Pore Formation in the Mitochondrial Membrane Triggers Apoptosis

Recent research on the molecular events leading to programmed cell death (apoptosis) showed the interaction between the Bak and Bax proteins that results in the formation of pores in the mitochondrial members that allow cytochrome c (cyt c), the primary signal protein of apoptosis, to leak out of the mitochondria into the cytoplasm.

Cyt c is released by the mitochondria in response to proapoptotic stimuli. The release of small amounts of cyt c leads to an interaction with the IP3 receptor (IP3R) on the endoplasmic reticulum (ER), causing ER calcium release. The overall increase in calcium triggers a massive release of cyt c, which then acts in the positive feedback loop to maintain ER calcium release through the IP3Rs. This release of cytochrome c in turn activates caspase 9, a cysteine protease. Caspase 9 can then go on to activate caspase 3 and caspase 7, which are responsible for destroying the cell from within.

Investigators from the Walter and Eliza Hall Institute of Medical Research (Melbourne, VIC, Australia), who have been studying the Bak/Bax interaction for several years, focused in this study on the process that causes Bak to form dimers and then oligomers of 18 subunits.

"The pivotal step towards cell death is the formation of a pore in the mitochondria; mitochondria make and supply energy to the cells,” said senior author Dr. Ruth Kluck, professor of molecular genetics at the Walter and Eliza Hall Institute. "Pore formation is the point of no return in apoptotic cell death as it allows cytochrome c, which is the protein that initiates cell death, to escape from the mitochondria. Only two proteins are known to form the pore, Bak and Bax. We have now identified the second step in how Bak forms that pore. Once the doublet is formed, it can combine with other Bak doublets by what is called a second interface. This second interface seems to allow doublets to assemble into the larger complexes that form the pore. 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.”

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Walter and Eliza Hall Institute of Medical Research