Skip to main content
SpringerLink
Log in

Mitochondrial UCP4 mediates an adaptive shift in energy metabolism and increases the resistance of neurons to metabolic and oxidative stress

  • Original Article
  • Published:
NeuroMolecular Medicine Aims and scope Submit manuscript

Abstract

The high-metabolic demand of neurons and their reliance on glucose as an energy source places them atrisk for dysfunction and death under conditions of metabolic and oxidative stress. Uncoupling proteins (UCPs) are mitochodrial inner membrane proteins implicated in the regulation of mitochondrial membrane potential (ΔΨm) and cellular energy metabolism. The authors cloned UCP4 cDNA from mouse and rat brain, and demonstrate that UCP4 mRNA is expressed abundantly in brain and at particularly high levels in populations of neurons believed to have high-energy requirements. Neural cells with increased levels of UCP4 exhibit decreased ΔΨm, reduced reactive oxygen species (ROS) production and decreased mitochondrial calcium accumulation. UCP4 expressing cells also exhibited changes of oxygen-consumption rate, GDP sensitivity, and response of ΔΨm to oligomycin that were consistent with mitochondrial uncoupling. UCP4 modulates neuronal energy metabolism by increasing glucose uptake and shifting the mode of ATP production from mitochodnrial respiration to glycolysis, thereby maintaining cellular ATP levels. The UCP4-mediated shift in energy metabolism reduces ROS production and increases the resistance of neurons to oxidative and mitochondrial stress. Knockdown of UCP4 expression by RNA interference in primary hippocampal neurons results in mitochondrial calcium overload and cell death. UCP4-mRNA expression is increased in neurons exposed to cold temperatures and in brain cells of rats maintained on caloric restriction, suggesting a role for UCP4 in the previously reported antiageing and neuroprotective effects of caloric restriction. By shifting energy metabolism to reduce ROS production and cellular reliance on mitochondrial respiration, UCP4 can protect neurons against oxidative stress and calcium overload.

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

Similar content being viewed by others

References

  • Alano C. C., Beutner G., Dirksen R. T., Gross R. A., and Sheu S. S. (2002) Mitochondrial permeability transition and calcium dynamics in striatal neurons upon intense NMDA receptor activation. J. Neurochem. 80, 531–538.

    Article  PubMed  CAS  Google Scholar 

  • Almeida A., Almeida J., Bolanos J. P., and Moncada S. (2001) Different responses of astrocytes and neurons to nitric oxide: the role of glycolytically generated ATP in astrocyte protection. Proc. Natl. Acad. Sci. USA 98, 15,294–15,299.

    Article  CAS  Google Scholar 

  • Andrews Z. B., Horvath B., Barnstable C. J., et al. (2005) Uncoupling protein-2 is critical for nigral dopamine cell survival in a mouse model of Parkinson's disease. J. Neurosci. 25, 184–191.

    Article  PubMed  CAS  Google Scholar 

  • Andreyev A., Bondareva T., Dedukhova V. I., et al. (1989) The ATP/ADP-antiporter is involved in the uncoupling effect of fatty acids on mitochondria. Eur. J. Biochem. 182, 585–592.

    Article  PubMed  Google Scholar 

  • Argiles J. M., Busquets S., and Lopez-Soriano F. J. (2002) The role of uncoupling proteins in pathophysiological states. Biochem. Biophys. Res. Commun. 293, 1145–1152.

    Article  PubMed  CAS  Google Scholar 

  • Argyropoulos G. and Harper M. E. (2002) Uncoupling proteins and thermoregulation. J. Appl. Physiol. 92, 2187–2198.

    PubMed  CAS  Google Scholar 

  • Arsenijevic D., Onuma H., Pecqueur C., 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.

    Article  PubMed  CAS  Google Scholar 

  • Beal M. F. (1998) Mitochondrial dysfunction in neurodegenerative diseases. Biochim. Biophys. Acta 1366, 211–223.

    Article  PubMed  CAS  Google Scholar 

  • Bechmann I., Diano S., Warden C. H., Cartfai T., Nitsch R., and Horvath T. L. (2002) Brain mitochondrial uncoupling protein 2 (UCP2): a protective stress signal in neuronal injury. Biochem. Pharmacol. 64, 363–367.

    Article  PubMed  CAS  Google Scholar 

  • Behrens M. L., Koh J. Y., Muller M. C., and Choi D. W. (1996) NADPH diaphorase-containing striatal or cortical neurons are resistant to apoptosis. Neurobiol. Dis. 3, 72–75.

    Article  PubMed  CAS  Google Scholar 

  • Bose O., Samec S., Dulloo A., Seydoux J., Muzzin P., and Giacobino J. P. (1997) Tissue-dependent upregulation of rat uncoupling protein-2 expression in response to fasting or cold. FEBS Lett. 412, 111–114.

    Article  Google Scholar 

  • Brouillet E., Hantraye P., Ferrante R. J., et al. (1995) Chronic mitochondrial energy impairment produces selective striatal degeneration and abnormal choreiform movements in primates. Proc. Natl. Acad. Sci. USA 92, 7105–7109.

    Article  PubMed  CAS  Google Scholar 

  • Brouillet E., Conde F., Beal M. F., and Hantraye P. (1999) Replicating Huntington's disease phenotype in experimental animals. Prog. Neurobiol. 59, 427–468.

    Article  PubMed  CAS  Google Scholar 

  • Brown G. C. and Bonitaite V. (2001) Nitric oxide, mitochondria, and cell death. IUBMB Life 52, 189–195.

    PubMed  CAS  Google Scholar 

  • Bruce-Keller A. J., Umberger G., McFall R., and Mattson M. P. (1999) Food restriction reduces brain damage and improves behavioral outcome following excitotoxic and metabolic insults. Ann. Neurol. 45, 8–15.

    Article  PubMed  CAS  Google Scholar 

  • Besquets S., Sanchis D., Alvarez B., Ricquier D., Lopez-Soriano F. J., and Argiles J. M. (1998) In the rat, tumor necrosis factor alpha administration results in an increase in both UCP2 and UCP3 mRNAs in skeletal muscle: a possible mechanism for cytokine-induced thermogenesis? FEBS Lett. 440, 348–350.

    Article  Google Scholar 

  • Cadenas S. and Brand M. D. (2000) Effects of magnesium and nucleotides on the proton conductance of rat skeletal-muscle mitochondria. Biochem. J. 348, 209–213.

    Article  PubMed  CAS  Google Scholar 

  • Cabo R. D., Fürer-Gálban S., Anson R. M., Gilman C., Gorospe M., and Lane M. A. (2003) An in vitro model of caloric restriction. Exp. Gerontol. 38, 631–639.

    Article  PubMed  CAS  Google Scholar 

  • Chan C. B., MacDonald P. E., Saleh M. C., John D. C., Marban E., and Wheeler M. B. (1999) Overexpression of uncoupling protein 2 inhibits glucose-stimulated insulin secretion from rat islets. Diabetes 48, 1482–1486.

    Article  PubMed  CAS  Google Scholar 

  • Chan S. L., Fu W., Zhang P., et al. (2004) Herp stabilizes neuronal Ca2+ homeostasis and mitochondrial function during endoplasmic reticulum stress. J. Biol. Chem. 279, 28,733–28,743.

    CAS  Google Scholar 

  • Chittajallu R., Alford S., and Collingridge G. L. (1998) Ca2+ and synaptic plasticity. Cell Calcium 24, 377–385.

    Article  PubMed  CAS  Google Scholar 

  • De Cabo R., Furer-Galban S., Anson R. M., Gilman C., Gorospe M., and Lane M. A. (2003) An in vitro model of caloric restriction. Exp. Gerontol. 38, 631–639.

    Article  PubMed  CAS  Google Scholar 

  • Deshmukh M. and Johnson E. M. (1997) Programmed cell death in neurons: focus on the pathway of nerve growth factor deprivation-induced death of sympathetic neurons. Mol. Pharmacol. 51, 897–906.

    PubMed  CAS  Google Scholar 

  • Diano S., Matthews R. T., Patrylo P., et al. (2003) Uncoupling protein 2 prevents neuronal death including that occurring during seizures: a mechanism for preconditioning. Endocrinology 144, 5014–5021.

    Article  PubMed  CAS  Google Scholar 

  • Dubinsky J. M. and Rothman S. M. (1991) Introcelullar calcium concentrations during “chemical hypoxia” and excitotoxic neuronal injury. J. Neurosci. 11, 2545–2551.

    PubMed  CAS  Google Scholar 

  • Duffy P. H., Feuers R., Nakamura K. D., Leakey J., and Hart R. W. (1990) Effect of chronic caloric restriction on the synchronization of various physiological measures in old female fischer 344 rats. Chronob. Int. 7, 113–124.

    CAS  Google Scholar 

  • Dulloo A. G., Samec S., and Seydoux J. (2001) Uncoupling protein 3 and fatty acid metabolism. Biochem. Soc. Trans. 29, 785–791.

    Article  PubMed  CAS  Google Scholar 

  • Echtay K. S., Roussel D., St-Pierre J., et al. (2002) Superoxide activates mitochondrial uncoupling proteins. Nature 415, 96–99.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Ellison G. (1994) Stimulant-induced psychosis, the dopamine theory of schizophrenia, and the habenula. Brain Res. Rev. 19, 223–239.

    Article  PubMed  CAS  Google Scholar 

  • Erlanson-Albertsson C. (2003) The role of uncoupling proteins in the regulation of metabolism. Acta Physiol. Scand. 178, 405–412.

    Article  PubMed  CAS  Google Scholar 

  • Fransteva M. V., Carlen P. L., and Perez Velazquez J. L. (2001) Dynamics of intracellular calcium and free radical production during ischemia in pyramidal neurons. Free Radic. Biol. Med. 31, 1216–1227.

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Gibson G. E. (2002) Interactions of oxidative stress with cellular calcium dynamics and glucose metabolism in Alzheimer's disease. Free Radic. Biol. Med. 32, 1061–1070.

    Article  PubMed  CAS  Google Scholar 

  • Giovannini C., Matarrese P., Scazzocchio B., Sanchez M., Masella R., and Malorni W. (2002) Mitochondria hyperpolarization is an early event in oxidized low-density lipoprotein-induced apoptosis in CaCo2 intestinal cells. FEBS Lett. 523, 200–206.

    Article  PubMed  CAS  Google Scholar 

  • Cjeode A. and Marrett S. (2001) Glycolysis in neurons, not astrocytes, delays oxidative metabolism of human visual cortex during sustained checker-board stimulation in vivo. Cereb. Blood Flow Metab. 21, 1384–1392.

    Google Scholar 

  • Hagen T. and Lowell B. B. (2000) Chimeric proteins between UCP1 and UCP3: the middle third of UCP1 is necessary and sufficient for activation by fatty acids. Biochem. Biophys. Res. Commun. 276, 642–648.

    Article  PubMed  CAS  Google Scholar 

  • Han D., Nolte L. A., Ju J., Coleman T., Holloszy J. O., and Semenkovich C. F. (2003) UCP-mediated energy depletion in skeletal muscle increases glucose transport despite lipid accumulation and mitochondrial dysfunction. Am. J. Physiol. Endocrinol. Metab. 286, E347-E353.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Haydon P. G. and Zoran M. J. (1994) Retrograde regulation of presynaptic development during synaptogenesis. J. Neurobiol. 25, 694–706.

    Article  PubMed  CAS  Google Scholar 

  • Herst P. M., Tan A. S., Scarlett D. G., and Berridge M. V. (2004) cell surface oxygen consumption by mitochondrial gene knockout cells. Biochim. Biophys. Acta 1656, 70–87.

    Google Scholar 

  • Hou S. T. and MacManus J. P. (2002) Molecular mechanisms of cerebral ischemia-induced neuronal death. Int. Rev. Cytol. 221, 93–148.

    PubMed  CAS  Google Scholar 

  • Huppertz C., Fischer B. M., Kim Y. B., et al. (2001) uncoupling protein 3 (UCP3) stimulates glucose uptake in muscle cells through a phosphoinositide 3-kinase-dependent mechanism. J. Biol. Chem. 276, 12,520–12,529.

    Article  CAS  Google Scholar 

  • II-chenko A. P., Ogorelyshev D. I., Shishkanova N. V., Sokolov A. P., Finogenova T. V., and Kondrashova M. N. (2005) The effect of succinate on respiration, transamination, and pyruvate formation in cells of the yeast Dipodascus magnusii. Mikrobiologiia 74, 609–615.

    Google Scholar 

  • IIjima T., Mishima T., Akagawa K., and Iwao Y. (2003) Mitochondrial hyperpolarization after transient oxygen-glucose deprivation and subsequent apoptosis in cultured rat hippocampal neurons. Brain Res. 993, 140–145.

    Article  PubMed  CAS  Google Scholar 

  • Kann O., Schuchmann S., Bucheim K., and Heinemann U. (2003) Coupling of neuronal activity and mitochondrial metabolism as revealed by NAD(P)H fluorescence signals in organotypic hippocampal slice cultures of the rat. Neuroscience 119, 87–100.

    Article  PubMed  CAS  Google Scholar 

  • Keller J. N., Kindy M. S., Holtsberg F. W., et al. (1998) Mitochondrial manganese superoxide dismutase prevents neural apoptosis and reduces ischemic brain injury: suppression of peroxynitrite production, lipid peroxidation, and mitochondrial dysfunction. J. Neurosci. 18, 687–697.

    PubMed  CAS  Google Scholar 

  • Kim G. W. and Chan P. H. (2001) Oxidative stress and neuronal DNA fragmentation mediate age-dependent vulnerability to the mitochondrial toxin, 3-nitropropionic acid, in the mouse striatum. Neurobiol. Dis. 8, 114–126.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Knapp L. T. and Klann E. (2002) Role of reactive oxygen species in hippocampal long-term potentiation contributory or inhibitory? J. Neurosci. Res. 70, 1–7.

    Article  PubMed  CAS  Google Scholar 

  • Kokaia Z., Andsberg G., Martinez-Serrano A., and Lindvall O. (1998) Focal cerebral ischemia in rats induces expression of P75 neurotrophin receptor in resistant striatal cholinergic neurons. Neuroscience 84, 1113–1125.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Korshunov S. S., Korkina O. V., Ruuge E. K., Skulachev V. P., and Starkov A. A. (1998) Fatty acids as natural uncouplers preventing generation of O2 − and H2O2 by mitochondria in the resting state. FEBS Lett. 435, 215–218.

    Article  PubMed  CAS  Google Scholar 

  • Kowaltowski A. J., Smaili S. S., Russell J. T., and Fiskum G. (2000) Elevation of resting mitochondrial membrane potential of neural cells by cyclosporin A, BAPTA-AM, and bcl-2. Am. J. Physiol. Cell Physiol. 279, C852-C859.

    PubMed  CAS  Google Scholar 

  • Kowaltowski A. J., Cosso R. G., Campos C. B., and Fiskum G. (2002) Effect of bcl-2 overexpression on mitochondrial structure and function. J. Biol. Chem. 277, 42,802–42,807.

    Article  CAS  Google Scholar 

  • Kristian T. and Siesjö B. K. (1998) Calcium in ischemic cell death. Stroke 29, 705–718.

    PubMed  CAS  Google Scholar 

  • Krohn A. L., Wahlbrink T., and Prehn J. H. M. (1999) Mitochondrial depolarization is not required for neuronal apoptosis. J. Neurosci. 19, 7394–7404.

    PubMed  CAS  Google Scholar 

  • Kruman I. I., Bruce-Keller A. J., Bredesen D., Waeg G., and Mattson M. P. (1997) Evidence that 4-hydroxynonenal mediates oxidative stress-induced neuronal apoptosis. J. Neurosci. 17, 5089–5100.

    PubMed  CAS  Google Scholar 

  • Kruman I. I. and Mattson M. P. (1999) Pivotal role of mitochondrial calcium uptake in neural cell apoptosis and necrosis. J. Neurochem. 72, 529–540.

    Article  PubMed  CAS  Google Scholar 

  • Li B., Nolte L. A., Ju J., et al. (2000) Skeletal muscle respiratory uncoupling prevents diet-induced obesity and insulin resistance in mice. Nat. Med. 6, 1115–1120.

    Article  PubMed  CAS  Google Scholar 

  • Li L., Prabhakaran K., Shou Y., Borowitz J. L., and Isom G. E. (2002) Oxidative stress and cyclooxygenase-2 induction mediate cyanide-induced apoptosis of cortical cells. Toxicol. Appl. Pharmacol. 185, 55–63.

    Article  PubMed  CAS  Google Scholar 

  • Lin S. and Huang X. F. (1997) Fasting increases leptin receptor mRNA expression in lean but not obese (ob/ob) mouse brain. Neuroreport 8, 3625–3629.

    PubMed  CAS  Google Scholar 

  • Liu D., Lu C., Wan R., Auyeung W. W., and Mattson M. P. (2002) Activation of mitochondrial ATP-dependent potassium channels protects neurons against ischemia-induced death by a mechanism involving suppression of Bax translocation and cytochrome c release. J. Cereb. Blood Flow Metab. 22, 431–443.

    Article  PubMed  CAS  Google Scholar 

  • Lynch R. M., Tompkins L. S., Brooks H. L., Dunn-Meynell A. A., and Levin B. E. (2000) Localization of glucokinase gene expression in the rat brain. Diabetes 49, 693–700.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Mark R. J., Pang Z., Geddes J. W., Uchida K., and Mattson M. P. (1997) Amyloid beta-peptide impairs glucose transport in hippocampal and cortical neurons: involvement of membrane lipid peroxidation. J. Neurosci. 17, 1046–1054.

    PubMed  CAS  Google Scholar 

  • Maswood N., Young J., Tilmont E., et al. (2004) Caloric restriction increases neurotrophic factor levels and attenuates neurochemical and behavioral deficits in a primate model of Parkinson's disease. Proc. Natl. Acad. Sci. USA 101, 18,171–18,176.

    Article  CAS  Google Scholar 

  • Mattiasson G., Shamboo M., Gido G., et al. (2003) Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nat. Med. 9, 1062–1068.

    Article  PubMed  CAS  Google Scholar 

  • Mattson M. P., Barger S. W., Begley J. G., and Mark R. L. (1995) Calcium, free radicals, and excitotoxic neuronal death in primary cell culture. Methods Cell Biol. 46, 187–216.

    PubMed  CAS  Google Scholar 

  • Mattson M. P. and Liu D. (2002) Energetics and oxidative stress in synaptic plasticity and neurodegenerative disorders. Neuromolecular Med. 2, 215–231.

    Article  PubMed  CAS  Google Scholar 

  • Mattson M. P. (2003) Gene-diet interactions in brain aging and neurodegenerative disorders. Ann. Intern. Med. 139, 441–444.

    PubMed  CAS  Google Scholar 

  • Mattson M. P. and Kroemer G. (2003) Mitochondria in cell death: novel targets for neuroprotection and cardioprotection. Trends Mol. Med. 9, 196–205.

    Article  PubMed  CAS  Google Scholar 

  • Merchenthaler I., Lane M., and Shughrue P. (1999) Distribution of pre-pro-glucagon and glucagon-like peptide-1 receptor messenger RNAs in the rat central nervous system. J. Comp. Neurol. 403 261–280.

    Article  PubMed  CAS  Google Scholar 

  • Merry B. J. (2004) Oxidative stress and mitochondrial function with aging—the effects of calorie restriction. Aging Cell 3, 7–12.

    Article  PubMed  CAS  Google Scholar 

  • Millet L., Vidal H., Andreelli F., et al. (1997) Increased uncoupling protein-2 and 3 mRNA expression during fasting in obese and lean humans. J. Clin. Invest. 100, 2665–2670.

    PubMed  CAS  Google Scholar 

  • Miwa S. and Brand M. D. (2003) Mitochondrial matrix reactive oxygen species production is very sensitive to mild uncoupling. Biochem. Soc. Trans. 31, 1300–1301.

    PubMed  CAS  Google Scholar 

  • Mizuno T., Miura-Suzuki T., Yamashita H., and 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.

    Article  PubMed  CAS  Google Scholar 

  • Murphy A. N. and Fiskum G. (1999) Bcl-2 and Ca(2+)-mediated mitochondrial dysfunction in neural cell death. Biochem. Soc. Symp. 66, 33–41.

    PubMed  CAS  Google Scholar 

  • Nasr P., Gursahani H. I., Pang Z., et al. (2003) Influence of cytosolic and mitochondrial Ca2+, ATP, mitochondrial membrane potential, and calpain activity on the mechanism of neuron death induced by 3-nitropropionic acid. J. Neurochem. 43, 89–99.

    Article  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Nicholls D. G. and Locke R. M. (1984) Thermogenic mechanisms in brown fat. Physiol. Rev. 64, 1–64.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • O'Brien J., Wilson I., Orton T., and Pognan F. (2000) Investigation of the alamar blue (resazurin) fluorescent dye for the assessment of mammalian cell cytotoxicity. Eur. J. Biochem. 267, 5421–5426.

    Article  PubMed  Google Scholar 

  • Pecqueur C., Couplan E., Bouillaud F., and Ricquier D. (2001) Genetic and physiological analysis of the role of uncoupling proteins in human energy homeostasis. J. Mol. Med. 79, 48–56.

    Article  PubMed  CAS  Google Scholar 

  • Peng T. L., Jou M. J., Sheu S. S., and Greenamyre J. T. (1998) Visualization of NMDA receptor-induced mitochondrial calcium accumulation in striatal neurons. Exp. Neurol. 149, 1–12.

    Article  PubMed  CAS  Google Scholar 

  • Pereira C., Santos M. S., and Oliverira C. (1999) Involvement of oxidative stress on the impairment of energy metabolism induced by Aβ peptides on PC12 cells: protection by antioxidants. Neurobiol. Dis. 6, 209–219.

    Article  PubMed  CAS  Google Scholar 

  • Pisani A., Bonsi P., Bernardi G., and Calabresi P. (2002) Impairment of mitochondrial metabolism differentially affects striatal neuronal subtypes. Neuroreport 13, 641–644.

    Article  PubMed  CAS  Google Scholar 

  • Poppe M., Reimertz C., Dussmann H., et al. (2001) Dissipation of potassium and proton gradients inhibits mitochondrial hyperpolarization and cytochrome crelease during neural apoptosis. J. Neurosci. 21, 4551–4563.

    PubMed  CAS  Google Scholar 

  • Rea S. and Johnson T. E. (2003) A metabolic model for life span determination in Caenorhabditis elegans. Dev. Cell 5, 197–203.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Rial E. and Nicholls D. G. (1984) The mitochondrial uncoupling protein from guinea-pig brown adiposetissue. Synchronous increase in structural and functional parameters during cold-adaptation. Biochem. J. 222, 685–693.

    PubMed  CAS  Google Scholar 

  • Rial E., González-Barroso M., Fleury C., et al. (1999) Retinoids activate proton transport by the uncoupling proteins UCP1 and UCP2. EMBO J. 18, 5827–5833.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Roth G. S., Lane M. A., Ingram D. K., et al. (2002) Biomarkers of caloric restriction may predict longevity in humans. Science 297, 811.

    Article  PubMed  CAS  Google Scholar 

  • Roussel D., Harding M., Runswick M. J., Walker J. E., and Brand M. D. (2002) Does any yeast mitochondrial carrier have a native uncoupling protein function. J. Bioenerg. Biomembr. 34, 165–176.

    Article  PubMed  CAS  Google Scholar 

  • Samartsev V. N., Mokhova E. N., and Skulachev V. P. (1997) The pH-dependent reciprocal changes in contributions of ADP/ATP antiporter and aspartate/glutamate antiporter to fatty acid-induced uncoupling. JEBS Lett. 412, 179–182.

    Article  CAS  Google Scholar 

  • Sanchis D., Fleury C., Chomiki N., 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, 34,611–23,615.

    Article  CAS  Google Scholar 

  • Simpson P. B. (2000) The local control of cytosolic Ca2+ as a propagator of CNS communication—integration of mitochondrial transport mechanisms and cellular responses. J. Bioenerg. Biomembr. 32, 5–13.

    Article  PubMed  CAS  Google Scholar 

  • Sokolova I. M. and Sokolov E. P. (2005) Evolution of mitochondrial uncoupling protein: novel invertebrate UCP homologues suggest early evolutionary divergence of the UCP family. FEBS Lett. 579, 313–317.

    Article  PubMed  CAS  Google Scholar 

  • Starkov A. A. (1997) Mild uncoupling of mitochondria. Biosci. Rec. 17, 273–279.

    Article  CAS  Google Scholar 

  • Starkov A. A. and Fiskum G. (2003) Regulation of brain mitochondrial H2O2 production by membrane potential and NAD(P)H redox state. J. Neurochemi. 86, 1101–1107.

    Article  CAS  Google Scholar 

  • Stuart J. A., Harper J. A., Brindle K. M., Jekabsons M. B., and Brand M. D. (2001) A mitochondrial uncoupling artifact can be caused by expression of uncoupling protein 1 in yeast. Biochem. J. 356, 779–789.

    Article  PubMed  CAS  Google Scholar 

  • Sullivan P. G., Dube C., Dorenbos K., Steward O., and Baram T. Z. (2003) Mitochondrial uncoupling protein-2 contributes crucially to the resistance of immature brain to excitotoxic neuronal death. Ann. Neurol. 53, 711–717.

    Article  PubMed  CAS  Google Scholar 

  • Vercesi A. E., Bernardes C. F., Hoffmann M. E., Gadelha F. R., and Docampo R. (1991) Digitonin permeabilization does not affect mitochondrial function and allow the determination of the mitochondrial potential of Trypanosome cruzi in situ. J. Biol. Chem. 266, 14,431–14,434.

    CAS  Google Scholar 

  • Vianello A., Petrussa E., and Macri F. (1994) ATP/ADP antiporteris involved in uncoupling of plant mitochondria induced by low concentratios of palmitate. FEBS Lett. 349, 407–410.

    Article  PubMed  CAS  Google Scholar 

  • Vidal-Puig A. J., Grujic D., Zhang C., et al. (2000) Energy metabolism in uncouple protein 3 gene knockout mice. J. Biol. Chem. 275, 16,258–16,266.

    Article  CAS  Google Scholar 

  • Vincent A. M., Olzmann J. A., Brownlee M., Sivitz W. I., and Russell J. W. (2004) Uncoupling proteins prevent glucose-induced neuronal oxidative stress and programmed cell death. Diabetes 53, 726–734.

    Article  PubMed  CAS  Google Scholar 

  • Weigle D. S., Selfridge L. E., Schwartz M. W., et al. (1998) Elevated free fatty acids induce uncoupling protein 3 expression in muscle: a potential explanation for the effect of fasting. Diabetes 47, 298–302.

    Article  PubMed  CAS  Google Scholar 

  • Weindruch R. and Sohal R. S. (1997) Seminars in medicine of the Beth Israel Deaconess Medical Center. Caloric intake and aging. N Engl J Med. 337, 986–994.

    Article  PubMed  CAS  Google Scholar 

  • White M. J., Dicaprio M. J., and Greenberg D. A. (1996) Assessment of neuronal viability with Alamar blue in cortical and granule cell cultures. J. Neurosci. Methods 70, 195–200.

    Article  PubMed  CAS  Google Scholar 

  • Wieckowski M. R. and Wojtczak L. (1997) Involvement of the dicarboxylate carrier in the protonophoric action of long-chain fatty acids in mitochondria. Biochem. Biophys. Res. Commun. 232, 414–417.

    Article  PubMed  CAS  Google Scholar 

  • Yang X., Pratley R. E., Tokraks S., Tataranni P. A., and Permana P. A. (2002) UCP5/BMCP1 transcript isoforms in human skeletal muscle: relationship of the short-insert isoform with lipid oxidation and resting metabolic rates. Mol. Genet. Metab. 75, 369–373.

    Article  PubMed  CAS  Google Scholar 

  • Yang F., He X. P., Russell J., and Lu B. (2003) Ca2+ influx-independent synaptic potentiation mediated by mitochondrial Na(+)−Ca2+ exchanger and protein kinase C. J. Cell Biol. 163, 511–523.

    Article  PubMed  CAS  Google Scholar 

  • Yu Z. F. and Mattson M. P. (1999) Dietary restriction and 2-deoxyglucose administration reduce focal ischemic brain damage and improve behavioral outcome: evidence for a preconditioning mechanism. J. Neurosci. Res. 57, 830–839.

    Article  PubMed  CAS  Google Scholar 

  • Yu X. X., Lewin D. A., Zhong A., et al. (2001) Overex-pression of the human 2-oxoglutarate carrier lowers mitochondrial membrane potential in HEK-293 cells: contrast with the unique cold-induced mitochondrial carrier CG1-69. Biochem. J. 353, 369–375.

    Article  PubMed  CAS  Google Scholar 

  • Yu X. X., Mao W., Zhong A., 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, 1611–1618.

    Article  PubMed  CAS  Google Scholar 

  • Zhang C., Baffy G., Perret P., et al. (2001) Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, β cell dysfunction, and type 2 diabetes. Cell 105, 745–755.

    Article  PubMed  CAS  Google Scholar 

  • Zorumski C. F. and Izumi Y. (1998) Modulation of LTP induction by NMDA receptor activation and nitric oxide release. Prog. Brain Res. 118, 173–182.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD

    Dong Liu, Sic L. Chan, John R. Slevin Jr., Khadija Mustafa & Mark P. Mattson

  2. Laboratory of Molecular Gerontology, National Institute of Aging Intramural Research Program, Baltimore, MD

    Nadja C. de Souza-Pinto

  3. Research Resources Branch, National Institute of Aging Intramural Research Program, Baltimore, MD

    Robert P. Wersto & Ming Zhan

  4. Laboratory of Experimental Gerontology, National Institute on Aging Intramural Research Program, Baltimore, MD

    Rafael de Cabo

  5. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD

    Mark P. Mattson

Authors
  1. Dong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sic L. Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nadja C. de Souza-Pinto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John R. Slevin Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robert P. Wersto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ming Zhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Khadija Mustafa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rafael de Cabo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mark P. Mattson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mark P. Mattson.

Additional information

These authors made equal contributions to this research.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, D., Chan, S.L., de Souza-Pinto, N.C. et al. Mitochondrial UCP4 mediates an adaptive shift in energy metabolism and increases the resistance of neurons to metabolic and oxidative stress. Neuromol Med 8, 389–413 (2006). https://doi.org/10.1385/NMM:8:3:389

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1385/NMM:8:3:389

Keywords

Search

Navigation