Release of caspase-9 from mitochondria during neuronal apoptosis and cerebral ischemia

Caspase-9 is critical for cytochrome c (cyto-c)-dependent apoptosis and nor mal brain development. We determined that this apical protease in the cyto- c pathway for apoptosis resides inside mitochondria in several types of cel ls, including cardiomyocytes and many neurons. Caspase-9 is released from i solated mitochondria on treatment with Ca2+ or Bar, stimuli implicated in i schemic neuronal cell death that are known to induce cyto-c release from mi tochondria. In neuronal cell culture models, apoptosis-inducing agents trig ger translocation of caspase-9 from mitochondria to the nucleus, which is i nhibitable by Bcl-2, Similarly, in an animal model of transient global cere bral ischemia, caspase-9 release from mitochondria and accumulation in nucl ei was observed in hippocampal and other vulnerable neurons exhibiting earl y postischemic changes preceding apoptosis. Loss of mitochondrial barrier f unction during neuronal damage from ischemia or other insults therefore may play an important role in making certain caspases available to participate in apoptosis.