Affiliation: School of Medicine, Department of Cell Biology and Physiology
Apoptosis is a genetically regulated evolutionarily conserved form of cell death. During the intrinsic pathway of apoptosis, the Bcl-2 family of proteins regulates the release of cytochrome c from the mitochondria. Cytosolic cytochrome c is then free to bind to the adaptor protein Apaf-1. This causes Apaf-1 to oligomerize and form what is known as the apoptosome complex. This apoptosome then recruits and activates proteases called caspases which cleave numerous cellular substrates ultimately killing the cell. Postmitotic neurons exhibit increased resistance to apoptosis. By increasing the regulation of caspase activation, they ensure they can survive long term to serve their vital function for the lifetime of the organism. This is particularly important since the death of postmitotic cells is associated with various pathophysiological conditions. For example, apoptosis causes the destruction of skeletal muscle in some neuromuscular diseases and endoplasmic reticulum (ER) stress triggered apoptosis is the underlying cause of several neurodegenerative diseases. Here I investigated the pathway and regulation of apoptosis in postmitotic cells. The mechanism by which ER stress induces neuronal apoptosis remains controversial. Here I identified the pathway of apoptosis carried out in neurons triggered to die by ER stress. Importantly, my results show that ER stress commits neurons to die prior to cytochrome c release and that this commitment requires Bax activation and JNK signaling. Furthermore, I identify the importance of the apoptosome as the non-redundant caspase activation pathway to execute neuronal apoptosis in response to ER stress. I have also examined the regulation of apoptosis in skeletal muscle. My results show that as skeletal muscle differentiate; they become resistant to apoptosis because of the ability of XIAP to regulate caspase activation. This increased resistance is due to a decrease in Apaf-1 expression which directly couples to the increased effectiveness of endogenous XIAP to block caspase activation and death. The increased restriction of apoptosis in myotubes is similar to that observed in neurons and cardiomyocytes and is presumably important to ensure the long term survival of these postmitotic cells as they play a vital role in the physiology of organisms.