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

doi:10.1006/taap.2001.9327

Toxicology and Applied Pharmacology

Volume 178, Issue 1, 1 January 2002, Pages 52-61

https://doi.org/10.1006/taap.2001.9327 Get rights and content

Abstract

Cerebellar granule cells are preferentially targeted during methylmercury (MeHg) poisoning. Following acute MeHg exposure, granule cells in culture undergo an increase in intracellular Ca²⁺ concentration ([Ca²⁺]_i) that apparently contributes to cell death. This effect consists of several temporally and kinetically distinct phases. The initial elevation arises from release of Ca²⁺_i stores; the second phase results from entry of Ca²⁺_e. In these experiments, we tested the hypothesis that release of mitochondrial Ca²⁺ through the mitochondrial permeability transition pore (MTP) contributes to the initial release of Ca²⁺_i. Neonatal rat cerebellar granule cells in culture and single cell microfluorimetry were used to examine MeHg-induced changes in [Ca²⁺]_i and mitochondrial membrane potential (Ψ_m). Pretreatment with the MTP inhibitor cyclosporin A (CsA, 5 μM) delayed the initial phase of increased [Ca²⁺]_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. Ca²⁺_e was not required for either effect, because the effect of CsA on the first phase increase in [Ca²⁺]_i and loss of Ψ_m was not altered in nominally Ca²⁺-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.

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^☆: Supported by NIEHS Grant ES03299. T. L. Limke (née Stringfellow) was supported by NIEHS Grant T32-ES07255. Submitted in partial fulfillment of the requirement for the Degree of Doctor of Philosophy (T.L.). Portions of this study were presented in abstract form (Soc. Neurosci. Abstr.24, 1080, 1998; Toxicologist48, 241, 1999).

²: To whom correspondence and reprint requests should be addressed at Michigan State University, Dept. Pharmacology/Toxicology, B331 Life Sciences, East Lansing, MI 48824-1317. Fax: (517) 353-8915; E-mail: [email protected].

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Regular ArticleAcute Exposure to Methylmercury Opens the Mitochondrial Permeability Transition Pore in Rat Cerebellar Granule Cells☆

Abstract

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

Neuroscience

Exp. Neurol.

Toxicol. Appl. Pharmacol.

Biophys. J.

Toxicology

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Biochim. Biophys. Acta

Biochem. Biophys. Res. Commun.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

J. Biol. Chem.

Int. J. Dev. Neurosci.

J. Biol. Chem.

Environ. Res.

Brain Res. Brain Res. Rev.

Toxicol. Appl. Pharmacol.

Irreversible suppression of calcium entry into nerve terminals by methylmercury

J. Pharmacol. Exp. Ther.

Methylmercury-induced depression of neuromuscular transmission in the rat

Neurotoxicology

Methylmercury poisoning in Iraq

Science

The permeability transition pore as a mitochondrial calcium release channel: A critical appraisal

J. Bioenerg. Biomembr.

A reevaluation of the role of mitochondria in neuronal Ca2+ homeostasis

J. Neurochem.

Mercury

Methylmercury-induced elevations in intrasynaptosomal zinc concentrations: An 19F-NMR study

J. Neurochem.

Intracellular calcium concentrations during “chemical hypoxia” and excitotoxic neuronal injury

J. Neurosci.

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

A reevaluation of the role of mitochondria in neuronal Ca²⁺ homeostasis

Methylmercury-induced elevations in intrasynaptosomal zinc concentrations: An ¹⁹F-NMR study