Calcium induced release of mitochondrial cytochrome c by different mechanisms selective for brain versus liver

Increased mitochondrial Ca2+ accumulation is a trigger for the release of c ytochrome c from the mitochondrial intermembrane space into the cytosol whe re it can activate caspases and lead to apoptosis, This study tested the hy pothesis that Ca2+-induced release of cytochrome c in vitro can occur by me mbrane permeability transition (MPT)-dependent and independent mechanisms, depending on the tissue from which mitochondria are isolated, Mitochondria were isolated from rat liver and brain and suspended at 37 degrees C in a K +-based medium containing oxidizable substrates, ATP, and Mg2+. Measurement s of changes in mitochondrial volume (via light scattering and electron mic roscopy), membrane potential and the medium free [Ca2+] indicated that the addition of 0.3-3.2 mu mol Ca2+ mg(-1) protein induced the MPT in liver but not brain mitochondria, Under these conditions, a Ca2+ dose-dependent rele ase of cytochrome c was observed with both types of mitochondria; however, the MPT inhibitor cyclosporin A was only capable of inhibiting this release from liver mitochondria. Therefore, the MPT is responsible for cytochrome c release from liver mitochondria, whereas an MPT-independent mechanism is responsible for release from brain mitochondria.