Distinct Ca 2+ thresholds determine cytochrome c release or permeability transition pore opening in brain mitochondria

In diseases associated with neuronal degeneration, such as Alzheimer’s or cerebral ischemia, the cytosolic Ca 2+ concentration ([Ca 2+ ] cyt ) is pathologically elevated. It is still unclear, however, under which conditions Ca 2+ induces either apoptotic or necrotic neuronal cell death. Studying respiration and morphology of rat brain mitochondria, we found that extramitochondrial [Ca 2+ ] above 1 μM causes reversible release of cytochrome c, a key trigger of apoptosis. This event was NO‐independent but required Ca 2+ influx into the mitochondrial matrix. The mitochondrial permeability transition pore (PTP), widely thought to underlie cytochrome c release, was not involved. In contrast to noncerebral tissue, only relatively high [Ca 2+ ] (≈ 200 μM) opened PTP and ruptured mitochondria. Our findings might reflect a fundamental mechanism to protect postmitotic neuronal tissue against necrotic devastation and inflammation.