Wednesday , December 2 2020

Fine Determination of Cell Death: Reveals a new component of death mechanisms



An important component of the microscopic machine that drives cell death has been identified by Walter and Elisa Hall's scientists.

Investigating the "death" machine, which forces the injured, diseased or unwanted cells to die, the research team revealed that a protein called VDAC2 was crucial to the function of a key protein protein called Bax.

The team also showed that VDAC2 contributes to the killing of some cancer cells by anticancer agents. The study, published today in the magazine Nature Communications, is led by Ph.D. student Hui-San Chin with Professor David Huang, Dr. Mark Van Delft and Associate Professor Grant Deuson.

QUESTION

  • Cell death by a process called apoptosis is essential for the removal of unwanted, damaged or diseased cells, and is governed by a fine-tuned protein machine.
  • Bax is a key component of cell death machines, which are part of a complex that takes cells to a "non-return point" at apoptotic death.
  • Our researchers have discovered that the protein called VDAC2 helps Bax manage apoptosis and can play a role in fine-tuning cancer cell response to anticancer agents.

DEATH MACHINES

Apoptotic cell death is critical to the development and maintenance of our body, and the deficiencies in protein machinery that govern apoptosis are associated with a number of diseases. Wrong cell death proteins are associated with both cancer development and resistance of cancer cells to treatment.

A key protein in cell death machines is called Bax, said Dr. Van Delft. "Baxx helps take a cell to a point without return when triggering apoptotic cell death, forming pores in the mitochondria, the cell's energy cells, which unleashes the ultimate" executable "proteins that break a cell.

"Understanding how Bax's functions can lead to new therapeutic agents that either promote cell death – with applications for diseases such as cancer – or therapeutic agents that prevent cell death that have the potential to save cells in conditions such as neurodegenerative diseases or stroke ",

The team investigates how Bax and its associated protein called Bak kill cells by destroying the function of different genes using CRISPR technology, said Associate Professor Dewson.

"To our surprise, we found a gene that is essential for Bax's function, but not for Bak, although these two proteins are functionally and structurally very similar.

"We were able to track this study to show that the protein called VDAC2 was a catalyst that helped Baqs connect with mitochondria and form pores in their membranes to kill the cell," said Associate Professor Deuson. "Interestingly, VDAC2's" task "is to support the function of mitochondria by pumping the metabolites into and out of mitochondria."

WORK CELLS FOR DEATH

The failure of cell death machines is a hallmark of cancer cells and is linked to the resistance of cancer cells to anti-cancer treatments, Professor Huang said.

"Bax is important to help kill anti-cancer agents – without Bax and its relative Bak, cancer cells can not undergo apoptosis when treated with a number of anti-cancer therapies.

"Our study showed that VDAC2 is necessary for Bax to manage the response of cancer cells to conventional chemotherapeutic agents as well as newly developed BH3 mimetics," said Professor Juan.

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The research is supported by the Australian National Council on Health and Medical Research, the Australian Research Council, Victoria Victoria Cancer, the Australian Cancer Research Foundation, the Society for Leukemia and Lymphoma (USA) and the Victorian Government. Dr. Hui San Chin is supported by a Ph.D. scholarship from the University of Melbourne.

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