Acute exposure to methylmercury opens the mitochondrial permeability transition pore in rat cerebellar granule cells

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 Ca-i(2+) stores; the second phase results from entry of Ca-e(2+). 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 Ca-i(2+). 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 (psi(m)). Pretreatment with the MTP inhibitor cyclosporin A (CsA, 5 muM) delayed the initial phase of increased [Ca2+](i) induced by 0.2 and 0.5 muM MeHg, but not 1.0 muM MeHg. CsA (5 muM) also delayed the irreversible loss of psi(m). induced by 0.5 muM MeHg. Ca-e(2+) was not required for either effect, because the effect of CsA on the first phase increase in [Ca2+](i) and loss of psi(m) was not altered in nominally Ca2+ -free buffer. Increasing concentrations of MeHg (0.2-2.0 muM) 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 muM), but not at higher MeHg concentrations (1.0-2.0 muM). Thus, the MTP appears to play a significant role in the cellular effects following acute exposure of cerebellar granule neurons to MeHg. (C) 2002 Elsevier Science.