Marco G, Martinez F, Alonso MP, Morcillo S, Rojo-Martinez G, Real JT, Ascaso JF, Redon J et al (2012) Polymorphisms of the UCP2 gene are associated with body fat distribution and risk of abdominal obesity in Spanish population. Eur J Clin Invest 42:171–178

    CAS  PubMed  Google Scholar 

  81. Hsiao TJ, Wu LS, Hwang Y, Huang SY, Lin E (2010) Effect of the common −866G/A polymorphism of the uncoupling protein 2 gene on weight loss and body composition under sibutramine therapy in an obese Taiwanese population. Mol Diagn Ther 14:101–106

    CAS  PubMed  Google Scholar 

  82. Oguzkan-Balci S, Col-Araz N, Nacak M, Araz M, Sabanci H, Balat A, Pehlivan S (2012) Mitochondrial uncoupling protein 2 (UCP2) gene polymorphisms are associated with childhood obesity and related metabolic disorders. J Pediatr Endocrinol Metab 1–7

  83. Cheurfa N, Dubois-Laforgue D, Ferrarezi DA, Reis AF, Brenner GM, Bouche C, Le Feuvre C, Fumeron F, Timsit J, Marre M et al (2008) The common −866G>A variant in the promoter of UCP2 is associated with decreased risk of coronary artery disease in type 2 diabetic men. Diabetes 57:1063–1068

    CAS  PubMed  Google Scholar 

  84. de Souza BM, Assmann TS, Kliemann LM, Marcon AS, Gross JL, Canani LH, Crispim D (2012) The presence of the −866A/55Val/Ins haplotype in the uncoupling protein 2 (UCP2) gene is associated with decreased UCP2 gene expression in human retina. Exp Eye Res 94:49–55

    PubMed  Google Scholar 

  85. Crispim D, Fagundes NJ, dos Santos KG, Rheinheimer J, Boucas AP, de Souza BM, Macedo GS, Leiria LB, Gross JL, Canani LH (2010) Polymorphisms of the UCP2 gene are associated with proliferative diabetic retinopathy in patients with diabetes mellitus. Clin Endocrinol (Oxford) 72:612–619

    CAS  Google Scholar 

  86. Vogler S, Goedde R, Miterski B, Gold R, Kroner A, Koczan D, Zettl UK, Rieckmann P, Epplen JT, Ibrahim SM (2005) Association of a common polymorphism in the promoter of UCP2 with susceptibility to multiple sclerosis. J Mol Med (Berlin) 83:806–811

    CAS  Google Scholar 

  87. Yu X, Wieczorek S, Franke A, Yin H, Pierer M, Sina C, Karlsen TH, Boberg KM, Bergquist A, Kunz M et al (2009) Association of UCP2 −866 G/A polymorphism with chronic inflammatory diseases. Genes Immun 10:601–605

    CAS  PubMed  Google Scholar 

  88. Pyle A, Ibbett IM, Gordon C, Keers SM, Walker M, Chinnery PF, Baudouin SV (2009) A common UCP2 polymorphism predisposes to stress hyperglycaemia in severe sepsis. J Med Genet 46:773–775

    CAS  PubMed  Google Scholar 

  89. Salpea KD, Talmud PJ, Cooper JA, Maubaret CG, Stephens JW, Abelak K, Humphries SE (2010) Association of telomere length with type 2 diabetes, oxidative stress and UCP2 gene variation. Atherosclerosis 209:42–50

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Lim JH, Ko MM, Lee H, Go HY, Moon TW, Cha MH, Lee MS (2012) Differential association of uncoupling protein 2 polymorphisms with pattern identification among Korean stroke patients: a diagnostic system in traditional Korean medicine. Evid Based Complem Altern Med 2012:532078

    Google Scholar 

  91. Nordfors L, Heimburger O, Lonnqvist F, Lindholm B, Helmrich J, Schalling M, Stenvinkel P (2000) Fat tissue accumulation during peritoneal dialysis is associated with a polymorphism in uncoupling protein 2. Kidney Int 57:1713–1719

    CAS  PubMed  Google Scholar 

  92. Wang J, Liu C, Zhao H, Wang F, Guo J, Xie H, Lu X, Bao Y, Pei L, Niu B et al (2011) Association between a 45-bp 3′ untranslated insertion/deletion polymorphism in exon 8 of UCP2 gene and neural tube defects in a high-risk area of China. Reprod Sci 18:556–560

    PubMed  Google Scholar 

  93. Yamada M, Hashida T, Shibusawa N, Iwasaki T, Murakami M, Monden T, Satoh T, Mori M (1998) Genomic organization and promoter function of the mouse uncoupling protein 2 (UCP2) gene. FEBS Lett 432:65–69

    CAS  PubMed  Google Scholar 

  94. Argyropoulos G, Brown AM, Peterson R, Likes CE, Watson DK, Garvey WT (1998) Structure and organization of the human uncoupling protein 2 gene and identification of a common biallelic variant in Caucasian and African–American subjects. Diabetes 47:685–687

    CAS  PubMed  Google Scholar 

  95. Reilly JM, Thompson MP (2000) Dietary fatty acids up-regulate the expression of UCP2 in 3T3-L1 preadipocytes. Biochem Biophys Res Commun 277:541–545

    CAS  PubMed  Google Scholar 

  96. Samec S, Seydoux J, Dulloo AG (1998) Interorgan signaling between adipose tissue metabolism and skeletal muscle uncoupling protein homologs: is there a role for circulating free fatty acids? Diabetes 47:1693–1698

    CAS  PubMed  Google Scholar 

  97. Aoyama T, Peters JM, Iritani N, Nakajima T, Furihata K, Hashimoto T, Gonzalez FJ (1998) Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARalpha). J Biol Chem 273:5678–5684

    CAS  PubMed  Google Scholar 

  98. Nakatani T, Tsuboyama-Kasaoka N, Takahashi M, Miura S, Ezaki O (2002) Mechanism for peroxisome proliferator-activated receptor-alpha activator-induced up-regulation of UCP2 mRNA in rodent hepatocytes. J Biol Chem 277:9562–9569

    CAS  PubMed  Google Scholar 

  99. Patterson AD, Shah YM, Matsubara T, Krausz KW, Gonzalez FJ (2012) Peroxisome proliferator-activated receptor alpha induction of uncoupling protein 2 protects against acetaminophen-induced liver toxicity. Hepatology 56:281–290

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Kondo T, Kishi M, Fushimi T, Kaga T (2009) Acetic acid upregulates the expression of genes for fatty acid oxidation enzymes in liver to suppress body fat accumulation. J Agric Food Chem 57:5982–5986

    CAS  PubMed  Google Scholar 

  101. Schuler M, Ali F, Chambon C, Duteil D, Bornert JM, Tardivel A, Desvergne B, Wahli W, Chambon P, Metzger D (2006) PGC1alpha expression is controlled in skeletal muscles by PPARbeta, whose ablation results in fiber-type switching, obesity, and type 2 diabetes. Cell Metab 4:407–414

    CAS  PubMed  Google Scholar 

  102. Oishi Y, Manabe I, Tobe K, Ohsugi M, Kubota T, Fujiu K, Maemura K, Kubota N, Kadowaki T, Nagai R (2008) SUMOylation of kruppel-like transcription factor 5 acts as a molecular switch in transcriptional programs of lipid metabolism involving PPAR-delta. Nat Med 14:656–666

    CAS  PubMed  Google Scholar 

  103. Nielsen R, Grontved L, Stunnenberg HG, Mandrup S (2006) Peroxisome proliferator-activated receptor subtype- and cell-type-specific activation of genomic target genes upon adenoviral transgene delivery. Mol Cell Biol 26:5698–5714

    CAS  PubMed Central  PubMed  Google Scholar 

  104. Tontonoz P, Hu E, Spiegelman BM (1994) Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 79:1147–1156

    CAS  PubMed  Google Scholar 

  105. Aubert J, Champigny O, Saint-Marc P, Negrel R, Collins S, Ricquier D, Ailhaud G (1997) Up-regulation of UCP-2 gene expression by PPAR agonists in preadipose and adipose cells. Biochem Biophys Res Commun 238:606–611

    CAS  PubMed  Google Scholar 

  106. Camirand A, Marie V, Rabelo R, Silva JE (1998) Thiazolidinediones stimulate uncoupling protein-2 expression in cell lines representing white and brown adipose tissues and skeletal muscle. Endocrinology 139:428–431

    CAS  PubMed  Google Scholar 

  107. Rieusset J, Auwerx J, Vidal H (1999) Regulation of gene expression by activation of the peroxisome proliferator-activated receptor gamma with rosiglitazone (BRL 49653) in human adipocytes. Biochem Biophys Res Commun 265:265–271

    CAS  PubMed  Google Scholar 

  108. Chen SD, Lin TK, Lin JW, Yang DI, Lee SY, Shaw FZ, Liou CW, Chuang YC (2010) Activation of calcium/calmodulin-dependent protein kinase IV and peroxisome proliferator-activated receptor gamma coactivator-1alpha signaling pathway protects against neuronal injury and promotes mitochondrial biogenesis in the hippocampal CA1 subfield after transient global ischemia. J Neurosci Res 88:3144–3154

    CAS  PubMed  Google Scholar 

  109. Chen SD, Wu HY, Yang DI, Lee SY, Shaw FZ, Lin TK, Liou CW, Chuang YC (2006) Effects of rosiglitazone on global ischemia-induced hippocampal injury and expression of mitochondrial uncoupling protein 2. Biochem Biophys Res Commun 351:198–203

    CAS  PubMed  Google Scholar 

  110. Chuang YC, Lin TK, Huang HY, Chang WN, Liou CW, Chen SD, Chang AY, Chan SH (2012) Peroxisome proliferator-activated receptors gamma/mitochondrial uncoupling protein 2 signaling protects against seizure-induced neuronal cell death in the hippocampus following experimental status epilepticus. J Neuroinflamm 9:184

    CAS  Google Scholar 

  111. Ij A, Jeannin E, Wahli W, Desvergne B (1997) Polarity and specific sequence requirements of peroxisome proliferator-activated receptor (PPAR)/retinoid X receptor heterodimer binding to DNA. A functional analysis of the malic enzyme gene PPAR response element. J Biol Chem 272:20108–20117

    Google Scholar 

  112. Gearing KL, Gottlicher M, Teboul M, Widmark E, Gustafsson JA (1993) Interaction of the peroxisome-proliferator-activated receptor and retinoid X receptor. Proc Natl Acad Sci USA 90:1440–1444

    CAS  PubMed Central  PubMed  Google Scholar 

  113. Medvedev AV, Snedden SK, Raimbault S, Ricquier D, Collins S (2001) Transcriptional regulation of the mouse uncoupling protein-2 gene. Double E-box motif is required for peroxisome proliferator-activated receptor-gamma-dependent activation. J Biol Chem 276:10817–10823

    CAS  PubMed  Google Scholar 

  114. Bugge A, Siersbaek M, Madsen MS, Gondor A, Rougier C, Mandrup S (2010) A novel intronic peroxisome proliferator-activated receptor gamma enhancer in the uncoupling protein (UCP) 3 gene as a regulator of both UCP2 and -3 expression in adipocytes. J Biol Chem 285:17310–17317

    CAS  PubMed Central  PubMed  Google Scholar 

  115. Yoshitomi H, Yamazaki K, Tanaka I (1999) Mechanism of ubiquitous expression of mouse uncoupling protein 2 mRNA: control by cis-acting DNA element in 5′-flanking region. Biochem J 340(Pt 2):397–404

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Oberkofler H, Linnemayr V, Weitgasser R, Klein K, Xie M, Iglseder B, Krempler F, Paulweber B, Patsch W (2004) Complex haplotypes of the PGC-1alpha gene are associated with carbohydrate metabolism and type 2 diabetes. Diabetes 53:1385–1393

    CAS  PubMed  Google Scholar 

  117. Oberkofler H, Klein K, Felder TK, Krempler F, Patsch W (2006) Role of peroxisome proliferator-activated receptor-gamma coactivator-1alpha in the transcriptional regulation of the human uncoupling protein 2 gene in INS-1E cells. Endocrinology 147:966–976

    CAS  PubMed  Google Scholar 

  118. Fukuchi M, Shimabukuro M, Shimajiri Y, Oshiro Y, Higa M, Akamine H, Komiya I, Takasu N (2002) Evidence for a deficient pancreatic beta-cell response in a rat model of hyperthyroidism. Life Sci 71:1059–1070

    CAS  PubMed  Google Scholar 

  119. Calegari VC, Zoppi CC, Rezende LF, Silveira LR, Carneiro EM, Boschero AC (2011) Endurance training activates AMP-activated protein kinase, increases expression of uncoupling protein 2 and reduces insulin secretion from rat pancreatic islets. J Endocrinol 208:257–264

    CAS  PubMed  Google Scholar 

  120. Lin J, Yang R, Tarr PT, Wu PH, Handschin C, Li S, Yang W, Pei L, Uldry M, Tontonoz P et al (2005) Hyperlipidemic effects of dietary saturated fats mediated through PGC-1beta coactivation of SREBP. Cell 120:261–273

    CAS  PubMed  Google Scholar 

  121. Oberkofler H, Hafner M, Felder T, Krempler F, Patsch W (2009) Transcriptional co-activator peroxisome proliferator-activated receptor (PPAR)gamma co-activator-1beta is involved in the regulation of glucose-stimulated insulin secretion in INS-1E cells. J Mol Med (Berlin) 87:299–306

    CAS  Google Scholar 

  122. Vatamaniuk MZ, Gupta RK, Lantz KA, Doliba NM, Matschinsky FM, Kaestner KH (2006) Foxa1-deficient mice exhibit impaired insulin secretion due to uncoupled oxidative phosphorylation. Diabetes 55:2730–2736

    CAS  PubMed  Google Scholar 

  123. Bordone L, Motta MC, Picard F, Robinson A, Jhala US, Apfeld J, McDonagh T, Lemieux M, McBurney M, Szilvasi A et al (2006) Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells. PLoS Biol 4:e31

    PubMed Central  PubMed  Google Scholar 

  124. Raval AP, Dave KR, Perez-Pinzon MA (2006) Resveratrol mimics ischemic preconditioning in the brain. J Cereb Blood Flow Metab 26:1141–1147

    CAS  PubMed  Google Scholar 

  125. Della-Morte D, Dave KR, DeFazio RA, Bao YC, Raval AP, Perez-Pinzon MA (2009) Resveratrol pretreatment protects rat brain from cerebral ischemic damage via a sirtuin 1-uncoupling protein 2 pathway. Neuroscience 159:993–1002

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297

    CAS  PubMed  Google Scholar 

  127. Pecqueur C, Alves-Guerra MC, Gelly C, Levi-Meyrueis C, Couplan E, Collins S, Ricquier D, Bouillaud F, Miroux B (2001) Uncoupling protein 2, in vivo distribution, induction upon oxidative stress, and evidence for translational regulation. J Biol Chem 276:8705–8712

    CAS  PubMed  Google Scholar 

  128. Chen X, Wang K, Chen J, Guo J, Yin Y, Cai X, Guo X, Wang G, Yang R, Zhu L et al (2009) In vitro evidence suggests that miR-133a-mediated regulation of uncoupling protein 2 (UCP2) is an indispensable step in myogenic differentiation. J Biol Chem 284:5362–5369

    CAS  PubMed  Google Scholar 

  129. Bodyak N, Rigor DL, Chen YS, Han Y, Bisping E, Pu WT, Kang PM (2007) Uncoupling protein 2 modulates cell viability in adult rat cardiomyocytes. Am J Physiol Heart Circ Physiol 293:H829–H835

    CAS  PubMed  Google Scholar 

  130. Sun LL, Jiang BG, Li WT, Zou JJ, Shi YQ, Liu ZM (2011) MicroRNA-15a positively regulates insulin synthesis by inhibiting uncoupling protein-2 expression. Diabetes Res Clin Pract 91:94–100

    CAS  PubMed  Google Scholar 

  131. Bomsztyk K, Denisenko O, Ostrowski J (2004) hnRNP K: one protein multiple processes. BioEssays 26:629–638

    CAS  PubMed  Google Scholar 

  132. Ostrowski J, Klimek-Tomczak K, Wyrwicz LS, Mikula M, Schullery DS, Bomsztyk K (2004) Heterogeneous nuclear ribonucleoprotein K enhances insulin-induced expression of mitochondrial UCP2 protein. J Biol Chem 279:54599–54609

    CAS  PubMed  Google Scholar 

  133. Mangge H, Almer G, Truschnig-Wilders M, Schmidt A, Gasser R, Fuchs D (2010) Inflammation, adiponectin, obesity and cardiovascular risk. Curr Med Chem 17:4511–4520

    CAS  PubMed  Google Scholar 

  134. Zhou M, Xu A, Tam PK, Lam KS, Chan L, Hoo RL, Liu J, Chow KH, Wang Y (2008) Mitochondrial dysfunction contributes to the increased vulnerabilities of adiponectin knockout mice to liver injury. Hepatology 48:1087–1096

    CAS  PubMed Central  PubMed  Google Scholar 

  135. Zhou M, Xu A, Tam PK, Lam KS, Huang B, Liang Y, Lee IK, Wu D, Wang Y (2012) Upregulation of UCP2 by adiponectin: the involvement of mitochondrial superoxide and hnRNP K. PLoS ONE 7:e32349

    CAS  PubMed Central  PubMed  Google Scholar 

  136. Giardina TM, Steer JH, Lo SZ, Joyce DA (2008) Uncoupling protein-2 accumulates rapidly in the inner mitochondrial membrane during mitochondrial reactive oxygen stress in macrophages. Biochim Biophys Acta 1777:118–129

    CAS  PubMed  Google Scholar 

  137. Hurtaud C, Gelly C, Bouillaud F, Levi-Meyrueis C (2006) Translation control of UCP2 synthesis by the upstream open reading frame. Cell Mol Life Sci 63:1780–1789

    CAS  PubMed  Google Scholar 

  138. Hurtaud C, Gelly C, Chen Z, Levi-Meyrueis C, Bouillaud F (2007) Glutamine stimulates translation of uncoupling protein 2mRNA. Cell Mol Life Sci 64:1853–1860

    CAS  PubMed  Google Scholar 

  139. Vesce S, Jekabsons MB, Johnson-Cadwell LI, Nicholls DG (2005) Acute glutathione depletion restricts mitochondrial ATP export in cerebellar granule neurons. J Biol Chem 280:38720–38728

    CAS  PubMed  Google Scholar 

  140. Mailloux RJ, Seifert EL, Bouillaud F, Aguer C, Collins S, Harper ME (2011) Glutathionylation acts as a control switch for uncoupling proteins UCP2 and UCP3. J Biol Chem 286:21865–21875

    CAS  PubMed Central  PubMed  Google Scholar 

  141. Mailloux RJ, Fu A, Robson-Doucette C, Allister EM, Wheeler MB, Screaton R, Harper ME (2012) Glutathionylation state of uncoupling protein-2 and the control of glucose-stimulated insulin secretion. J Biol Chem 287:39673–39685

    CAS  PubMed Central  PubMed  Google Scholar 

  142. Pfefferle A, Mailloux RJ, Adjeitey CN, Harper ME (2012) Glutathionylation of UCP2 sensitizes drug resistant leukemia cells to chemotherapeutics. Biochim Biophys Acta 1833:80–89

    PubMed  Google Scholar 

  143. Azzu V, Jastroch M, Divakaruni AS, Brand MD (2010) The regulation and turnover of mitochondrial uncoupling proteins. Biochim Biophys Acta 1797:785–791

    CAS  PubMed Central  PubMed  Google Scholar 

  144. Rousset S, Mozo J, Dujardin G, Emre Y, Masscheleyn S, Ricquier D, Cassard-Doulcier AM (2007) UCP2 is a mitochondrial transporter with an unusual very short half-life. FEBS Lett 581:479–482

    CAS  PubMed  Google Scholar 

  145. Puigserver P, Herron D, Gianotti M, Palou A, Cannon B, Nedergaard J (1992) Induction and degradation of the uncoupling protein thermogenin in brown adipocytes in vitro and in vivo. Evidence for a rapidly degradable pool. Biochem J 284(Pt 2):393–398

    CAS  PubMed Central  PubMed  Google Scholar 

  146. Azzu V, Affourtit C, Breen EP, Parker N, Brand MD (2008) Dynamic regulation of uncoupling protein 2 content in INS-1E insulinoma cells. Biochim Biophys Acta 1777:1378–1383

    CAS  PubMed Central  PubMed  Google Scholar 

  147. Brand MD, Parker N, Affourtit C, Mookerjee SA, Azzu V (2010) Mitochondrial uncoupling protein 2 in pancreatic beta-cells. Diabetes Obes Metab 12(Suppl 2):134–140

    CAS  PubMed  Google Scholar 

  148. Azzu V, Brand MD (2010) Degradation of an intramitochondrial protein by the cytosolic proteasome. J Cell Sci 123:578–585

    CAS  PubMed Central  PubMed  Google Scholar 

  149. Wojtczak L, Lebiedzinska M, Suski JM, Wieckowski MR, Schonfeld P (2011) Inhibition by purine nucleotides of the release of reactive oxygen species from muscle mitochondria: indication for a function of uncoupling proteins as superoxide anion transporters. Biochem Biophys Res Commun 407:772–776

    CAS  PubMed  Google Scholar 

  150. Heuett WJ, Periwal V (2010) Autoregulation of free radicals via uncoupling protein control in pancreatic beta-cell mitochondria. Biophys J 98:207–217

    CAS  PubMed Central  PubMed  Google Scholar 

  151. Mailloux RJ, Harper ME (2011) Uncoupling proteins and the control of mitochondrial reactive oxygen species production. Free Radic Biol Med 51:1106–1115

    CAS  PubMed  Google Scholar 

  152. Echtay KS, Murphy MP, Smith RA, Talbot DA, Brand MD (2002) Superoxide activates mitochondrial uncoupling protein 2 from the matrix side. Studies using targeted antioxidants. J Biol Chem 277:47129–47135

    CAS  PubMed  Google Scholar 

  153. Echtay KS, Winkler E, Bienengraeber M, Klingenberg M (2000) Site-directed mutagenesis identifies residues in uncoupling protein (UCP1) involved in three different functions. Biochemistry 39:3311–3317

    CAS  PubMed  Google Scholar 

  154. Klingenberg M, Echtay KS (2001) Uncoupling proteins: the issues from a biochemist point of view. Biochim Biophys Acta 1504:128–143

    CAS  PubMed  Google Scholar 

  155. Garlid KD, Orosz DE, Modriansky M, Vassanelli S, Jezek P (1996) On the mechanism of fatty acid-induced proton transport by mitochondrial uncoupling protein. J Biol Chem 271:2615–2620

    CAS  PubMed  Google Scholar 

  156. Skulachev VP (1991) Fatty acid circuit as a physiological mechanism of uncoupling of oxidative phosphorylation. FEBS Lett 294:158–162

    CAS  PubMed  Google Scholar 

  157. Beck V, Jaburek M, Demina T, Rupprecht A, Porter RK, Jezek P, Pohl EE (2007) Polyunsaturated fatty acids activate human uncoupling proteins 1 and 2 in planar lipid bilayers. Faseb J 21:1137–1144

    CAS  PubMed  Google Scholar 

  158. Brand MD (2000) Uncoupling to survive? The role of mitochondrial inefficiency in ageing. Exp Gerontol 35:811–820

    CAS  PubMed  Google Scholar 

  159. Echtay KS, Esteves TC, Pakay JL, Jekabsons MB, Lambert AJ, Portero-Otin M, Pamplona R, Vidal-Puig AJ, Wang S, Roebuck SJ et al (2003) A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling. EMBO J 22:4103–4110

    CAS  PubMed Central  PubMed  Google Scholar 

  160. Echtay KS, Pakay JL, Esteves TC, Brand MD (2005) Hydroxynonenal and uncoupling proteins: a model for protection against oxidative damage. BioFactors 24:119–130

    CAS  PubMed  Google Scholar 

  161. Woyda-Ploszczyca A, Jarmuszkiewicz W (2013) Hydroxynonenal-stimulated activity of the uncoupling protein in Acanthamoeba castellanii mitochondria under phosphorylating conditions. Biol Chem 394:649–658

    PubMed  Google Scholar 

  162. Rupprecht A, Sokolenko EA, Beck V, Ninnemann O, Jaburek M, Trimbuch T, Klishin SS, Jezek P, Skulachev VP, Pohl EE (2010) Role of the transmembrane potential in the membrane proton leak. Biophys J 98:1503–1511

    CAS  PubMed Central  PubMed  Google Scholar 

  163. Parker N, Vidal-Puig A, Brand MD (2008) Stimulation of mitochondrial proton conductance by hydroxynonenal requires a high membrane potential. Biosci Rep 28:83–88

    CAS  PubMed Central  PubMed  Google Scholar 

  164. Woyda-Ploszczyca A, Jarmuszkiewicz W (2011) Ubiquinol (QH(2)) functions as a negative regulator of purine nucleotide inhibition of Acanthamoeba castellanii mitochondrial uncoupling protein. Biochim Biophys Acta 1807:42–52

    CAS  PubMed  Google Scholar 

  165. Echtay KS, Winkler E, Frischmuth K, Klingenberg M (2001) Uncoupling proteins 2 and 3 are highly active H(+) transporters and highly nucleotide sensitive when activated by coenzyme Q (ubiquinone). Proc Natl Acad Sci USA 98:1416–1421

    CAS  PubMed Central  PubMed  Google Scholar 

  166. Zackova M, Skobisova E, Urbankova E, Jezek P (2003) Activating omega-6 polyunsaturated fatty acids and inhibitory purine nucleotides are high affinity ligands for novel mitochondrial uncoupling proteins UCP2 and UCP3. J Biol Chem 278:20761–20769

    CAS  PubMed  Google Scholar 

  167. Ivanova MV, Hoang T, McSorley FR, Krnac G, Smith MD, Jelokhani-Niaraki M (2010) A comparative study on conformation and ligand binding of the neuronal uncoupling proteins. Biochemistry 49:512–521

    CAS  PubMed  Google Scholar 

  168. Dehez F, Pebay-Peyroula E, Chipot C (2008) Binding of ADP in the mitochondrial ADP/ATP carrier is driven by an electrostatic funnel. J Am Chem Soc 130:12725–12733

    CAS  PubMed  Google Scholar 

  169. Nagy TR, Blaylock ML, Garvey WT (2004) Role of UCP2 and UCP3 in nutrition and obesity. Nutrition 20:139–144

    CAS  PubMed  Google Scholar 

  170. Yonezawa T, Kurata R, Hosomichi K, Kono A, Kimura M, Inoko H (2009) Nutritional and hormonal regulation of uncoupling protein 2. IUBMB Life 61:1123–1131

    CAS  PubMed  Google Scholar 

  171. Pereira AF, Sa LL, Reis FH, Cardoso FC, Alberici RM, Prado IM, Eberlin MN, Uyemura SA, Curti C, Alberici LC (2012) Administration of a murine diet supplemented with conjugated linoleic acid increases the expression and activity of hepatic uncoupling proteins. J Bioenergy Biomembr 44:587–596

    CAS  Google Scholar 

  172. Kanamoto Y, Yamashita Y, Nanba F, Yoshida T, Tsuda T, Fukuda I, Nakamura-Tsuruta S, Ashida H (2011) A black soybean seed coat extract prevents obesity and glucose intolerance by up-regulating uncoupling proteins and down-regulating inflammatory cytokines in high-fat diet-fed mice. J Agric Food Chem 59:8985–8993

    CAS  PubMed  Google Scholar 

  173. Lionetti L, Cavaliere G, Bergamo P, Trinchese G, De Filippo C, Gifuni G, Gaita M, Pignalosa A, Donizzetti I, Putti R et al (2012) Diet supplementation with donkey milk upregulates liver mitochondrial uncoupling, reduces energy efficiency and improves antioxidant and antiinflammatory defences in rats. Mol Nutr Food Res 56:1596–1600

    CAS  PubMed  Google Scholar 

  174. Anedda A, Rial E, Gonzalez-Barroso MM (2008) Metformin induces oxidative stress in white adipocytes and raises uncoupling protein 2 levels. J Endocrinol 199:33–40

    CAS  PubMed  Google Scholar 

  175. Kim JE, Kim YW, Lee IK, Kim JY, Kang YJ, Park SY (2008) AMP-activated protein kinase activation by 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) inhibits palmitate-induced endothelial cell apoptosis through reactive oxygen species suppression. J Pharmacol Sci 106:394–403

    CAS  PubMed  Google Scholar 

  176. Wang Q, Zhang M, Liang B, Shirwany N, Zhu Y, Zou MH (2011) Activation of AMP-activated protein kinase is required for berberine-induced reduction of atherosclerosis in mice: the role of uncoupling protein 2. PLoS ONE 6:e25436

    CAS  PubMed Central  PubMed  Google Scholar 

  177. Bugger H, Guzman C, Zechner C, Palmeri M, Russell KS, Russell RR 3rd (2011) Uncoupling protein downregulation in doxorubicin-induced heart failure improves mitochondrial coupling but increases reactive oxygen species generation. Cancer Chemother Pharmacol 67:1381–1388

    CAS  PubMed Central  PubMed  Google Scholar 

  178. Selimovic D, Hassan M, Haikel Y, Hengge UR (2008) Taxol-induced mitochondrial stress in melanoma cells is mediated by activation of c-Jun N-terminal kinase (JNK) and p38 pathways via uncoupling protein 2. Cell Signal 20:311–322

    CAS  PubMed  Google Scholar 

  179. Rial E, Rodriguez-Sanchez L, Aller P, Guisado A, Mar Gonzalez-Barroso M, Gallardo-Vara E, Redondo-Horcajo M, Castellanos E, Fernandez de la Pradilla R, Viso A (2011) Development of chromanes as novel inhibitors of the uncoupling proteins. Chem Biol 18:264–274

    CAS  PubMed  Google Scholar 

  180. El-Khoury TG, Bahr GM, Echtay KS (2011) Muramyl-dipeptide-induced mitochondrial proton leak in macrophages is associated with upregulation of uncoupling protein 2 and the production of reactive oxygen and reactive nitrogen species. FEBS J 278:3054–3064

    CAS  PubMed  Google Scholar 

  181. Zhang X, Li L, Zhang L, Borowitz JL, Isom GE (2009) Cyanide-induced death of dopaminergic cells is mediated by uncoupling protein-2 up-regulation and reduced Bcl-2 expression. Toxicol Appl Pharmacol 238:11–19

    CAS  PubMed Central  PubMed  Google Scholar 

  182. Mizuno T, Miura-Suzuki T, Yamashita H, Mori N (2000) Distinct regulation of brain mitochondrial carrier protein-1 and uncoupling protein-2 genes in the rat brain during cold exposure and aging. Biochem Biophys Res Commun 278:691–697

    CAS  PubMed  Google Scholar 

  183. Sullivan PG, Dube C, Dorenbos K, Steward O, Baram TZ (2003) Mitochondrial uncoupling protein-2 protects the immature brain from excitotoxic neuronal death. Ann Neurol 53:711–717

    CAS  PubMed Central  PubMed  Google Scholar 

  184. Alves-Guerra MC, Aheng C, Pecqueur C, Masscheleyn S, Tharaux PL, Druilhe A, Ricquier D, Challet E, Miroux B (2012) Analysis of uncoupling protein 2-deficient mice upon anaesthesia and sedation revealed a role for UCP2 in locomotion. PLoS ONE 7:e41846

    CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by Associazione Italiana Ricerca Cancro (AIRC), Milan, Italy; Fondazione CariPaRo, Padova, Italy; Ministero dell’Istruzione, dell’Università e della Ricerca (PRIN, MIUR), Rome, Italy.

Conflict of interest

The authors declare that they have no conflicts of interest.

Author information

Authors and Affiliations

  1. Section of Biochemistry, Deparment of Life and Reproduction Sciences, University of Verona, Strada Le Grazie 8, 37134, Verona, Italy

    Massimo Donadelli, Ilaria Dando, Claudia Fiorini & Marta Palmieri

Authors
  1. Massimo Donadelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ilaria Dando
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Claudia Fiorini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marta Palmieri
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Massimo Donadelli.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Donadelli, M., Dando, I., Fiorini, C. et al. UCP2, a mitochondrial protein regulated at multiple levels. Cell. Mol. Life Sci. 71, 1171–1190 (2014). https://doi.org/10.1007/s00018-013-1407-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-013-1407-0

Keywords

Search

Navigation