Pivotal Role of Mitochondrial Calcium Uptake in Neural Cell Apoptosis and Necrosis
: Perturbed cellular calcium homeostasis has been implicated in both apoptosis and necrosis, but the role of altered mitochondrial calcium handling in the cell death process is unclear. The temporal ordering of changes in cytoplasmic ([Ca2+]C) and intramitochondrial ([Ca2+]M) calcium levels in relat...
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Veröffentlicht in: | Journal of neurochemistry 1999-02, Vol.72 (2), p.529-540 |
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Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | : Perturbed cellular calcium homeostasis has been
implicated in both apoptosis and necrosis, but the role of altered
mitochondrial calcium handling in the cell death process is unclear. The
temporal ordering of changes in cytoplasmic ([Ca2+]C) and
intramitochondrial ([Ca2+]M) calcium levels in relation to
mitochondrial reactive oxygen species (ROS) accumulation and membrane
depolarization (MD) was examined in cultured neural cells exposed to either an
apoptotic (staurosporine ; STS) or a necrotic (the toxic aldehyde
4‐hydroxynonenal ; HNE) insult. STS and HNE each induced an early increase of
[Ca2+]C followed by delayed increase of [Ca2+]M.
Overexpression of Bcl‐2 blocked the elevation of [Ca2+]M and the MD
in cells exposed to STS but not in cells exposed to HNE. The cytoplasmic
calcium chelator BAPTA‐AM and the inhibitor of mitochondrial calcium uptake
ruthenium red prevented both apoptosis and necrosis. STS and HNE each induced
mitochondrial ROS accumulation and MD, which followed the increase of
[Ca2+]M. Cyclosporin A prevented both apoptosis and necrosis,
indicating critical roles for MD in both forms of cell death. Caspase
activation occurred only in cells undergoing apoptosis and preceded increased
[Ca2+]M. Collectively, these findings suggest that mitochondrial calcium overload is a critical event in both apoptotic and necrotic cell death. |
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ISSN: | 0022-3042 1471-4159 |
DOI: | 10.1046/j.1471-4159.1999.0720529.x |