Researchers at the Science and Technology Facilities Council (STFC) ISIS Neutron and Muon Source in Oxfordshire have used neutron reflectometry to study how Bax interacts with lipids in the mitochondrial membrane to trigger the cell death process known as apoptosis. The research, which was conducted with partners at the University of Umea and European Spallation Source in Sweden, found that when Bax creates pores in the membrane, it extracts lipids to form clusters on the mitochondrial surface via a two-stage process. This process is essential for human life, and its disruption can cause cancerous cells to grow and not respond to cancer treatment.
Scientists at the Science and Technology Facilities Council (STFC) ISIS Neutron and Muon Source (ISIS) in Oxfordshire have made a breakthrough in determining the molecular mechanism involved in the early stages of apoptosis. The study, published in Science Advances, was led by Dr Luke Clifton and his team, who have been investigating the cellular proteins responsible for apoptosis.
Apoptosis is a process that is essential for human life, and its disruption can cause cancerous cells to grow and not respond to cancer treatment. The process is regulated by two proteins with opposing roles known as Bax and Bcl-2.
In normal cells, the soluble Bax protein is responsible for the clearance of old or diseased cells and, when activated, it perforates the cell mitochondrial membrane to form pores that trigger cell death. This can be offset by Bcl-2, which is embedded within the mitochondrial membrane, where it acts to prevent untimely cell death by capturing and sequestering Bax proteins.
However, in cancerous cells, the survival protein Bcl-2 is overproduced, leading to uninhibited cell proliferation. The precise role that Bax and the mitochondrial membrane play in this process has been unclear until now.
The team used a technique known as neutron reflectometry, conducted using the advanced ISIS Surf and Offspec instruments, which enabled them to study in real-time how BAX interacts with lipids in the mitochondrial membrane. This showed that when Bax creates pores in the membrane, it extracts lipids to form clusters on the mitochondrial surface via a two-stage process:
- Fast adsorption of Bax on the mitochondrial membrane surface.
- Simultaneous formation of membrane-destroying pores and Bax-lipid clusters.
The study provides crucial new insights into the molecular mechanisms underlying apoptosis, which could be used to develop new treatments for cancer and other diseases.
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