Mitochondria at the crossroad of apoptotic cell death

In the past few years, it has become widely appreciated that apoptotic cell death generally involves activation of a family of proteases, the caspases , which undermine the integrity of the cell by cleavage of critical intrace llular substrates. Caspases, which are synthesized as inactive zymogens, ar e themselves caspase substrates and this cleavage leads to their activation . Hence, the potential exists for cascades of caspases leading to cell deat h. However, it has been recently recognized that another, perhaps more prom inent route to caspase activation, involves the mitochondria. Upon receipt of apoptotic stimuli, either externally or internally generated, cells init iate signaling pathways which converge upon the mitochondria to promote rel ease of cytochrome C to the cytoplasm; cytochrome cl thus released, acts as a potent cofactor in caspase activation. Even cell surface "death receptor s" such as Fas, which can trigger direct caspase activation (and potentiall y a caspase cascade), appear to utilize mitochondria as part of an amplific ation mechanism; it has been recently demonstrated that activated caspases can cleave key substrates to trigger mitochondrial release of cytochrome c, thereby inducing further caspase activation and amplifying the apoptotic s ignal. Therefore, mitochondria play a central role in apoptotic cell death, serving as a repository for cytochrome c.