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 intracellular substrates. Caspases, which are synthesized as inactive zymogens, are themselves caspase substrates and this cleavage leads to their activation. Hence, the potential exists for cascades of caspases leading to cell death. However, it has been recently recognized that another, perhaps more prominent route to caspase activation, involves the mitochondria. Upon receipt of apoptotic stimuli, either externally or internally generated, cells initiate signaling pathways which converge upon the mitochondria to promote release of cytochrome C to the cytoplasm; cytochrome c, thus released, acts as a potent cofactor in caspase activation. Even cell surface "death receptors" such as Fas, which can trigger direct caspase activation (and potentially a caspase cascade), appear to utilize mitochondria as part of an amplification 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 signal. Therefore, mitochondria play a central role in apoptotic cell death, serving as a repository for cytochrome c.