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Pivotal Role of Mitochondrial Calcium Uptake in Neural Cell Apoptosis and Necrosis
Author(s) -
Kruman Inna I.,
Mattson Mark P.
Publication year - 1999
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1999.0720529.x
Subject(s) - apoptosis , necrosis , programmed cell death , calcium , staurosporine , microbiology and biotechnology , mitochondrion , calcium in biology , reactive oxygen species , biology , bapta , mitochondrial apoptosis induced channel , calcium signaling , chemistry , biochemistry , intracellular , signal transduction , protein kinase c , genetics , organic chemistry
: Perturbed cellular calcium homeostasis has beenimplicated in both apoptosis and necrosis, but the role of alteredmitochondrial calcium handling in the cell death process is unclear. Thetemporal ordering of changes in cytoplasmic ([Ca 2+ ]C) andintramitochondrial ([Ca 2+ ]M) calcium levels in relation tomitochondrial reactive oxygen species (ROS) accumulation and membranedepolarization (MD) was examined in cultured neural cells exposed to either anapoptotic (staurosporine ; STS) or a necrotic (the toxic aldehyde4‐hydroxynonenal ; HNE) insult. STS and HNE each induced an early increase of[Ca 2+ ]C followed by delayed increase of [Ca 2+ ]M.Overexpression of Bcl‐2 blocked the elevation of [Ca 2+ ]M and the MDin cells exposed to STS but not in cells exposed to HNE. The cytoplasmiccalcium chelator BAPTA‐AM and the inhibitor of mitochondrial calcium uptakeruthenium red prevented both apoptosis and necrosis. STS and HNE each inducedmitochondrial ROS accumulation and MD, which followed the increase of[Ca 2+ ]M. Cyclosporin A prevented both apoptosis and necrosis,indicating critical roles for MD in both forms of cell death. Caspaseactivation occurred only in cells undergoing apoptosis and preceded increased[Ca 2+ ]M. Collectively, these findings suggest that mitochondrial calcium overload is a critical event in both apoptotic and necrotic cell death.