Cytochrome c release from brain mitochondria is independent of the mitochondrial permeability transition

Ca2+ uptake by brain mitochondria induces the release of up to 40% of total cytochrome c in a cyclosporin A-insensitive manner. In the presence of ATP and Mg2+, this process is not accompanied by mitochondrial swelling. There is a moderate decrease in membrane potential under these conditions, but it is completely reversible upon removal of accumulated Ca2+ by addition of EGTA+A23187 but not by EGTA alone. These observations provide evidence that cytochrome c release from brain mitochondria does not require the membrane permeability transition. However, brain mitochondria can undergo the permeability transition in the absence of ATP and Mg2+, which results in cyclosporin A-sensitive large amplitude swelling, loss of Ca2+ uptake capacity and release of matrix solutes.