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Molecular Medicine

, Volume 13, Issue 7–8, pp 350–355 | Cite as

Intracellular Zinc Release, 12-Lipoxygenase Activation and MAPK Dependent Neuronal and Oligodendroglial Death

  • Yumin Zhang
  • Elias Aizenman
  • Donald B. DeFranco
  • Paul A. Rosenberg
Proceedings

Abstract

Zinc translocation from presynaptic nerve terminals to postsynaptic neurons has generally been considered the critical step leading to the accumulation of intracellular free zinc and subsequent neuronal injury. Recent evidence, however, strongly suggests that the liberation of zinc from intracellular stores upon oxidative and nitrative stimulation contributes significantly to the toxicity of this metal not only to neurons, but also to oligodendrocytes. The exact cell death signaling pathways triggered by zinc are beginning to be deciphered. In this review, we describe how the activation of 12-lipoxygenase and mitogen-activated protein kinase (MAPK) contribute to the toxicity of liberated zinc to neurons and oligodendrocytes.

Notes

Acknowledgments

This work is supported by grants from the United Cerebral Palsy Foundation (R-759 to Y.Z.), the National Multiple Sclerosis Society (RG3741 to Y.Z.) and the National Institutes of Health (NS043277 to E.A., NS038319 to D.B.D., and NS038475 to P.A.R.).

References

  1. 1.
    Weiss JH, Sensi SL, Koh JY. (2000) Zn(2+): a novel ionic mediator of neural injury in brain disease. Trends Pharmacol. Sci. 21:395–401.CrossRefGoogle Scholar
  2. 2.
    Qian J, Noebels JL. (2006) Exocytosis of vesicular zinc reveals persistent depression of neurotransmitter release during metabotropic glutamate receptor long-term depression at the hippocampal CA3-CA1 synapse. J. Neurosci. 26:6089–95.CrossRefGoogle Scholar
  3. 3.
    Qian J, Noebels JL. (2005) Visualization of transmitter release with zinc fluorescence detection at the mouse hippocampal mossy fiber synapse. J. Physiol. 566:747–58.CrossRefGoogle Scholar
  4. 4.
    Frederickson CJ, Koh JY, Bush AI. (2005) The neurobiology of zinc in health and disease. Nat. Rev. Neurosci. 6:449–62.CrossRefGoogle Scholar
  5. 5.
    Sensi SL, Jeng JM. (2004) Rethinking the excitotoxic ionic milieu: the emerging role of Zn(2+) in ischemic neuronal injury. Curr. Mol. Med. 4:87–111.CrossRefGoogle Scholar
  6. 6.
    Frederickson CJ. (1989) Neurobiology of zinc and zinc-containing neurons. Int. Rev. Neurobiol 31:145–238.CrossRefGoogle Scholar
  7. 7.
    Suh SW et al. (1999) Detection of pathological zinc accumulation in neurons: methods for autopsy, biopsy, and cultured tissue. J. Histochem. Cytochem. 47:969–72.CrossRefGoogle Scholar
  8. 8.
    Lee JY, Cole TB, Palmiter RD, Koh JY. (2000) Accumulation of zinc in degenerating hippocampal neurons of ZnT3-null mice after seizures: evidence against synaptic vesicle origin. J. Neurosci. 20:RC79.CrossRefGoogle Scholar
  9. 9.
    Frazzini V, Rockabrand E, Mocchegiani E, Sensi SL. (2006) Oxidative stress and brain aging: is zinc the link? Biogerontology. 7:307–14.CrossRefGoogle Scholar
  10. 10.
    Outten CE, O’Halloran TV. (2001) Femtomolar sensitivity of metalloregulatory proteins controlling zinc homeostasis. Science. 292:2488–92.CrossRefGoogle Scholar
  11. 11.
    Krezel A, Maret W. (2006) Zinc-buffering capacity of a eukaryotic cell at physiological pZn. J. Biol. Inorg. Chem. 11:1049–62.CrossRefGoogle Scholar
  12. 12.
    Palmiter RD. (1987) Molecular biology of metallothionein gene expression. Experientia. Suppl. 52:63–80.CrossRefGoogle Scholar
  13. 13.
    Masters BA et al. (1994) Metallothionein III is expressed in neurons that sequester zinc in synaptic vesicles. J. Neurosci. 14:5844–57.CrossRefGoogle Scholar
  14. 14.
    Quaife CJ, Findley SD, Erickson JC, et al. (1994) Induction of a new metallothionein isoform (MT-IV) occurs during differentiation of stratified squamous epithelia. Biochemistry. 33:7250–9.CrossRefGoogle Scholar
  15. 15.
    Maret W. (2000) The function of zinc metallothionein: a link between cellular zinc and redox state. J. Nutr. 130:1455S–8S.CrossRefGoogle Scholar
  16. 16.
    Maret W, Vallee BL. (1998) Thiolate ligands in metallothionein confer redox activity on zinc clusters. Proc. Natl. Acad. Sci. U. S. A. 95:3478–82.CrossRefGoogle Scholar
  17. 17.
    Aizenman E, Stout AK, Hartnett KA, Dineley KE, McLaughlin B, Reynolds IJ. (2000) Induction of neuronal apoptosis by thiol oxidation: putative role of intracellular zinc release. J. Neurochem. 75:1878–88.CrossRefGoogle Scholar
  18. 18.
    Malaiyandi LM, Dineley KE, Reynolds IJ. (2004) Divergent consequences arise from metallothionein overexpression in astrocytes: zinc buffering and oxidant-induced zinc release. Glia. 45:346–53.CrossRefGoogle Scholar
  19. 19.
    Lee JY, Kim JH, Palmiter RD, Koh JY. (2003) Zinc released from metallothionein-iii may contribute to hippocampal CA1 and thalamic neuronal death following acute brain injury. Exp. Neurol. 184:337–47.CrossRefGoogle Scholar
  20. 20.
    Land PW, Aizenman E. (2005) Zinc accumulation after target loss: an early event in retrograde degeneration of thalamic neurons. Eur. J. Neurosci. 21:647–57.CrossRefGoogle Scholar
  21. 21.
    Dineley KE, Votyakova TV, Reynolds IJ. (2003) Zinc inhibition of cellular energy production: implications for mitochondria and neurodegeneration. J. Neurochem. 85:563–70.CrossRefGoogle Scholar
  22. 22.
    Chang DT, Honick AS, Reynolds IJ. (2006) Mitochondrial trafficking to synapses in cultured primary cortical neurons. J. Neurosci. 26:7035–45.CrossRefGoogle Scholar
  23. 23.
    Cai AL, Zipfel GJ, Sheline CT. (2006) Zinc neurotoxicity is dependent on intracellular NAD levels and the sirtuin pathway. Eur. J. Neurosci. 24:2169–76.CrossRefGoogle Scholar
  24. 24.
    Jiang D, Sullivan PG, Sensi SL, Steward O, Weiss JH. (2001) Zn(2+) induces permeability transition pore opening and release of pro-apoptotic pep-tides from neuronal mitochondria. J. Biol. Chem. 276:47524–9.CrossRefGoogle Scholar
  25. 25.
    Sensi SL et al. (2003) Modulation of mitochondrial function by endogenous Zn2+ pools. Proc. Natl. Acad. Sci. U. S. A. 100:6157–62.CrossRefGoogle Scholar
  26. 26.
    Cheng EH, Kirsch DG, Clem RJ, et al. (1997) Conversion of Bcl-2 to a Bax-like death effector by caspases. Science. 278:1966–8.CrossRefGoogle Scholar
  27. 27.
    Jonas EA, Hickman JA, Hardwick JM, Kaczmarek LK. (2005) Exposure to hypoxia rapidly induces mitochondrial channel activity within a living synapse. J. Biol. Chem. 280:4491–7.CrossRefGoogle Scholar
  28. 28.
    Bonanni L et al. (2006) Zinc-dependent multi-conductance channel activity in mitochondria isolated from ischemic brain. J. Neurosci. 26:6851–62.CrossRefGoogle Scholar
  29. 29.
    McLaughlin B et al. (2001) p38 activation is required upstream of potassium current enhancement and caspase cleavage in thiol oxidant-induced neuronal apoptosis. J. Neurosci. 21:3303–11.CrossRefGoogle Scholar
  30. 30.
    Du S, McLaughlin B, Pal S, Aizenman E. (2002) In vitro neurotoxicity of methylisothiazolinone, a commonly used industrial and household biocide, proceeds via a zinc and extracellular signal-regulated kinase mitogen-activated protein kinase-dependent pathway. J. Neurosci. 22:7408–16.CrossRefGoogle Scholar
  31. 31.
    Zhang Y et al. (2004) Peroxynitrite-induced neuronal apoptosis is mediated by intracellular zinc release and 12-lipoxygenase activation. J. Neurosci. 24:10616–27.CrossRefGoogle Scholar
  32. 32.
    Zhang Y et al. (2006) Intracellular zinc release and ERK phosphorylation are required upstream of 12-lipoxygenase activation in peroxynitrite toxicity to mature rat oligodendrocytes. J. Biol. Chem. 281:9460–70.CrossRefGoogle Scholar
  33. 33.
    Pal S, Hartnett KA, Nerbonne JM, Levitan ES, Aizenman E. (2003) Mediation of neuronal apoptosis by Kv2.1-encoded potassium channels. J. Neurosci. 23:4798–802.CrossRefGoogle Scholar
  34. 34.
    Pal SK, Takimoto K, Aizenman E, Levitan ES. (2006) Apoptotic surface delivery of K+ channels. Cell Death Differ. 13:661–7.CrossRefGoogle Scholar
  35. 35.
    Redman PT et al. (2007) Apoptotic surge of potassium currents is mediated by p38 phosphorylation of Kv2.1. Proc. Natl. Acad. Sci. U. S. A. 104:3568–73.CrossRefGoogle Scholar
  36. 36.
    Bossy-Wetzel E et al. (2004) Crosstalk between nitric oxide and zinc pathways to neuronal cell death involving mitochondrial dysfunction and p38-activated K+ channels. Neuron. 41:351–65.CrossRefGoogle Scholar
  37. 37.
    Pal S, He K, Aizenman E. (2004) Nitrosative stress and potassium channel-mediated neuronal apoptosis: is zinc the link? Pflugers Arch. 448:296–303.CrossRefGoogle Scholar
  38. 38.
    Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME. (1995) Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science. 270:1326–31.CrossRefGoogle Scholar
  39. 39.
    Chu CT, Levinthal DJ, Kulich SM, Chalovich EM, DeFranco DB. (2004) Oxidative neuronal injury. The dark side of ERK1/2. Eur. J. Biochem. 271:2060–6.CrossRefGoogle Scholar
  40. 40.
    Park JA, Koh JY. (1999) Induction of an immediate early gene egr-1 by zinc through extracellular signal-regulated kinase activation in cortical culture: its role in zinc-induced neuronal death. J. Neurochem. 73:450–6.CrossRefGoogle Scholar
  41. 41.
    Noh KM, Koh JY. (2000) Induction and activation by zinc of NADPH oxidase in cultured cortical neurons and astrocytes. J. Neurosci. 20:RC111.CrossRefGoogle Scholar
  42. 42.
    Kim YH, Koh JY. (2002) The role of NADPH oxidase and neuronal nitric oxide synthase in zinc-induced poly(ADP-ribose) polymerase activation and cell death in cortical culture. Exp. Neurol. 177:407–18.CrossRefGoogle Scholar
  43. 43.
    Kohda Y et al. (2006) Involvement of Raf-1/MEK/ERK1/2 signaling pathway in zinc-induced injury in rat renal cortical slices. J. Toxicol. Sci. 31:207–17.CrossRefGoogle Scholar
  44. 44.
    Stanciu M et al. (2000) Persistent activation of ERK contributes to glutamate-induced oxidative toxicity in a neuronal cell line and primary cortical neuron cultures. J. Biol. Chem. 275:12200–6.CrossRefGoogle Scholar
  45. 45.
    Luo Y, DeFranco DB. (2006) Opposing roles for ERK1/2 in neuronal oxidative toxicity: distinct mechanisms of ERK1/2 action at early versus late phases of oxidative stress. J. Biol. Chem. 281:16436–42.CrossRefGoogle Scholar
  46. 46.
    Shimizu T, Wolfe LS. (1990) Arachidonic acid cascade and signal transduction. J. Neurochem. 55:1–15.CrossRefGoogle Scholar
  47. 47.
    Kudo I, Murakami M. (2002) Phospholipase A2 enzymes. Prostaglandins Other Lipid Medial. 68–69:3–58.CrossRefGoogle Scholar
  48. 48.
    Li Y, Maher P, Schubert D. (1997) Arole for 12-lipoxygenase in nerve cell death caused by glutathione depletion. Neuron. 19:453–63.CrossRefGoogle Scholar
  49. 49.
    van Leyen K, Kim HY, Lee SR, Jin G, Arai K, Lo EH. (2006) Baicalein and 12/15-lipoxygenase in the ischemic brain. Stroke. 37:3014–8.CrossRefGoogle Scholar
  50. 50.
    Khanna S et al. (2005) Neuroprotective properties of the natural vitamin E alpha-tocotrienol. Stroke. 36:2258–64.CrossRefGoogle Scholar
  51. 51.
    Koh JY, Suh SW, Gwag BJ, He YY, Hsu CY, Choi DW. (1996) The role of zinc in selective neuronal death after transient global cerebral ischemia. Science. 272:1013–16.CrossRefGoogle Scholar
  52. 52.
    Stork CJ, Li YV. (2006) Intracellular zinc elevation measured with a “calcium-specific” indicator during ischemia and reperfusion in rat hippocampus: a question on calcium overload. J. Neurosci. 26:10430–7.CrossRefGoogle Scholar
  53. 53.
    Wang H et al. (2004) 12-Lipoxygenase plays a key role in cell death caused by glutathione depletion and arachidonic acid in rat oligodendrocytes. Eur. J. Neurosci. 20:2049–58.CrossRefGoogle Scholar
  54. 54.
    Meng TC, Fukada T, Tonks NK. (2002) Reversible oxidation and inactivation of protein tyrosine phosphatases in vivo. Mol. Cell. 9:387–99.CrossRefGoogle Scholar
  55. 55.
    Tonks NK. (2003) PTP1B: from the sidelines to the front lines! FEBS Lett. 546:140–8.CrossRefGoogle Scholar
  56. 56.
    Levinthal DJ, Defranco DB. (2005) Reversible oxidation of ERK-directed protein phosphatases drives oxidative toxicity in neurons. J. Biol. Chem. 280:5875–83.CrossRefGoogle Scholar
  57. 57.
    Ho Y, Logue E, Callaway CW, Defranco DB. (2007) Different mechanisms account for extracellular-signal regulated kinase activation in distinct brain regions following global ischemia and reperfusion. Neuroscience. 145:248–55.CrossRefGoogle Scholar

Copyright information

© Feinstein Institute for Medical Research 2007

Authors and Affiliations

  • Yumin Zhang
    • 1
  • Elias Aizenman
    • 2
  • Donald B. DeFranco
    • 3
  • Paul A. Rosenberg
    • 4
  1. 1.Department of Anatomy Physiology and Genetics and Program in NeuroscienceUniformed Services University of the Health SciencesBethesdaUSA
  2. 2.Department of NeurobiologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  3. 3.Department of Pharmacology and Pittsburgh Institute for Neurodegenerative DiseasesUniversity of Pittsburgh School of MedicinePittsburghUSA
  4. 4.Department of Neurology and Program in NeuroscienceChildren’s Hospital and Harvard Medical SchoolBostonUSA

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