NOV 26, 2018 3:10 PM PST

New Insight Into the Machinery That Drives Cell Death

WRITTEN BY: Carmen Leitch

When cells are worn out and damaged or diseased, they can initiate a self-destruct sequence called apoptosis. Now researchers at the Walter and Eliza Hall Institute (WEHI) have learned more about the molecular machinery that drives apoptosis. When unwanted cells are programmed to die, the team found that a protein called VDAC2 is essential to Bax, a pro-apoptosis protein. The findings, which also showed that VDAC2 helps certain therapeutics to kill cancer, have been published in Nature Communications.

Apoptosis is animated in the video above from WEHI.

Our cells have to be able to kill themselves off when necessary, and apoptosis is an essential process in the proper development and maintenance of our bodies. Dysfunction in apoptotic machinery has been linked to the development of many disorders including heart, neurodegenerative, autoimmune and infectious diseases as well as cancer.

"Bax helps to take a cell to a 'point of no return' when apoptotic cell death is triggered, forming pores in mitochondria, the powerhouses of the cell. This unleashes the final 'executioner' proteins that dismantle a cell,” said study co-author Dr. Mark van Delft of the University of Melbourne.

"Understanding how Bax functions could lead to new therapeutics that either promote cell death - with applications for diseases such as cancer - or therapeutics that prevent cell death, which have the potential to save cells in conditions such as neurodegenerative disorders or stroke," he said.

The team wanted to know more about how Bax and Bak, another related protein, work to kill cells. They used CRISPR to test the function of various genes, explained co-author Grant Dewson, WEHI associate professor.

"To our surprise, we discovered a gene that was essential for the function of Bax but not Bak, despite these two proteins being functionally and structurally very similar. We were able to follow up on this research to show that the protein, called VDAC2, was a catalyst that helped Bax associate with mitochondria and form pores in their membranes, to kill the cell," Dewson said. "Intriguingly VDAC2's 'day job' is to maintain the function of the mitochondria, pumping metabolites in and out of the mitochondria."

Huang noted that in cancer cells, the cell death machinery tends to fail, which has also been linked to cancer cells that are resistant to therapeutics. 

"Bax is important for helping anti-cancer agents kill cells - without Bax and its relative Bak, cancer cells cannot undergo apoptosis when treated with a range of anti-cancer therapies. Our research showed that VDAC2 is required for Bax to drive the response of cancer cells to conventional chemotherapy agents as well as the recently developed BH3-mimetics," added Huang.

Sources: AAAS/Eurekalert! Via Walter and Eliza Hall Institute, Nature Communications

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