Role of oxidative stress and the mitochondrial permeability transition in methylmercury cytotoxicity

Document Type

Article

Abstract

Oxidative stress has been implicated in the pathogenesis of methylmercury (MeHg) neurotoxicity. Studies of mature neurons suggest that the mitochondrion may be a major source of MeHg-induced reactive oxygen species and a critical mediator of MeHg-induced neuronal death, likely by activation of apoptotic pathways. It is unclear, however, whether the mitochondria of developing and mature neurons are equally susceptible to MeHg. Murine embryonal carcinoma (EC) cells, which differentiate into neurons following exposure to retinoic acid, were used to compare the differentiation-dependent effects of MeHg on ROS production and mitochondrial depolarization. EC cells and their neuronal derivatives were pre-incubated with the ROS indicator 2',7'-dichlorofluoroscein diacetate or tetramethylrhodamine methyl ester, an indicator of mitochondrial membrane potential, with or without cyclosporin A (CsA), an inhibitor of mitochondrial permeability transition pore opening, and examined by laser scanning confocal microscopy in the presence of 1.5 μM MeHg. To examine consequences of mitochondrial perturbation, immunohistochemical localization of cytochrome c (cyt c) was determined after incubation of cells in MeHg for 4 h. MeHg treatment induced earlier and significantly higher levels of ROS production and more extensive mitochondrial depolarization in neurons than in undifferentiated EC cells. CsA completely inhibited mitochondrial depolarization by MeHg in EC cells but only delayed this response in the neurons. In contrast, CsA significantly inhibited MeHg-induced neuronal ROS production. Cyt c release was also more extensive in neurons, with less protection afforded by CsA. These data indicate that neuronal differentiation state influences mitochondrial transition pore dynamics and MeHg-stimulated production of ROS.

Medical Subject Headings

Animals; Cell Differentiation (drug effects, physiology); Cell Line, Tumor; Cytotoxins (metabolism, toxicity); Intracellular Membranes (drug effects, metabolism); Membrane Potential, Mitochondrial (drug effects, physiology); Methylmercury Compounds (metabolism, toxicity); Mice; Mitochondria (drug effects, metabolism); Oxidative Stress (physiology); Permeability (drug effects)

Publication Date

10-1-2011

Publication Title

Neurotoxicology

E-ISSN

1872-9711

Volume

32

Issue

5

First Page

526

Last Page

34

PubMed ID

21871920

Digital Object Identifier (DOI)

10.1016/j.neuro.2011.07.006

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