Mitochondrial uncoupling proteins in the cns: in support of function and survival


Mitochondrial uncoupling mediated by uncoupling protein 1 (UCP1) is classically associated with non-shivering thermogenesis by brown fat. Recent evidence indicates that UCP family proteins are also present in selected neurons. Unlike UCP1, these proteins (UCP2, UCP4 and BMCP1/UCP5) are not constitutive uncouplers and are not crucial for non-shivering thermogenesis. However, they can be activated by free radicals and free fatty acids, and their activity has a profound influence on neuronal function. By regulating mitochondrial biogenesis, calcium flux, free radical production and local temperature, neuronal UCPs can directly influence neurotransmission, synaptic plasticity and neurodegenerative processes. Insights into the regulation and function of these proteins offer unsuspected avenues for a better understanding of synaptic transmission and neurodegeneration.

Key Points

  • Neuronal uncoupling proteins (UCP2, UCP4, BMCP1/UCP5) are integral membrane proteins located in the inner mitochondrial membrane that allow controlled 'proton leak' into the mitochondrial matrix. This controlled proton leak, or uncoupling activity, reduces the mitochondrial membrane potential — the proton motive force that drives ATP synthesis and dissipates energy as heat.

  • UCP mRNA and protein are found throughout the CNS, including in the hypothalamus, hippocampus, cerebellum, limbic system, spinal cord, brainstem, cortex, substantia nigra and ventral tegmentum. The global distribution of UCP proteins in the CNS suggests that they have an important role in neuronal function.

  • Chronic mitochondrial uncoupling leads to reduced reactive oxygen species production, reduced membrane potential-dependent mitochondrial calcium influx, increased local temperature in neuronal microenvironments, and, paradoxically, promotes cellular ATP concentrations by activating mitochondrial biogenesis. Through these mechanisms, it is thought that neuronal UCPs can positively influence neuronal function, including synaptic plasticity and synaptic transmission, and retard the neuronal deterioration that is associated with neurological disorders.

  • Neuronal uncoupling activity is known to help prevent neuronal death in ageing and in many models of neurodegeneration, including Parkinson's disease, epilepsy, ischaemia, stroke and traumatic brain injury in vivo. In all of these neuropathologies, neuronal mitochondrial uncoupling reduces free radical production and oxidative stress.

  • Many other debilitating neurological conditions that have similar aetiologies to those described above, such as Alzhemier's diease and amyotrophic lateral sclerosis, are also likely to benefit from neuronal uncoupling activity. However, this hypothesis eagerly awaits future research.

  • Because mitochondrial dysfunction lies at the heart of many neurological disorders, advances in our understanding of neuronal UCP function are likely to deliver successful clinical treatment strategies against these neurological pathologies. Many of these advances will rely on improved technical approaches to clarify tissue-specific functions of UCP biology.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: The mechanism of mitochondrial uncoupling.
Figure 2: Proposed mechanism through which neuronal uncoupling proteins can regulate neuronal function.
Figure 3: Uncoupling protein 2 reduces reactive oxygen species production in vivo.
Figure 4: Superoxides activate uncoupling proteins via a mitochondrial feedback loop.
Figure 5: Fatty acid-induced uncoupling activity in UCP2-knockout mice and mice that overexpress human UCP2.
Figure 6: Uncoupling protein 2 prevents dopamine cell loss in the substantia nigra after MPTP treatment.


  1. 1

    Krauss, S., Zhang, C. Y. & Lowell, B. B. The mitochondrial uncoupling-protein homologues. Nature Rev. Mol. Cell Biol. 6, 248–261 (2005). An up-to-date review on the biochemical regulation of UCPs.

  2. 2

    Nicholls, D. G. & Locke, R. M. Thermogenic mechanisms in brown fat. Physiol. Rev. 64, 1–64 (1984). Seminal review on the actions of UCP1 in brown adipose tissue.

  3. 3

    Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).

  4. 4

    Skulachev, V. P. Uncoupling: new approaches to an old problem of bioenergetics. Biochim. Biophys. Acta 1363, 100–124 (1998).

  5. 5

    Fleury, C. et al. Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nature Genet. 15, 269–272 (1997).

  6. 6

    Boss, O. et al. Uncoupling protein-3: a new member of the mitochondrial carrier family with tissue-specific expression. FEBS Lett. 408, 39–42 (1997).

  7. 7

    Mao, W. et al. UCP4, a novel brain-specific mitochondrial protein that reduces membrane potential in mammalian cells. FEBS Lett. 443, 326–330 (1999).

  8. 8

    Sanchis, D. 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. 273, 34611–34615 (1998). References 5, 7 and 8 are the original papers describing the discovery of UCP2, UCP4 and BMCP1/UCP5.

  9. 9

    Miroux, B., Frossard, V., Raimbault, S., Ricquier, D. & Bouillaud, F. The topology of the brown adipose tissue mitochondrial uncoupling protein determined with antibodies against its antigenic sites revealed by a library of fusion proteins. EMBO J. 12, 3739–3745 (1993).

  10. 10

    Saier, M. H. Jr. Vectorial metabolism and the evolution of transport systems. J. Bacteriol. 182, 5029–5035 (2000).

  11. 11

    Richard, D. et al. Distribution of the uncoupling protein 2 mRNA in the mouse brain. J. Comp. Neurol. 397, 549–560 (1998).

  12. 12

    Richard, D., Clavel, S., Huang, Q., Sanchis, D. & Ricquier, D. Uncoupling protein 2 in the brain: distribution and function. Biochem. Soc. Trans. 29, 812–817 (2001).

  13. 13

    Diano, S. et al. Mitochondrial uncoupling protein 2 (UCP2) in the nonhuman primate brain and pituitary. Endocrinology 141, 4226–4638 (2000).

  14. 14

    Horvath, T. L. et al. Brain uncoupling protein 2: uncoupled neuronal mitochondria predict thermal synapses in homeostatic centers. J. Neurosci. 19, 10417–10427 (1999). Illustrates hypothalamic expression of UCP2 protein and establishes the putative role of UCP2 in producing local temperature gradients that may enhance synaptic function.

  15. 15

    Horvath, T. L. et al. Coenzyme Q induces nigral mitochondrial uncoupling and prevents dopamine cell loss in a primate model of Parkinson's disease. Endocrinology 144, 2757–2760 (2003).

  16. 16

    Kim-Han, J. S., Reichert, S. A., Quick, K. L. & Dugan, L. L. BMCP1: a mitochondrial uncoupling protein in neurons which regulates mitochondrial function and oxidant production. J. Neurochem. 79, 658–668 (2001).

  17. 17

    Yamada, S., Isojima, Y., Yamatodani, A. & Nagai, K. Uncoupling protein 2 influences dopamine secretion in PC12h cells. J. Neurochem. 87, 461–469 (2003).

  18. 18

    Zhang, C. Y. et al. 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 (2001).

  19. 19

    Arsenijevic, D. et al. Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nature Genet. 26, 435–439 (2000).

  20. 20

    Fuxe, K. et al. Dynamics of volume transmission in the brain. Focus on catecholamine and opioid peptide communication and the role of uncoupling protein 2. J. Neural Transm. 112, 65–76 (2005).

  21. 21

    Nicholls, D. G. & Ward, M. W. Mitochondrial membrane potential and neuronal glutamate excitotoxicity: mortality and millivolts. Trends Neurosci. 23, 166–174 (2000).

  22. 22

    Stout, A. K., Raphael, H. M., Kanterewicz, B. I., Klann, E. & Reynolds, I. J. Glutamate-induced neuron death requires mitochondrial calcium uptake. Nature Neurosci. 1, 366–373 (1998). Shows that mitochondrial uncoupling agents reduce the mitochondrial membrane potential, decrease calcium overload and prevent glutamatergic neuronal death.

  23. 23

    Teshima, Y., Akao, M., Jones, S. P. & Marban, E. Uncoupling protein-2 overexpression inhibits mitochondrial death pathway in cardiomyocytes. Circ. Res. 93, 192–200 (2003).

  24. 24

    Diano, S. et al. Uncoupling protein 2 prevents neuronal death including that occurring during seizures: a mechanism for preconditioning. Endocrinology 144, 5014–5021 (2003). Provides the first experimental indication that sustained elevated mitochondrial uncoupling triggers mitochondrial proliferation in which elevated ATP levels are associated with decreased free radical-induced damage. Therefore, cells are better prepared to withstand toxic insults.

  25. 25

    Garcia-Martinez, C. et al. 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, 2033–2035 (2001).

  26. 26

    Andrews, Z. B. et al. Uncoupling protein-2 is critical for nigral dopamine cell survival in a mouse model of Parkinson's disease. J. Neurosci. 25, 184–191 (2005). The first report to show that UCP2-knockout mice are predisposed, whereas animals that overexpress UCP2 are resistant, to nigral neurodegeneration, probably owing to alterations in buffering in vivo ROS production.

  27. 27

    Rossmeisl, M. et al. Expression of the uncoupling protein 1 from the aP2 gene promoter stimulates mitochondrial biogenesis in unilocular adipocytes in vivo. Eur. J. Biochem. 269, 19–28 (2002).

  28. 28

    Wu, Z. et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98, 115–124 (1999). Shows that PGC1 stimulates mitochondrial biogenesis and respiration through induction of UCP2.

  29. 29

    Wisloff, U. et al. Cardiovascular risk factors emerge after artificial selection for low aerobic capacity. Science 307, 418–420 (2005).

  30. 30

    Korshunov, S. S., Skulachev, V. P. & Starkov, A. A. High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett. 416, 15–18 (1997).

  31. 31

    Sullivan, P. G., Dube, C., Dorenbos, K., Steward, O. & Baram, T. Z. Mitochondrial uncoupling protein-2 protects the immature brain from excitotoxic neuronal death. Ann. Neurol. 53, 711–717 (2003).

  32. 32

    Negre-Salvayre, A. et al. A role for uncoupling protein-2 as a regulator of mitochondrial hydrogen peroxide generation. FASEB J. 11, 809–815 (1997).

  33. 33

    Mattson, M. P. & Liu, D. Mitochondrial potassium channels and uncoupling proteins in synaptic plasticity and neuronal cell death. Biochem. Biophys. Res. Commun. 304, 539–549 (2003).

  34. 34

    Mattiasson, G. et al. Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nature Med. 9, 1062–1068 (2003). The first study to show that UCP2 provides neuroprotection against stroke and ischaemic insults. The results also suggest that UCP2 has the ability to channel ROS from the mitochondrial matrix to the cytosol, where they can be neutralized by antioxidants.

  35. 35

    Pecqueur, C. et al. Uncoupling protein 2, in vivo distribution, induction upon oxidative stress, and evidence for translational regulation. J. Biol. Chem. 276, 8705–8712 (2001).

  36. 36

    Voehringer, D. W. et al. Gene microarray identification of redox and mitochondrial elements that control resistance or sensitivity to apoptosis. Proc. Natl Acad. Sci. USA 97, 2680–2685 (2000).

  37. 37

    Echtay, K. S. et al. Superoxide activates mitochondrial uncoupling proteins. Nature 415, 96–99 (2002).

  38. 38

    Echtay, K. S., Murphy, M. P., Smith, R. A., Talbot, D. A. & Brand, M. D. Superoxide activates mitochondrial uncoupling protein 2 from the matrix side. Studies using targeted antioxidants. J. Biol. Chem. 277, 47129–47135 (2002).

  39. 39

    Echtay, K. S. et al. A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling. EMBO J. 22, 4103–4110 (2003).

  40. 40

    Couplan, E. et al. 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 (2002). References 37–40 debate the role of superoxide and markers of oxidative damage as regulators of UCP function.

  41. 41

    Mattson, M. P. Pathways towards and away from Alzheimer's disease. Nature 430, 631–639 (2004).

  42. 42

    Aihara, H., Okada, Y. & Tamaki, N. The effects of cooling and rewarming on the neuronal activity of pyramidal neurons in guinea pig hippocampal slices. Brain Res. 893, 36–45 (2001).

  43. 43

    Yu, X. X. et al. Characterization of novel UCP5/BMCP1 isoforms and differential regulation of UCP4 and UCP5 expression through dietary or temperature manipulation. FASEB J. 14, 1611–1618 (2000).

  44. 44

    Masino, S. A. & Dunwiddie, T. V. Temperature-dependent modulation of excitatory transmission in hippocampal slices is mediated by extracellular adenosine. J. Neurosci. 19, 1932–1939 (1999).

  45. 45

    Scarpace, P. J., Matheny, M., Borst, S. & Tumer, N. Thermoregulation with age: role of thermogenesis and uncoupling protein expression in brown adipose tissue. Proc. Soc. Exp. Biol. Med. 205, 154–161 (1994).

  46. 46

    Smythies, J. Redox mechanisms at the glutamate synapse and their significance: a review. Eur. J. Pharmacol. 370, 1–7 (1999).

  47. 47

    Li, Z., Okamoto, K., Hayashi, Y. & Sheng, M. The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 119, 873–887 (2004).

  48. 48

    Horvath, B., Spies, C., Warden, C. H., Diano, S. & Horvath, T. L. Uncoupling protein 2 in primary pain and temperature afferents of the spinal cord. Brain Res. 955, 260–263 (2002).

  49. 49

    Morris, R., Cheunsuang, O., Stewart, A. & Maxwell, D. Spinal dorsal horn neurone targets for nociceptive primary afferents: do single neurone morphological characteristics suggest how nociceptive information is processed at the spinal level. Brain Res. Brain Res. Rev. 46, 173–190 (2004).

  50. 50

    Horvath, B. et al. Uncoupling protein 2 (UCP2) lowers alcohol sensitivity and pain threshold. Biochem. Pharmacol. 64, 369–374 (2002).

  51. 51

    Ding, Y., Cesare, P., Drew, L., Nikitaki, D. & Wood, J. N. ATP, P2X receptors and pain pathways. J. Auton. Nerv. Syst. 81, 289–294 (2000).

  52. 52

    Mogil, J. S. The genetic mediation of individual differences in sensitivity to pain and its inhibition. Proc. Natl Acad. Sci. USA 96, 7744–7751 (1999).

  53. 53

    Henshall, D. C. & Simon, R. P. Epilepsy and apoptosis pathways. J. Cereb. Blood Flow Metab. 11 May 2005 (10.1038/sj.jcbfm.9600149).

  54. 54

    Patel, M., Day, B. J., Crapo, J. D., Fridovich, I. & McNamara, J. O. Requirement for superoxide in excitotoxic cell death. Neuron 16, 345–355 (1996).

  55. 55

    Reynolds, I. J. & Hastings, T. G. Glutamate induces the production of reactive oxygen species in cultured forebrain neurons following NMDA receptor activation. J. Neurosci. 15, 3318–3327 (1995).

  56. 56

    Schulz, J. B. et al. Involvement of free radicals in excitotoxicity in vivo. J. Neurochem. 64, 2239–2247 (1995).

  57. 57

    Billups, B. & Forsythe, I. D. Presynaptic mitochondrial calcium sequestration influences transmission at mammalian central synapses. J. Neurosci. 22, 5840–5847 (2002).

  58. 58

    Nicholls, D. G. & Budd, S. L. Mitochondria and neuronal glutamate excitotoxicity. Biochim. Biophys. Acta 1366, 97–112 (1998).

  59. 59

    Maragos, W. F., Rockich, K. T., Dean, J. J. & Young, K. L. Pre- or post-treatment with the mitochondrial uncoupler 2,4-dinitrophenol attenuates striatal quinolinate lesions. Brain Res. 966, 312–316 (2003).

  60. 60

    Bagetta, G. et al. Abnormal expression of neuronal nitric oxide synthase triggers limbic seizures and hippocampal damage in rat. Biochem. Biophys. Res. Commun. 291, 255–260 (2002).

  61. 61

    Bellissimo, M. I. et al. Superoxide dismutase, glutathione peroxidase activities and the hydroperoxide concentration are modified in the hippocampus of epileptic rats. Epilepsy Res. 46, 121–128 (2001).

  62. 62

    Gupta, R. C., Milatovic, D. & Dettbarn, W. D. Nitric oxide modulates high-energy phosphates in brain regions of rats intoxicated with diisopropylphosphorofluoridate or carbofuran: prevention by N-tert-butyl-alpha-phenylnitrone or vitamin E. Arch. Toxicol. 75, 346–356 (2001).

  63. 63

    Blumcke, I. et al. Cellular pathology of hilar neurons in Ammon's horn sclerosis. J. Comp. Neurol. 414, 437–453 (1999).

  64. 64

    Clavel, S., Paradis, E., Ricquier, D. & Richard, D. Kainic acid upregulates uncoupling protein-2 mRNA expression in the mouse brain. Neuroreport 14, 2015–2017 (2003).

  65. 65

    Schauwecker, P. E. & Steward, O. Genetic determinants of susceptibility to excitotoxic cell death: implications for gene targeting approaches. Proc. Natl Acad. Sci. USA 94, 4103–4108 (1997).

  66. 66

    Sullivan, P. G., Springer, J. E., Hall, E. D. & Scheff, S. W. Mitochondrial uncoupling as a therapeutic target following neuronal injury. J. Bioenerg. Biomembr. 36, 353–356 (2004).

  67. 67

    Nevo, Y. et al. Unprovoked seizures and developmental disabilities: clinical characteristics of children referred to a child development center. Pediatr. Neurol. 13, 235–241 (1995).

  68. 68

    Hauser, W. A. The prevalence and incidence of convulsive disorders in children. Epilepsia 35 (Suppl. 2), S1–S6 (1994).

  69. 69

    Dal-Pizzol, F. et al. Lipid peroxidation in hippocampus early and late after status epilepticus induced by pilocarpine or kainic acid in Wistar rats. Neurosci. Lett. 291, 179–182 (2000).

  70. 70

    Sullivan, P. G. et al. The ketogenic diet increases mitochondrial uncoupling protein levels and activity. Ann. Neurol. 55, 576–580 (2004).

  71. 71

    Conti, B. et al. Uncoupling protein 2 protects dopaminergic neurons from acute 1,2,3,6-methyl-phenyl-tetrahydropyridine toxicity. J. Neurochem. 93, 493–501 (2005).

  72. 72

    Duan, W. & Mattson, M. P. Dietary restriction and 2-deoxyglucose administration improve behavioral outcome and reduce degeneration of dopaminergic neurons in models of Parkinson's disease. J. Neurosci. Res. 57, 195–206 (1999).

  73. 73

    Beal, M. F., Matthews, R. T., Tieleman, A. & Shults, C. W. Coenzyme Q10 attenuates the 1-methyl-4-phenyl-1,2,3,tetrahydropyridine (MPTP) induced loss of striatal dopamine and dopaminergic axons in aged mice. Brain Res. 783, 109–114 (1998).

  74. 74

    Shults, C. W. et al. Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch. Neurol. 59, 1541–1550 (2002).

  75. 75

    Thiruchelvam, M. et al. Age-related irreversible progressive nigrostriatal dopaminergic neurotoxicity in the paraquat and maneb model of the Parkinson's disease phenotype. Eur. J. Neurosci. 18, 589–600 (2003).

  76. 76

    Gonzalez-Polo, R. A., Soler, G., Rodriguezmartin, A., Moran, J. M. & Fuentes, J. M. Protection against MPP+ neurotoxicity in cerebellar granule cells by antioxidants. Cell Biol. Int. 28, 373–380 (2004).

  77. 77

    McCarthy, S., Somayajulu, M., Sikorska, M., Borowy-Borowski, H. & Pandey, S. Paraquat induces oxidative stress and neuronal cell death; neuroprotection by water-soluble Coenzyme Q10. Toxicol. Appl. Pharmacol. 201, 21–31 (2004).

  78. 78

    Bechmann, I. et al. Brain mitochondrial uncoupling protein 2 (UCP2): a protective stress signal in neuronal injury. Biochem. Pharmacol. 64, 363–367 (2002). Provided the first in vivo experimental evidence that UCP2 may function as a neuroprotector in the brain.

  79. 79

    Sullivan, P. G., Keller, J. N., Mattson, M. P. & Scheff, S. W. Traumatic brain injury alters synaptic homeostasis: implications for impaired mitochondrial and transport function. J. Neurotrauma 15, 789–798 (1998).

  80. 80

    Sullivan, P. G. et al. Exacerbation of damage and altered NF-κB activation in mice lacking tumor necrosis factor receptors after traumatic brain injury. J. Neurosci. 19, 6248–6256 (1999).

  81. 81

    de Bilbao, F. et al. 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, 1283–1292 (2004).

  82. 82

    Ross, C. A. & Poirier, M. A. Protein aggregation and neurodegenerative disease. Nature Med. 10 (Suppl.), S10–S17 (2004).

  83. 83

    Watson, G. S. & Craft, S. The role of insulin resistance in the pathogenesis of Alzheimer's disease: implications for treatment. CNS Drugs 17, 27–45 (2003).

  84. 84

    Blass, J. P. Brain metabolism and brain disease: is metabolic deficiency the proximate cause of Alzheimer dementia? J. Neurosci. Res. 66, 851–856 (2001).

  85. 85

    Hand, C. K. & Rouleau, G. A. Familial amyotrophic lateral sclerosis. Muscle Nerve 25, 135–159 (2002).

  86. 86

    Rosen, D. R. et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59–62 (1993).

  87. 87

    Menzies, F. M., Ince, P. G. & Shaw, P. J. Mitochondrial involvement in amyotrophic lateral sclerosis. Neurochem. Int. 40, 543–551 (2002).

  88. 88

    Balaban, R. S., Nemoto, S. & Finkel, T. Mitochondria, oxidants, and aging. Cell 120, 483–495 (2005).

  89. 89

    Harman, D. Aging: a theory based on free radical and radiation chemistry. J. Gerontol. 11, 298–300 (1956).

  90. 90

    Dauer, W. & Przedborski, S. Parkinson's disease: mechanisms and models. Neuron 39, 889–909 (2003).

  91. 91

    Horvath, T. L. et al. Uncoupling proteins-2 and 3 influence obesity and infIammation in transgenic mice. Int. J. Obes. 27, 433–442 (2003).

  92. 92

    Fridell, Y. W., Sanchez-Blanco, A., Silvia, B. A. & Helfand, S. L. Targeted expression of the human uncoupling protein 2 (hUCP2) to adult neurons extends life span in the fly. Cell Metab. 1, 145–152 (2005). The first study to show that neuron-specific UCP2 promotes longevity, through a reduction in oxidative stress, without compromising fertility or physical activity.

  93. 93

    Speakman, J. R. et al. Uncoupled and surviving: individual mice with high metabolism have greater mitochondrial uncoupling and live longer. Aging Cell 3, 87–95 (2004).

  94. 94

    Brand, M. D. Uncoupling to survive? The role of mitochondrial inefficiency in ageing. Exp. Gerontol. 35, 811–820 (2000). First formulation of the hypothesis that enhanced uncoupled respiration promotes longevity.

  95. 95

    Echtay, K. S., Winkler, E., Frischmuth, K. & Klingenberg, M. 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 (2001).

  96. 96

    Echtay, K. S., Winkler, E. & Klingenberg, M. Coenzyme Q is an obligatory cofactor for uncoupling protein function. Nature 408, 609–613 (2000).

  97. 97

    Esteves, T. C. & Brand, M. D. The reactions catalysed by the mitochondrial uncoupling proteins UCP2 and UCP3. Biochim. Biophys. Acta 1709, 35–44 (2005).

  98. 98

    Jaburek, M. et al. Transport function and regulation of mitochondrial uncoupling proteins 2 and 3. J. Biol. Chem. 274, 26003–26007 (1999).

  99. 99

    Echtay, K. S. et al. Regulation of UCP3 by nucleotides is different from regulation of UCP1. FEBS Lett. 450, 8–12 (1999).

  100. 100

    Jaburek, M. & Garlid, K. D. Reconstitution of recombinant uncoupling proteins: UCP1, -2, and -3 have similar affinities for ATP and are unaffected by coenzyme Q10. J. Biol. Chem. 278, 25825–25831 (2003).

  101. 101

    Brand, M. D. & Esteves, T. C. Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3. Cell Metab. 2, 85–93 (2005).

  102. 102

    Garlid, K. D., Jaburek, M. & Jezek, P. Mechanism of uncoupling protein action. Biochem. Soc. Trans. 29, 803–806 (2001).

  103. 103

    Sivitz, W. I., Fink, B. D. & Donohoue, P. A. Fasting and leptin modulate adipose and muscle uncoupling protein: divergent effects between messenger ribonucleic acid and protein expression. Endocrinology 140, 1511–1519 (1999).

Download references


Authors' research projects associated with mechanisms discussed in this paper have been supported by an OTKA grant and the following institutes of the National Institutes of Health (NIH): National Institute on Aging (NIA), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of Neurological Disorders and Stroke (NINDS).

Author information

Correspondence to Tamas L. Horvath.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links


Entrez Gene


caspase 3









Alzheimer's disease

Amyotrophic lateral sclerosis

Parkinson's disease



This comprises a series of five enzyme and protein complexes associated with the inner mitochondrial membrane. It converts energy in the form of the electron transfer potential of NADH and FADH2 into the energy found in the terminal phosphate of ATP, consuming oxygen and producing water in the process.


An exogenous system used to generate superoxide and study the molecular and cellular consequences of superoxide production.


A cloned rat pheochromocytomal cell line that retains a number of chromaffin cell characteristics, including the synthesis and secretion of catecholamines and the expression of various neuropeptide genes. PC12 cells are often used to study the cell biology of neuronal genes after transfection.


(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). A toxic by-product of the chemical synthesis of a meperidine analogue that induces a parkinsonian syndrome that is almost indistinguishable from Parkinson's disease. MPTP is commonly used to study cellular and molecular aspects of Parkinson's disease in mice and monkeys, as it specifically induces dopaminergic neurodegeneration in the substantia nigra.


(2,3-dimethyloxy-5-methyl-6-multiprenyl-1,4-benzoquinone; also known as ubiquinone). A mobile electron carrier from complexes 1 and 2 to complex 3 of the electron transfer chain that is located in the hydrophobic domain of the inner mitochondrial membrane. It also acts, with vitamin E, to provide anitoxidative protection.


A state of mitochondrial respiration that requires oligomycin to prevent ADP phosphorylation (state 3 respiration) by blocking protons from interacting with ATP synthase. State 4 respiration is a direct measure of mitochondrial uncoupling activity.


A process that occurs after sublethal ischaemic insults. Neurons activate defensive mechanisms, such as cellular calcium buffering and antioxidants systems, that counteract ischaemic damage.

Rights and permissions

Reprints and Permissions

About this article

Further reading