Perspectives on mitochondrial uncoupling proteins-mediated neuroprotection

Journal of Bioenergetics and Biomembranes

Volumn 47, Issue 1-2, 2015, Pages 119-131

  Cardoso, Susana ^a,b   Correia, Sónia ^a,b   Carvalho, Cristina ^a   Candeias, Emanuel ^a,b   Plácido, Ana I ^a,c   Duarte, Ana I ^a,b   Seiça, Raquel M ^c   Moreira, Paula I ^a,c  

^a UNIVERSITY OF COIMBRA   (Portugal)

^b UNIVERSITY OF COIMBRA   (Portugal)

^c UNIVERSITY OF COIMBRA   (Portugal)

Author keywords

Brain; Mitochondria; Neuronal uncoupling proteins; Neuroprotection; Oxidative stress

Indexed keywords

REACTIVE OXYGEN METABOLITE; UNCLASSIFIED DRUG; UNCOUPLING PROTEIN; UNCOUPLING PROTEIN 2; UNCOUPLING PROTEIN 4; UNCOUPLING PROTEIN 5; ADENOSINE TRIPHOSPHATE; ION CHANNEL; MITOCHONDRIAL PROTEIN; MITOCHONDRIAL UNCOUPLING PROTEIN;

BRAIN DISEASE; CENTRAL NERVOUS SYSTEM; HUMAN; MITOCHONDRION; NEUROPATHOLOGY; NEUROPROTECTION; NONHUMAN; OXIDATIVE PHOSPHORYLATION UNCOUPLING; PROTEIN EXPRESSION; PROTEIN STRUCTURE; REGULATORY MECHANISM; REVIEW; THERMOGENESIS AND THERMOREGULATION; ANIMAL; BRAIN; BRAIN DISEASES; ENERGY METABOLISM; METABOLISM; NERVE CELL; PATHOLOGY;

ADENOSINE TRIPHOSPHATE; ANIMALS; BRAIN; BRAIN DISEASES; ENERGY METABOLISM; HUMANS; ION CHANNELS; MITOCHONDRIA; MITOCHONDRIAL PROTEINS; NEURONS; REACTIVE OXYGEN SPECIES;

EID: 84922536968     PISSN: 0145479X     EISSN: 15736881     Source Type: Journal    
DOI: 10.1007/s10863-014-9580-x     Document Type: Review

References (135)

1. Abdul-Rahman O, Sasvari-Szekely M, Ver A, Rosta K, Szasz BK, Kereszturi E et al (2012) Altered gene expression profiles in the hippocampus and prefrontal cortex of type 2 diabetic rats. BMC Genomics 13:81
2. Ali SS, Marcondes MC, Bajova H, Dugan LL, Conti B (2010) Metabolic depression and increased reactive oxygen species production by isolated mitochondria at moderately lower temperatures. J Biol Chem 285(42):32522–32528
3. Andrews ZB (2010) Uncoupling protein-2 and the potential link between metabolism and longevity. Curr Aging Sci 3(2):102–112
4. Andrews ZB, Horvath TL (2009) Uncoupling protein-2 regulates lifespan in mice. Am J Physiol Endocrinol Metab 296(4):E621–E627
5. Andrews ZB, Diano S, Horvath TL (2005a) Mitochondrial uncoupling proteins in the CNS: in support of function and survival. Nat Rev Neurosci 6(11):829–840
6. Andrews ZB, Horvath B, Barnstable CJ, Elsworth J, Yang L, Beal MF et al (2005b) Uncoupling protein-2 is critical for nigral dopamine cell survival in a mouse model of Parkinson’s disease. J Neurosci 25(1):184–191
7. Andrews ZB, Rivera A, Elsworth JD, Roth RH, Agnati L, Gago B et al (2006) Uncoupling protein-2 promotes nigrostriatal dopamine neuronal function. Eur J Neurosci 24(1):32–36
8. Arechaga I, Ledesma A, Rial E (2001) The mitochondrial uncoupling protein UCP1: a gated pore. IUBMB Life 52(3–5):165–173
9. Arsenijevic D, Onuma H, Pecqueur C, Raimbault S, Manning BS, Miroux B 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(4):435–439
10. Barbieri M, Boccardi V, Esposito A, Papa M, Vestini F, Rizzo MR et al (2012) A/ASP/VAL allele combination of IGF1R, IRS2, and UCP2 genes is associated with better metabolic profile, preserved energy expenditure parameters, and low mortality rate in longevity. Age (Dordr) 34(1):235–245
11. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297
12. Bayir H, Kagan VE (2008) Bench-to-bedside review: mitochondrial injury, oxidative stress and apoptosis–there is nothing more practical than a good theory. Crit Care 12(1):206
13. Beal MF (2005) Mitochondria take center stage in aging and neurodegeneration. Ann Neurol 58(4):495–505
14. Bechmann I, Diano S, Warden CH, Bartfai T, Nitsch R, Horvath TL (2002) Brain mitochondrial uncoupling protein 2 (UCP2): a protective stress signal in neuronal injury. Biochem Pharmacol 64(3):363–367
15. Beck V, Jaburek M, Demina T, Rupprecht A, Porter RK, Jezek P et al (2007) Polyunsaturated fatty acids activate human uncoupling proteins 1 and 2 in planar lipid bilayers. FASEB J 21(4):1137–1144
16. Bevilacqua L, Ramsey JJ, Hagopian K, Weindruch R, Harper ME (2004) Effects of short- and medium-term calorie restriction on muscle mitochondrial proton leak and reactive oxygen species production. Am J Physiol Endocrinol Metab 286(5):E852–E861
17. Bouillaud F, Couplan E, Pecqueur C, Ricquier D (2001) Homologues of the uncoupling protein from brown adipose tissue (UCP1): UCP2, UCP3, BMCP1 and UCP4. Biochim Biophys Acta 1504(1):107–119
18. Brand MD (2000) Uncoupling to survive? The role of mitochondrial inefficiency in ageing. Exp Gerontol 35(6–7):811–820
19. Brand MD, Esteves TC (2005) Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3. Cell Metab 2(2):85–93
20. Brand MD, Affourtit C, Esteves TC, Green K, Lambert AJ, Miwa S et al (2004) Mitochondrial superoxide: production, biological effects, and activation of uncoupling proteins. Free Radic Biol Med 37(6):755–767
21. Brouillet E, Jacquard C, Bizat N, Blum D (2005) 3-Nitropropionic acid: a mitochondrial toxin to uncover physiopathological mechanisms underlying striatal degeneration in Huntington’s disease. J Neurochem 95(6):1521–1540
22. Buchanan TA, Cane P, Eng CC, Sipos GF, Lee C (1991) Hypothermia is critical for survival during prolonged insulin-induced hypoglycemia in rats. Metabolism 40(3):330–334
23. Caldeira da Silva CC, Cerqueira FM, Barbosa LF, Medeiros MH, Kowaltowski AJ (2008) Mild mitochondrial uncoupling in mice affects energy metabolism, redox balance and longevity. Aging Cell 7(4):552–560
24. Cardoso S, Santos MS, Moreno A, Moreira PI (2013) UCP2 and ANT differently modulate proton-leak in brain mitochondria of long-term hyperglycemic and recurrent hypoglycemic rats. J Bioenerg Biomembr 45(4):397–407
25. Casteilla L, Rigoulet M, Penicaud L (2001) Mitochondrial ROS metabolism: modulation by uncoupling proteins. IUBMB Life 52(3–5):181–188
26. Chan SL, Wei Z, Chigurupati S, Tu W (2010) Compromised respiratory adaptation and thermoregulation in aging and age-related diseases. Ageing Res Rev 9(1):20–40
27. Chaturvedi RK, Beal MF (2013) Mitochondria targeted therapeutic approaches in Parkinson’s and Huntington’s diseases. Mol Cell Neurosci 55:101–114
28. Chen SD, Lin TK, Lin JW, Yang DI, Lee SY, Shaw FZ et al (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(14):3144–3154
29. Chu AC, Ho PW, Kwok KH, Ho JW, Chan KH, Liu HF et al (2009) Mitochondrial UCP4 attenuates MPP+ - and dopamine-induced oxidative stress, mitochondrial depolarization, and ATP deficiency in neurons and is interlinked with UCP2 expression. Free Radic Biol Med 46(6):810–820
30. Cioffi F, Senese R, de Lange P, Goglia F, Lanni A, Lombardi A (2009) Uncoupling proteins: a complex journey to function discovery. Biofactors 35(5):417–428
31. Conti B, Sugama S, Lucero J, Winsky-Sommerer R, Wirz SA, Maher P et al (2005) Uncoupling protein 2 protects dopaminergic neurons from acute 1,2,3,6-methyl-phenyl-tetrahydropyridine toxicity. J Neurochem 93(2):493–501
32. Correia SC, Carvalho C, Cardoso S, Santos RX, Santos MS, Oliveira CR et al (2010) Mitochondrial preconditioning: a potential neuroprotective strategy. Front Aging Neurosci 2
33. Dalgaard LT, Pedersen O (2001) Uncoupling proteins: functional characteristics and role in the pathogenesis of obesity and Type II diabetes. Diabetologia 44(8):946–965
34. de Bilbao F, Arsenijevic D, Vallet P, Hjelle OP, Ottersen OP, Bouras C et al (2004) Resistance to cerebral ischemic injury in UCP2 knockout mice: evidence for a role of UCP2 as a regulator of mitochondrial glutathione levels. J Neurochem 89(5):1283–1292
35. de la Monte SM, Wands JR (2006) Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer’s disease. J Alzheimers Dis 9(2):167–181
36. 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(3):993–1002
37. Desquiret V, Loiseau D, Jacques C, Douay O, Malthiery Y, Ritz P et al (2006) Dinitrophenol-induced mitochondrial uncoupling in vivo triggers respiratory adaptation in HepG2 cells. Biochim Biophys Acta 1757(1):21–30
38. Diano S, Horvath TL (2012) Mitochondrial uncoupling protein 2 (UCP2) in glucose and lipid metabolism. Trends Mol Med 18(1):52–58
39. Diano S, Matthews RT, Patrylo P, Yang L, Beal MF, Barnstable CJ et al (2003) Uncoupling protein 2 prevents neuronal death including that occurring during seizures: a mechanism for preconditioning. Endocrinology 144(11):5014–5021
40. Dietrich MO, Horvath TL (2010) The role of mitochondrial uncoupling proteins in lifespan. Pflugers Arch 459(2):269–275
41. Divakaruni AS, Brand MD (2011) The regulation and physiology of mitochondrial proton leak. Physiology (Bethesda) 26(3):192–205
42. Donadelli M, Dando I, Fiorini C, Palmieri M (2013) UCP2, a mitochondrial protein regulated at multiple levels. Cell Mol Life Sci 71(7):1171–1190
43. Droge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82(1):47–95
44. Duchen MR (2004) Mitochondria in health and disease: perspectives on a new mitochondrial biology. Mol Aspects Med 25(4):365–451
45. Dulloo AG, Samec S (2001) Uncoupling proteins: their roles in adaptive thermogenesis and substrate metabolism reconsidered. Br J Nutr 86(2):123–139
46. Echtay KS (2007) Mitochondrial uncoupling proteins–what is their physiological role? Free Radic Biol Med 43(10):1351–1371
47. Erecinska M, Thoresen M, Silver IA (2003) Effects of hypothermia on energy metabolism in Mammalian central nervous system. J Cereb Blood Flow Metab 23(5):513–530
48. Esterbauer H, Schaur RJ, Zollner H (1991) Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med 11(1):81–128
49. Fontana L, Klein S, Holloszy JO (2010) Effects of long-term calorie restriction and endurance exercise on glucose tolerance, insulin action, and adipokine production. Age (Dordr) 32(1):97–108
50. Fridell YW, Sanchez-Blanco A, Silvia BA, Helfand SL (2005) Targeted expression of the human uncoupling protein 2 (hUCP2) to adult neurons extends life span in the fly. Cell Metab 1(2):145–152
51. Frisard M, Ravussin E (2006) Energy metabolism and oxidative stress: impact on the metabolic syndrome and the aging process. Endocrine 29(1):27–32
52. Gallogly MM, Mieyal JJ (2007) Mechanisms of reversible protein glutathionylation in redox signaling and oxidative stress. Curr Opin Pharmacol 7(4):381–391
53. Garcia-Martinez C, Sibille B, Solanes G, Darimont C, Mace K, Villarroya F et al (2001) Overexpression of UCP3 in cultured human muscle lowers mitochondrial membrane potential, raises ATP/ADP ratio, and favors fatty acid vs. glucose oxidation. FASEB J 15(11):2033–2035
54. 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(5):2615–2620
55. 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(2):118–129
56. Goglia F, Skulachev VP (2003) A function for novel uncoupling proteins: antioxidant defense of mitochondrial matrix by translocating fatty acid peroxides from the inner to the outer membrane leaflet. FASEB J 17(12):1585–1591
57. Gonzalez-Lima F, Barksdale BR, Rojas JC (2014) Mitochondrial respiration as a target for neuroprotection and cognitive enhancement. Biochem Pharmacol 88(4):584–593
58. Gruber J, Fong S, Chen CB, Yoong S, Pastorin G, Schaffer S et al (2013) Mitochondria-targeted antioxidants and metabolic modulators as pharmacological interventions to slow ageing. Biotechnol Adv 31(5):563–592
59. Guevara R, Santandreu FM, Valle A, Gianotti M, Oliver J, Roca P (2009) Sex-dependent differences in aged rat brain mitochondrial function and oxidative stress. Free Radic Biol Med 46(2):169–175
60. Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11(3):298–300
61. Ho PW, Chu AC, Kwok KH, Kung MH, Ramsden DB, Ho SL (2006) Knockdown of uncoupling protein-5 in neuronal SH-SY5Y cells: Effects on MPP+-induced mitochondrial membrane depolarization, ATP deficiency, and oxidative cytotoxicity. J Neurosci Res 84(6):1358–1366
62. Ho PW, Ho JW, Tse HM, So DH, Yiu DC, Liu HF et al (2012a) Uncoupling protein-4 (UCP4) increases ATP supply by interacting with mitochondrial Complex II in neuroblastoma cells. PLoS One 7(2):e32810
63. Ho JW, Ho PW, Liu HF, So DH, Chan KH, Tse ZH et al (2012b) UCP4 is a target effector of the NF-kappaB c-Rel prosurvival pathway against oxidative stress. Free Radic Biol Med 53(2):383–394
64. 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(19):4004–4014
65. Horvath TL, Warden CH, Hajos M, Lombardi A, Goglia F, Diano S (1999) Brain uncoupling protein 2: uncoupled neuronal mitochondria predict thermal synapses in homeostatic centers. J Neurosci 19(23):10417–10427
66. Horvath TL, Diano S, Leranth C, Garcia-Segura LM, Cowley MA, Shanabrough M et al (2003) Coenzyme Q induces nigral mitochondrial uncoupling and prevents dopamine cell loss in a primate model of Parkinson’s disease. Endocrinology 144(7):2757–2760
67. Hudman D, Rainbow RD, Lawrence CL, Standen NB (2002) The origin of calcium overload in rat cardiac myocytes following metabolic inhibition with 2,4-dinitrophenol. J Mol Cell Cardiol 34(7):859–871
68. Hurd TR, Costa NJ, Dahm CC, Beer SM, Brown SE, Filipovska A et al (2005) Glutathionylation of mitochondrial proteins. Antioxid Redox Signal 7(7–8):999–1010
69. Jastroch M, Divakaruni AS, Mookerjee S, Treberg JR, Brand MD (2010) Mitochondrial proton and electron leaks. Essays Biochem 47:53–67
70. Jiang L, Qiu W, Zhou Y, Wen P, Fang L, Cao H et al (2013) A microRNA-30e/mitochondrial uncoupling protein 2 axis mediates TGF-beta1-induced tubular epithelial cell extracellular matrix production and kidney fibrosis. Kidney Int 84(2):285–296
71. Katz LM, Young AS, Frank JE, Wang Y, Park K (2004) Regulated hypothermia reduces brain oxidative stress after hypoxic-ischemia. Brain Res 1017(1–2):85–91
72. Kim-Han JS, Dugan LL (2005) Mitochondrial uncoupling proteins in the central nervous system. Antioxid Redox Signal 7(9–10):1173–1181
73. Kim-Han JS, Reichert SA, Quick KL, Dugan LL (2001) BMCP1: a mitochondrial uncoupling protein in neurons which regulates mitochondrial function and oxidant production. J Neurochem 79(3):658–668
74. Klingenberg M (1993) Dialectics in carrier research: the ADP/ATP carrier and the uncoupling protein. J Bioenerg Biomembr 25(5):447–457
75. Klingenberg M (1999) Uncoupling protein–a useful energy dissipator. J Bioenerg Biomembr 31(5):419–430
76. Klingenberg M, Winkler E (1985) The reconstituted isolated uncoupling protein is a membrane potential driven H + translocator. EMBO J 4(12):3087–3092
77. Korshunov SS, Skulachev VP, Starkov AA (1997) High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett 416(1):15–18
78. Krauss S, Zhang CY, Lowell BB (2005) The mitochondrial uncoupling-protein homologues. Nat Rev Mol Cell Biol 6(3):248–261
79. Kwok KH, Ho PW, Chu AC, Ho JW, Liu HF, Yiu DC et al (2010) Mitochondrial UCP5 is neuroprotective by preserving mitochondrial membrane potential, ATP levels, and reducing oxidative stress in MPP+ and dopamine toxicity. Free Radic Biol Med 49(6):1023–1035
80. Langston JW, Ballard P, Tetrud JW, Irwin I (1983) Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219(4587):979–980
81. Li LX, Skorpen F, Egeberg K, Jorgensen IH, Grill V (2002) Induction of uncoupling protein 2 mRNA in beta-cells is stimulated by oxidation of fatty acids but not by nutrient oversupply. Endocrinology 143(4):1371–1377
82. Lin J, Yang R, Tarr PT, Wu PH, Handschin C, Li S et al (2005) Hyperlipidemic effects of dietary saturated fats mediated through PGC-1beta coactivation of SREBP. Cell 120(2):261–273
83. Liu D, Chan SL, de Souza-Pinto NC, Slevin JR, Wersto RP, Zhan M et al (2006) Mitochondrial UCP4 mediates an adaptive shift in energy metabolism and increases the resistance of neurons to metabolic and oxidative stress. Neuromol Med 8(3):389–414
84. Liu Y, Chen L, Xu X, Vicaut E, Sercombe R (2009) Both ischemic preconditioning and ghrelin administration protect hippocampus from ischemia/reperfusion and upregulate uncoupling protein-2. BMC Physiol 9:17
85. Lockie SH, Muller TD, Tschop MH (2009) Coupled with uncouplers: the curious case of lifespan. Am J Physiol Endocrinol Metab 296(4):E619–E620
86. Lu M, Zhao FF, Tang JJ, Su CJ, Fan Y, Ding JH et al (2012) The neuroprotection of hydrogen sulfide against MPTP-induced dopaminergic neuron degeneration involves uncoupling protein 2 rather than ATP-sensitive potassium channels. Antioxid Redox Signal 17(6):849–859
87. Lu M, Sun XL, Qiao C, Liu Y, Ding JH, Hu G (2013) Uncoupling protein 2 deficiency aggravates astrocytic endoplasmic reticulum stress and nod-like receptor protein 3 inflammasome activation. Neurobiol Aging 35(2):421–430
88. Mailloux RJ, Harper ME (2012) Mitochondrial proticity and ROS signaling: lessons from the uncoupling proteins. Trends Endocrinol Metab 23(9):451–458
89. Mailloux RJ, Fu A, Robson-Doucette C, Allister EM, Wheeler MB, Screaton R et al (2012) Glutathionylation state of uncoupling protein-2 and the control of glucose-stimulated insulin secretion. J Biol Chem 287(47):39673–39685
90. Mailloux RJ, McBride SL, Harper ME (2013) Unearthing the secrets of mitochondrial ROS and glutathione in bioenergetics. Trends Biochem Sci 38(12):592–602
91. Mao W, Yu XX, Zhong A, Li W, Brush J, Sherwood SW et al (1999) UCP4, a novel brain-specific mitochondrial protein that reduces membrane potential in mammalian cells. FEBS Lett 443(3):326–330
92. Mattiasson G, Shamloo M, Gido G, Mathi K, Tomasevic G, Yi S et al (2003) Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nat Med 9(8):1062–1068
93. McDonald RB, Walker KM, Warman DB, Griffey SM, Warden CH, Ramsey JJ et al (2008) Characterization of survival and phenotype throughout the life span in UCP2/UCP3 genetically altered mice. Exp Gerontol 43(12):1061–1068
94. 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(3):691–697
95. Mozo J, Emre Y, Bouillaud F, Ricquier D, Criscuolo F (2005) Thermoregulation: what role for UCPs in mammals and birds? Biosci Rep 25(3–4):227–249
96. Murphy MP, Echtay KS, Blaikie FH, Asin-Cayuela J, Cocheme HM, Green K et al (2003) Superoxide activates uncoupling proteins by generating carbon-centered radicals and initiating lipid peroxidation: studies using a mitochondria-targeted spin trap derived from alpha-phenyl-N-tert-butylnitrone. J Biol Chem 278(49):48534–48545
97. Nakase T, Yoshida Y, Nagata K (2007) Amplified expression of uncoupling proteins in human brain ischemic lesions. Neuropathology 27(5):442–447
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(11):9562–9569
99. Negre-Salvayre A, Hirtz C, Carrera G, Cazenave R, Troly M, Salvayre R et al (1997) A role for uncoupling protein-2 as a regulator of mitochondrial hydrogen peroxide generation. FASEB J 11(10):809–815
100. Nicholls DG, Rial E (1999) A history of the first uncoupling protein, UCP1. J Bioenerg Biomembr 31(5):399–406
101. Nicholls DG, Bernson VS, Heaton GM (1978) The identification of the component in the inner membrane of brown adipose tissue mitochondria responsible for regulating energy dissipation. Experientia Suppl 32:89–93
102. 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(52):54599–54609
103. Pawlikowska L, Hu D, Huntsman S, Sung A, Chu C, Chen J et al (2009) Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity. Aging Cell 8(4):460–472
104. Pebay-Peyroula E, Dahout-Gonzalez C, Kahn R, Trezeguet V, Lauquin GJ, Brandolin G (2003) Structure of mitochondrial ADP/ATP carrier in complex with carboxyatractyloside. Nature 426(6962):39–44
105. Pecqueur C, Alves-Guerra MC, Gelly C, Levi-Meyrueis C, Couplan E, Collins S et al (2001) Uncoupling protein 2, in vivo distribution, induction upon oxidative stress, and evidence for translational regulation. J Biol Chem 276(12):8705–8712
106. Peixoto PM, Kim HJ, Sider B, Starkov A, Horvath TL, Manfredi G (2013) UCP2 overexpression worsens mitochondrial dysfunction and accelerates disease progression in a mouse model of amyotrophic lateral sclerosis. Mol Cell Neurosci 57:104–110
107. Pfeiffer M, Kayzer EB, Yang X, Abramson E, Kenaston MA, Lago CU et al (2011) Caenorhabditis elegans UCP4 protein controls complex II-mediated oxidative phosphorylation through succinate transport. J Biol Chem 286(43):37712–37720
108. Pieczenik SR, Neustadt J (2007) Mitochondrial dysfunction and molecular pathways of disease. Exp Mol Pathol 83(1):84–92
109. Ramsden DB, Ho PW, Ho JW, Liu HF, So DH, Tse HM et al (2012) Human neuronal uncoupling proteins 4 and 5 (UCP4 and UCP5): structural properties, regulation, and physiological role in protection against oxidative stress and mitochondrial dysfunction. Brain Behav 2(4):468–478
110. 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(12):e29650
111. Rossmeisl M, Syrovy I, Baumruk F, Flachs P, Janovska P, Kopecky J (2000) Decreased fatty acid synthesis due to mitochondrial uncoupling in adipose tissue. FASEB J 14(12):1793–1800
112. Rudofsky G Jr, Schroedter A, Schlotterer A, Vorońko OE, Schlimme M, Tafel J et al (2006) Functional polymorphisms of UCP2 and UCP3 are associated with a reduced prevalence of diabetic neuropathy in patients with type 1 diabetes. Diabetes Care 29(1):89–94
113. Sanchis D, Fleury C, Chomiki N, Goubern M, Huang Q, Neverova M et al (1998) 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 273(51):34611–34615
114. Schrauwen P, Hesselink M (2002) UCP2 and UCP3 in muscle controlling body metabolism. J Exp Biol 205(Pt 15):2275–2285
115. Senapedis WT, Kennedy CJ, Boyle PM, Silver PA (2011) Whole genome siRNA cell-based screen links mitochondria to Akt signaling network through uncoupling of electron transport chain. Mol Biol Cell 22(10):1791–1805
116. Shabalina IG, Jacobsson A, Cannon B, Nedergaard J (2004) Native UCP1 displays simple competitive kinetics between the regulators purine nucleotides and fatty acids. J Biol Chem 279(37):38236–38248
117. 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(8):e42911
118. Skulachev VP (1991) Fatty acid circuit as a physiological mechanism of uncoupling of oxidative phosphorylation. FEBS Lett 294(3):158–162
119. Skulachev VP (1996) Role of uncoupled and non-coupled oxidations in maintenance of safely low levels of oxygen and its one-electron reductants. Q Rev Biophys 29(2):169–202
120. Sluse FE (1996) Mitochondrial metabolite carrier family, topology, structure and functional properties: an overview. Acta Biochim Pol 43(2):349–360
121. Sluse FE (2012) Uncoupling proteins: molecular, functional, regulatory, physiological and pathological aspects. Adv Exp Med Biol 942:137–156
122. Solanes G, Pedraza N, Iglesias R, Giralt M, Villarroya F (2003) Functional relationship between MyoD and peroxisome proliferator-activated receptor-dependent regulatory pathways in the control of the human uncoupling protein-3 gene transcription. Mol Endocrinol 17(10):1944–1958
123. Speakman JR, Talbot DA, Selman C, Snart S, McLaren JS, Redman P et al (2004) Uncoupled and surviving: individual mice with high metabolism have greater mitochondrial uncoupling and live longer. Aging Cell 3(3):87–95
124. Speijer D (2014) How the mitochondrion was shaped by radical differences in substrates: what carnitine shuttles and uncoupling tell us about mitochondrial evolution in response to ROS. Bioessays 36(7):634–643
125. Sun XL, Liu Y, Dai T, Ding JH, Hu G (2011) Uncoupling protein 2 knockout exacerbates depression-like behaviors in mice via enhancing inflammatory response. Neuroscience 192:507–514
126. Szklarczyk R, Huynen MA (2010) Mosaic origin of the mitochondrial proteome. Proteomics 10(22):4012–4024
127. Taguchi A, White MF (2008) Insulin-like signaling, nutrient homeostasis, and life span. Annu Rev Physiol 70:191–212
128. 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(10):2730–2736
129. Velloso LA, Degasperi GR, Vercesi AE, Saad MA (2009) Methods for assessing and modulating UCP2 expression and function. Methods Enzymol 457:395–404
130. Wei Z, Chigurupati S, Bagsiyao P, Henriquez A, Chan SL (2009) The brain uncoupling protein UCP4 attenuates mitochondrial toxin-induced cell death: role of extracellular signal-regulated kinases in bioenergetics adaptation and cell survival. Neurotox Res 16(1):14–29
131. Wolkow CA, Iser WB (2006) Uncoupling protein homologs may provide a link between mitochondria, metabolism and lifespan. Ageing Res Rev 5(2):196–208
132. Yu XX, Mao W, Zhong A, Schow P, Brush J, Sherwood SW et al (2000) Characterization of novel UCP5/BMCP1 isoforms and differential regulation of UCP4 and UCP5 expression through dietary or temperature manipulation. FASEB J 14(11):1611–1618
133. Zhang CY, Baffy G, Perret P, Krauss S, Peroni O, Grujic D 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(6):745–755
134. Zhang M, Wang B, Ni YH, Liu F, Fei L, Pan XQ et al (2006) Overexpression of uncoupling protein 4 promotes proliferation and inhibits apoptosis and differentiation of preadipocytes. Life Sci 79(15):1428–1435
135. Zhou M, Xu A, Tam PK, Lam KS, Huang B, Liang Y et al (2012) Upregulation of UCP2 by adiponectin: the involvement of mitochondrial superoxide and hnRNP K. PLoS One 7(2):e32349