The Inner Trigger

Intrinsic Apoptosis involves the ced-4 homolog Apaf-1. Recall that ced-4 is the apoptosis initiator gene in C. Elegans. In higher organisms, the protein is called Apaf-1, and it normally hangs out in the cytosol, just waiting. So how does it trigger apoptosis?

Once again, we are going to see how The Horseman back each other up. Recall that early during reperfusion there's a burst of free radical activity, and that free radicals can be both products and instigators of mitochondrial stress and dysfunction. We don't know exactly how mitochondrial stress leads to what happens next, but one thing is clear: at some point, the mitochondrial releases a protein called cytochrome c. As you may know, cytochrome c is a vital component of the respiratory chain, and so you can imagine that leaking cytochrome c from your mitochondria can throw a major monkey wrench into the processes of energy metabolism.

Of course, this is brain reperfusion, so you know it's even worse than that.

Once cytochrome c gets into the cytoplasm, it binds with Apaf-1, the product of the ced-4 homolog. When that happens, Apaf-1 undergoes a conformational change and exposes its own CARD domain.  (Have you noticed how these death domains are just everywhere?). The exposed CARD domain hanging off the cyto-c/Apaf-1 complex recruits another CARD-containing initiator caspase, caspase 9. Interaction between the death domains activates caspase 9. We now have a complex of cytochrome c, Apaf-1 and activated caspase 9--the apoptosome. The apoptosome cleaves executioner caspases, and again you have a caspase cascade. Let's face it: leaky power plants are not good for you. It's going to be a bad day.

Animation. Intrinsic Apoptosis for Dummies.