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Citrate, a Ubiquitous Key Metabolite with Regulatory Function in the CNS

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Abstract

Citrate is key constituent of the tricarboxylic acid (TCA) cycle, serves as substrate for fatty acid and sterol biosynthesis, and functions as a key regulator of intermediary energy metabolism. Ursula Sonnewald had initiated studies using for the first time both proton- and 13C-NMR to investigate metabolic processes in cultured neurons and astrocytes resulting in the important observation that citrate was specifically synthesized in and released from astrocytes in large amounts which is in keeping with the high concentration found in the CSF. The aim of this review is to highlight the possible roles of citrate in physiological and pathophysiological processes in the CNS. An interesting feature of citrate is its ability to chelate Ca2+, Mg2+ and Zn2+and thereby playing a pivotal role as an endogenous modulator of glutamate receptors and in particular the NMDA subtypes of these receptors in the CNS. Besides its presence in cerebrospinal fluid (CSF) citrate is also found in high amounts in prostate fluid reaching concentrations as high as 180 mM and here Zn2+ seems also to play an important role, which makes prostate cells interesting for comparison of features of citrate and Zn2+ between these cells and cells in the CNS.

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References

  1. Srere PA (1992) The molecular physiology of citrate. Curr Top Cell Regul 33:261–275

    Article  CAS  PubMed  Google Scholar 

  2. Glusker JP (1992) Structural aspects of citrate biochemistry. Curr Top Cell Regul 33:169–184

    Article  CAS  PubMed  Google Scholar 

  3. Iacobazzi V, Infantino V (2014) Citrate—new functions for an old metabolite. Biol Chem 395:387–399

    Article  CAS  PubMed  Google Scholar 

  4. Schousboe A, Westergaard N, Waagepetersen HS, Larsson OM, Bakken IJ, Sonnewald U (1997) Trafficking between glia and neurons of TCA cycle intermediates and related metabolites. Glia 21:99–105

    Article  CAS  PubMed  Google Scholar 

  5. Westergaard N, Banke T, Wahl P, Sonnewald U, Schousboe A (1995) Citrate modulates the regulation by Zn2+ of N-methyl-D-aspartate receptor-mediated channel current and neurotransmitter release. Proc Natl Acad Sci USA 92:3367–3370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Sonnewald U, Westergaard N, Krane J, Unsgard G, Petersen SB, Schousboe A (1991) First direct demonstration of preferential release of citrate from astrocytes using [13C]NMR spectroscopy of cultured neurons and astrocytes. Neurosci Lett 128:235–239

    Article  CAS  PubMed  Google Scholar 

  7. Sonnewald U, Risan AG, Hole HB, Westergaard N, Qu H (2002) Citrate, beneficial or deleterious in the CNS? Neurochem Res 27:155–159

    Article  CAS  PubMed  Google Scholar 

  8. Mycielska ME, Milenkovic VM, Wetzel CH, Rummele P, Geissler EK (2015) Extracellular citrate in health and disease. Curr Mol Med 15:884–891

    Article  CAS  PubMed  Google Scholar 

  9. Sonnewald U, Petersen SB, Krane J, Westergaard N, Schousboe A (1992) 1 H NMR study of cortex neurons and cerebellar granule cells on microcarriers and their PCA extracts: lactate production under hypoxia. Magn Reson Med 23:166–171

    Article  CAS  PubMed  Google Scholar 

  10. Badar-Goffer RS, Bachelard HS, Morris PG (1990) Cerebral metabolism of acetate and glucose studied by 13 C-n.m.r. spectroscopy. A technique for investigating metabolic compartmentation in the brain. Biochem J 266:133–139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Schousboe A, Walls AB, Bak LK, Waagepetersen HS (2015) Astroglia and brain metabolism: focus on energy and neurotransmitter amino acid homeostasis. In: Verkhratsky A, Parpura V (eds) Colloquium series onneuroglia in biology and medicine from physiology to disease. Morgan & Claypool Life Sciences, San Rafael, pp 1–63

    Google Scholar 

  12. Fonnum F, Johnsen A, Hassel B (1997) Use of fluorocitrate and fluoroacetate in the study of brain metabolism. Glia 21:106–113

    Article  CAS  PubMed  Google Scholar 

  13. Hassel B, Westergaard N, Schousboe A, Fonnum F (1995) Metabolic differences between primary cultures of astrocytes and neurons from cerebellum and cerebral cortex. Effects of fluorocitrate. Neurochem Res 20:413–420

    Article  CAS  PubMed  Google Scholar 

  14. Hassel B, Bachelard H, Jones P, Fonnum F, Sonnewald U (1997) Trafficking of amino acids between neurons and glia in vivo. Effects of inhibition of glial metabolism by fluoroacetate. J Cereb Blood Flow Metab 17:1230–1238

    Article  CAS  PubMed  Google Scholar 

  15. Miyake S, Yamashita T, Taniguchi M, Tamatani M, Sato K, Kawai Y, Senba E, Mitsuda N, Hori O, Yamaguchi A, Tohyama M (2002) Expression of mitochondrial tricarboxylate carrier TCC mRNA and protein in the rat brain. Brain Res Mol Brain Res 100:67–73

    Article  CAS  PubMed  Google Scholar 

  16. Gnoni GV, Priore P, Geelen MJ, Siculella L (2009) The mitochondrial citrate carrier: metabolic role and regulation of its activity and expression. IUBMB Life 61:987–994

    Article  CAS  PubMed  Google Scholar 

  17. Munday MR (2002) Regulation of mammalian acetyl-CoA carboxylase. Biochem Soc Trans 30:1059–1064

    Article  CAS  PubMed  Google Scholar 

  18. Lopes-Cardozo M, Larsson OM, Schousboe A (1986) Acetoacetate and glucose as lipid precursors and energy substrates in primary cultures of astrocytes and neurons from mouse cerebral cortex. J Neurochem 46:773–778

    Article  CAS  PubMed  Google Scholar 

  19. Schmoll D, Fuhrmann E, Gebhardt R, Hamprecht B (1995) Significant amounts of glycogen are synthesized from 3-carbon compounds in astroglial primary cultures from mice with participation of the mitochondrial phosphoenolpyruvate carboxykinase isoenzyme. Eur J Biochem 227:308–315

    Article  CAS  PubMed  Google Scholar 

  20. Nieweg K, Schaller H, Pfrieger FW (2009) Marked differences in cholesterol synthesis between neurons and glial cells from postnatal rats. J Neurochem 109:125–134

    Article  CAS  PubMed  Google Scholar 

  21. Yu AC, Drejer J, Hertz L, Schousboe A (1983) Pyruvate carboxylase activity in primary cultures of astrocytes and neurons. J Neurochem 41:1484–1487

    Article  CAS  PubMed  Google Scholar 

  22. Shank RP, Bennett GS, Freytag SO, Campbell GL (1985) Pyruvate carboxylase: an astrocyte-specific enzyme implicated in the replenishment of amino acid neurotransmitter pools. Brain Res 329:364–367

    Article  CAS  PubMed  Google Scholar 

  23. Lovatt D, Sonnewald U, Waagepetersen HS, Schousboe A, He W, Lin JH, Han X, Takano T, Wang S, Sim FJ, Goldman SA, Nedergaard M (2007) The transcriptome and metabolic gene signature of protoplasmic astrocytes in the adult murine cortex. J Neurosci 27:12255–12266

    Article  CAS  PubMed  Google Scholar 

  24. Murin R, Cesar M, Kowtharapu BS, Verleysdonk S, Hamprecht B (2009) Expression of pyruvate carboxylase in cultured oligodendroglial, microglial and ependymal cells. Neurochem Res 34:480–489

    Article  CAS  PubMed  Google Scholar 

  25. Westergaard N, Sonnewald U, Unsgard G, Peng L, Hertz L, Schousboe A (1994) Uptake, release, and metabolism of citrate in neurons and astrocytes in primary cultures. J Neurochem 62:1727–1733

    Article  CAS  PubMed  Google Scholar 

  26. Westergaard N, Sonnewald U, Schousboe A (1994) Release of alpha-ketoglutarate, malate and succinate from cultured astrocytes: possible role in amino acid neurotransmitter homeostasis. Neurosci Lett 176:105–109

    Article  CAS  PubMed  Google Scholar 

  27. Yodoya E, Wada M, Shimada A, Katsukawa H, Okada N, Yamamoto A, Ganapathy V, Fujita T (2006) Functional and molecular identification of sodium-coupled dicarboxylate transporters in rat primary cultured cerebrocortical astrocytes and neurons. J Neurochem 97:162–173

    Article  CAS  PubMed  Google Scholar 

  28. Sonnewald U, Westergaard N, Schousboe A, Svendsen JS, Unsgard G, Petersen SB (1993) Direct demonstration by [13C]NMR spectroscopy that glutamine from astrocytes is a precursor for GABA synthesis in neurons. Neurochem Int 22:19–29

    Article  CAS  PubMed  Google Scholar 

  29. Waagepetersen HS, Sonnewald U, Larsson OM, Schousboe A (2001) Multiple compartments with different metabolic characteristics are involved in biosynthesis of intracellular and released glutamine and citrate in astrocytes. Glia 35:246–252

    Article  CAS  PubMed  Google Scholar 

  30. Meshitsuka S, Aremu DA (2008) (13)C heteronuclear NMR studies of the interaction of cultured neurons and astrocytes and aluminum blockade of the preferential release of citrate from astrocytes. J Biol Inorg Chem 13:241–247

    Article  CAS  PubMed  Google Scholar 

  31. Kaufman EE, Driscoll BF (1992) Carbon dioxide fixation in neuronal and astroglial cells in culture. J Neurochem 58:258–262

    Article  CAS  PubMed  Google Scholar 

  32. Petroff OA, Yu RK, Ogino T (1986) High-resolution proton magnetic resonance analysis of human cerebrospinal fluid. J Neurochem 47:1270–1276

    Article  CAS  PubMed  Google Scholar 

  33. Levine J, Panchalingam K, Rapoport A, Gershon S, McClure RJ, Pettegrew JW (2000) Increased cerebrospinal fluid glutamine levels in depressed patients. Biol Psychiatry 47:586–593

    Article  CAS  PubMed  Google Scholar 

  34. Musteata M, Nicolescu A, Solcan G, Deleanu C (2013) The 1 H NMR profile of healthy dog cerebrospinal fluid. PLoS ONE 8:e81192

    Article  PubMed  PubMed Central  Google Scholar 

  35. Monaghan DT, Jane DE (2009) Pharmacology of NMDA receptors. In: Van Dongen AM (ed) Biology of the NMDA receptor. CRC Press, Boca Raton

    Google Scholar 

  36. Clarke DD (1991) Fluoroacetate and fluorocitrate: mechanism of action. Neurochem Res 16:1055–1058

    Article  CAS  PubMed  Google Scholar 

  37. Goldberg ND, Passonneau JV, Lowry OH (1966) Effects of changes in brain metabolism on the levels of citric acid cycle intermediates. J Biol Chem 241:3997–4003

    CAS  PubMed  Google Scholar 

  38. Hassel B, Sonnewald U, Unsgard G, Fonnum F (1994) NMR spectroscopy of cultured astrocytes: effects of glutamine and the gliotoxin fluorocitrate. J Neurochem 62:2187–2194

    Article  CAS  PubMed  Google Scholar 

  39. Hornfeldt CS, Larson AA (1990) Seizures induced by fluoroacetic acid and fluorocitric acid may involve chelation of divalent cations in the spinal cord. Eur J Pharmacol 179:307–313

    Article  CAS  PubMed  Google Scholar 

  40. Harrison NL, Gibbons SJ (1994) Zn2+: an endogenous modulator of ligand- and voltage-gated ion channels. Neuropharmacology 33:935–952

    Article  CAS  PubMed  Google Scholar 

  41. Salazar G, Craige B, Love R, Kalman D, Faundez V (2005) Vglut1 and ZnT3 co-targeting mechanisms regulate vesicular zinc stores in PC12 cells. J Cell Sci 118:1911–1921

    Article  CAS  PubMed  Google Scholar 

  42. Smidt K, Rungby J (2012) ZnT3: a zinc transporter active in several organs. Biometals 25:1–8

    Article  CAS  PubMed  Google Scholar 

  43. Assaf SY, Chung SH (1984) Release of endogenous Zn2+ from brain tissue during activity. Nature 308:734–736

    Article  CAS  PubMed  Google Scholar 

  44. Howell GA, Welch MG, Frederickson CJ (1984) Stimulation-induced uptake and release of zinc in hippocampal slices. Nature 308:736–738

    Article  CAS  PubMed  Google Scholar 

  45. Charton G, Rovira C, Ben-Ari Y, Leviel V (1985) Spontaneous and evoked release of endogenous Zn2+ in the hippocampal mossy fiber zone of the rat in situ. Exp Brain Res 58:202–205

    Article  CAS  PubMed  Google Scholar 

  46. Peters S, Koh J, Choi DW (1987) Zinc selectively blocks the action of N-methyl-D-aspartate on cortical neurons. Science 236:589–593

    Article  CAS  PubMed  Google Scholar 

  47. Eimerl S, Schramm M (1993) Potentiation of 45Ca uptake and acute toxicity mediated by the N-methyl-D-aspartate receptor: the effect of metal binding agents and transition metal ions. J Neurochem 61:518–525

    Article  CAS  PubMed  Google Scholar 

  48. Smart TG, Xie X, Krishek BJ (1994) Modulation of inhibitory and excitatory amino acid receptor ion channels by zinc. Prog Neurobiol 42:393–441

    Article  CAS  PubMed  Google Scholar 

  49. Radford RJ, Lippard SJ (2013) Chelators for investigating zinc metalloneurochemistry. Curr Opin Chem Biol 17:129–136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Mayer ML, Vyklicky L Jr, Westbrook GL (1989) Modulation of excitatory amino acid receptors by group IIB metal cations in cultured mouse hippocampal neurones. J Physiol 415:329–350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Rassendren FA, Lory P, Pin JP, Nargeot J (1990) Zinc has opposite effects on NMDA and non-NMDA receptors expressed in Xenopus oocytes. Neuron 4:733–740

    Article  CAS  PubMed  Google Scholar 

  52. Koh JY, Choi DW (1988) Zinc alters excitatory amino acid neurotoxicity on cortical neurons. J Neurosci 8:2164–2171

    CAS  PubMed  Google Scholar 

  53. Larson AA, Kitto KF (1999) Chelation of zinc in the extracellular area of the spinal cord, using ethylenediaminetetraacetic acid disodium-calcium salt or dipicolinic acid, inhibits the antinociceptive effect of capsaicin in adult mice. J Pharmacol Exp Ther 288:759–765

    CAS  PubMed  Google Scholar 

  54. Wong EH, Kemp JA, Priestley T, Knight AR, Woodruff GN, Iversen LL (1986) The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist. Proc Natl Acad Sci USA 83:7104–7108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kavanagh JP (1994) Isocitric and citric acid in human prostatic and seminal fluid: implications for prostatic metabolism and secretion. Prostate 24:139–142

    Article  CAS  PubMed  Google Scholar 

  56. Franklin RB, Ma J, Zou J, Guan Z, Kukoyi BI, Feng P, Costello LC (2003) Human ZIP1 is a major zinc uptake transporter for the accumulation of zinc in prostate cells. J Inorg Biochem 96:435–442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Costello LC, Franklin RB (2016) A comprehensive review of the role of zinc in normal prostate function and metabolism; and its implications in prostate cancer. Arch Biochem Biophys 611:100–112

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Biopeople, Denmark’s Life Science Cluster, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark

    Niels Westergaard

  2. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark

    Helle S. Waagepetersen & Arne Schousboe

  3. Bispebjerg Hospital, University of Copenhagen, Bispebjerg Bakke 23, 2400, Copenhagen, Denmark

    Bo Belhage

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  1. Niels Westergaard
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  2. Helle S. Waagepetersen
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  3. Bo Belhage
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  4. Arne Schousboe
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Correspondence to Niels Westergaard.

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Westergaard, N., Waagepetersen, H.S., Belhage, B. et al. Citrate, a Ubiquitous Key Metabolite with Regulatory Function in the CNS. Neurochem Res 42, 1583–1588 (2017). https://doi.org/10.1007/s11064-016-2159-7

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  • DOI: https://doi.org/10.1007/s11064-016-2159-7

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