It is known that cell death is a mechanism used by multicellular organisms to help them survive by removing infected, damaged or unwanted cells. Mitochondria are known as the energy-generating organelles of the cell, or cell powerhouses. However, they may also activate cell death under certain conditions and assist in the removal of damaged cells from the body. Now, a study from researchers at St. Jude Children’s Research Hospital has uncovered a new pathway for mitochondrial cell death which involves the protein BCL-2 ovarian killer, otherwise known as BOK. The team state that their findings may lead to new ways to trigger cell death in some types of cancer cells. The opensource study is published in the journal Cell.
Previous studies show that the mitochondrial pathway of cell death or apoptosis starts by permeabilization of the mitochondrial outer membrane which becomes peppered with small holes. The leakage of proteins and other molecules from the space between the inner and outer membranes of the mitochondria into the cytosol sets in motion a series of reactions that lead to the rapid demise of the cell. BOK is an effector of mitochondrial apoptosis that appears to work in a different way to known proteins that initiate mitchondrial cell death. The stability of BOK appears to be directly related to the amount of cellular stress experienced within the endoplasmic reticulum. The current study reveals a newly discovered mechanism for mitochondrial cell death involving the effector protein BOK.
The current study shows that BOK is controlled at the level of protein stability by components of the Endoplasmic Reticulum Associated Degradation (ERAD) pathway. Data findings show that ERAD is a quality control mechanism that helps to detect and eliminate damaged and often unfolded proteins.
Results show that BOK works independently of BAK and BAX, two other members of the BCL-2 family of proteins that regulate and contribute to mitochondrial cell death. Data findings show that the fate of the cell during stress appears to be intricately linked to the signaling pathways, such as the BOK pathway, that trigger mitochondrial cell death. The lab note that this suggests that cancer cells expressing high levels of BOK may be particularly sensitive to inhibitors that target the proteasome or the ERAD pathway.
The team surmise that the development of specific inhibitors that target the ERAD pathway could provide useful alternatives to some of the known proteasome inhibitors that stop the growth of cancer cells. They go on to add that some proteasome inhibitors affect multiple targets in ways that do not meet the desired level of specificity and an ERAD inhibitor might overcome this drawback. For the future, the researchers state that more work is needed to identify suitable molecules to target the ERAD pathway.
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An avid campaigner in the fight against child sex abuse and trafficking, Michelle is a passionate humanist striving for a better quality of life for all humans by helping to provide traction for new technologies and techniques within healthcare.