Acute Exposure to Methylmercury Opens the Mitochondrial Permeability Transition Pore in Rat Cerebellar Granule Cells

Acute Exposure to Methylmercury Opens the Mitochondrial Permeability Transition Pore in Rat... Cerebellar granule cells are preferentially targeted during methylmercury (MeHg) poisoning. Following acute MeHg exposure, granule cells in culture undergo an increase in intracellular Ca 2+ concentration ((Ca 2+ ) i ) that apparently contributes to cell death. This effect consists of several temporally and kinetically distinct phases. The initial elevation arises from release of Ca 2+ i stores; the second phase results from entry of Ca 2+ e . In these experiments, we tested the hypothesis that release of mitochondrial Ca 2+ through the mitochondrial permeability transition pore (MTP) contributes to the initial release of Ca 2+ i . Neonatal rat cerebellar granule cells in culture and single cell microfluorimetry were used to examine MeHg-induced changes in (Ca 2+ ) i and mitochondrial membrane potential (Ψ m ). Pretreatment with the MTP inhibitor cyclosporin A (CsA, 5 μM) delayed the initial phase of increased (Ca 2+ ) i induced by 0.2 and 0.5 μM MeHg, but not 1.0 μM MeHg. CsA (5 μM) also delayed the irreversible loss of Ψ m induced by 0.5 μM MeHg. Ca 2+ e was not required for either effect, because the effect of CsA on the first phase increase in (Ca 2+ ) i and loss of Ψ m was not altered in nominally Ca 2+ -free buffer. Increasing concentrations of MeHg (0.2–2.0 μM) caused increasing incidence of cell death at 24 h postexposure. Treatment with CsA provided protection against cytotoxicity at lower MeHg concentrations (0.2–0.5 μM), but not at higher MeHg concentrations (1.0–2.0 μM). Thus, the MTP appears to play a significant role in the cellular effects following acute exposure of cerebellar granule neurons to MeHg. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Toxicology and Applied Pharmacology Elsevier

Acute Exposure to Methylmercury Opens the Mitochondrial Permeability Transition Pore in Rat Cerebellar Granule Cells

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Publisher
Elsevier
Copyright
Copyright © 2002 Elsevier Science (USA)
ISSN
0041-008x
D.O.I.
10.1006/taap.2001.9327
Publisher site
See Article on Publisher Site

Abstract

Cerebellar granule cells are preferentially targeted during methylmercury (MeHg) poisoning. Following acute MeHg exposure, granule cells in culture undergo an increase in intracellular Ca 2+ concentration ((Ca 2+ ) i ) that apparently contributes to cell death. This effect consists of several temporally and kinetically distinct phases. The initial elevation arises from release of Ca 2+ i stores; the second phase results from entry of Ca 2+ e . In these experiments, we tested the hypothesis that release of mitochondrial Ca 2+ through the mitochondrial permeability transition pore (MTP) contributes to the initial release of Ca 2+ i . Neonatal rat cerebellar granule cells in culture and single cell microfluorimetry were used to examine MeHg-induced changes in (Ca 2+ ) i and mitochondrial membrane potential (Ψ m ). Pretreatment with the MTP inhibitor cyclosporin A (CsA, 5 μM) delayed the initial phase of increased (Ca 2+ ) i induced by 0.2 and 0.5 μM MeHg, but not 1.0 μM MeHg. CsA (5 μM) also delayed the irreversible loss of Ψ m induced by 0.5 μM MeHg. Ca 2+ e was not required for either effect, because the effect of CsA on the first phase increase in (Ca 2+ ) i and loss of Ψ m was not altered in nominally Ca 2+ -free buffer. Increasing concentrations of MeHg (0.2–2.0 μM) caused increasing incidence of cell death at 24 h postexposure. Treatment with CsA provided protection against cytotoxicity at lower MeHg concentrations (0.2–0.5 μM), but not at higher MeHg concentrations (1.0–2.0 μM). Thus, the MTP appears to play a significant role in the cellular effects following acute exposure of cerebellar granule neurons to MeHg.

Journal

Toxicology and Applied PharmacologyElsevier

Published: Jan 1, 2002

References

  • Ca 2+ acting at the external side of the inner mitochondrial membrane can stimulate mitochondrial permeability transition induced by phenylarsine oxide
    Kowaltowski, A.J.; Castilho, R.F.
  • Pathways mediating Ca 2+ entry in rat cerebellar granule cells following in vitro exposure to methyl mercury
    Marty, M.S.; Atchison, W.D.
  • Elevations of intracellular Ca 2+ as a probable contributor to decreased viability in cerebellar granule cells following acute exposure to methylmercury
    Marty, M.S.; Atchison, W.D.
  • Low-level methylmercury exposure causes human T-cells to undergo apoptosis: Evidence of mitochondrial dysfunction
    Shenker, B.J.; Guo, T.L.; Shapiro, I.M.
  • Role of mitochondrial Ca 2+ regulation in neuronal and glial cell signalling
    Simpson, P.B.; Russell, J.T.
  • Role of the mitochondrial permeability transition in salicylate toxicity to cultured rat hepatocytes: Implications for the pathogenesis of Reye's syndrome
    Trost, L.C.; Lemasters, J.J.
  • Organic mercurial encephalopathy: In vivo and in vitro effects of methyl mercury on synaptosomal respiration
    Verity, M.A.; Brown, W.J.; Cheung, M.
  • Methyl mercury inhibition of synaptosome and brain slice protein synthesis: In vivo and in vitro studies
    Verity, M.A.; Brown, W.J.; Cheung, M.; Czer, G.

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