Mitochondrial Pore Formation Sheds Light On Cancer and Degenerative Diseases.

Walter and Eliza Hall Institute scientists have identified a key step in the biological process of programmed cell death, also called apoptosis.Apoptosis is a form of cell death in which a programmed sequence of events leads to the elimination of cells. Apoptosis plays a crucial role in developing and maintaining health by eliminating old cells, unnecessary cells, and unhealthy cells. The human body replaces perhaps a million cells a second. Too little or too much apoptosis plays a role in a great many diseases. When programmed cell death does not work right, cells that should be eliminated may hang around and become immortal. For example, in cancer and leukemia. When apoptosis works overly well, it kills too many cells and inflicts grave tissue damage. This is the case in strokes and neurodegenerative disorders such as Alzheimer,Huntington and Parkinson diseases.

The research, led by Dr Ruth Kluck from the institute’s Molecular Genetics of Cancer Division, is crucial to the development of drugs that can turn on apoptosis, thereby more effectively killing cancer cells. It could also be used in developing compounds that turn off the apoptosis that leads to degenerative disorders.

Dr Kluck has been investigating the role in apoptosis of two proteins, Bak and Bax. It is thought that understanding their role will identify targets against which drugs to regulate cell death could be designed.

The pivotal step towards cell death is the formation of a pore in the mitochondria.In a healthy cell, the outer membranes of its mitochondria display the protein Bcl-2 on their surface. Bcl-2 inhibits apoptosis. Internal damage to the cell causes a related protein, Bax, to migrate to the surface of the mitochondrion where it inhibits the protective effect of Bcl-2 and inserts itself into the outer mitochondrial membrane punching holes in it and causing cytochrome c ,which is the protein that initiates cell death,to leak out.Pore formation is the point of no return in apoptosis. Only two proteins are known to form the pore, Bak and Bax.”

In 2008 Dr Kluck and her colleagues published their finding that, in order to form the pore, Bak first changes shape and then combines with another Bak protein to form a doublet.

“We have now identified the second step in how Bak forms that pore,” Dr Kluck said. “Once the doublet is formed it can combine with other Bak doublets by what’s called a second interface. This second interface seems to allow doublets to assemble into the larger complexes that form the pore.”

Dr Kluck said the team would continue to study how the large complexes of Bak and Bax force a hole in the mitochondrial membrane, how to start this process more effectively in cancer cells, and how to prevent it in brain and other healthy cells.

“A major black box in understanding apoptosis is how Bak and Bax work. Because these proteins change shape and lodge in a membrane they are hard to study. Any understanding we gain about how Bak and Bax form a pore, how they change shape and how they bind to each other, will help us understand how cancer cells can be targeted to die.”

Source: Penny Fannin
Walter and Eliza Hall Institute