Is the Cell Death Pathway Triggered by the Mitochondrion or the Endoplasmic Reticulum?

As discussed in the comprehensive and stimulating hypothesis article by Paschen and Doutheil (1999), neuronal cell damage in acute neurodegenerative disease traditionally has been linked to a perturbed cell calcium metabolism (for a recent review article, see Kristian and Siesjo 1998). Central to the calcium hypothesis of cell death is the fact that a compromise of the bioenergetic status of the cell leads to an increase in the free cytosolic calcium concentration (Ca2+i). This increase is caused by an influx of extracellular Ca2+ through plasma membrane channels modulated by voltage or agonists, particularly that gated when glutamate activates N-methyl-D-aspartate receptors, and to release of calcium ions from intracellular stores and binding sites. The major stores are endoplasmic reticulum (ER) and less well characterized intracellular organelles (“calciosomes”) which release calcium in response to an increase in Ca2+i (Ca2+-dependent Ca2+ release). The mitochondria can also release Ca2+, particularly if they have previously been loaded with calcium, e.g. by intense cellular activity or during reperfusion after ischemia.