Researchers have identified a new molecular switch that controls programmed cell death, opening possibilities for future treatments that could force cancer cells to self-destruct or prevent the unwanted death of nerve cells in diseases such as Alzheimer’s and Parkinson’s.
The team at Technical University of Munich discovered that the protein VDAC1 can override Bcl-xL, an inhibitor that normally prevents cells from accidentally destroying themselves through apoptosis. When cell stress increases, indicating abnormal cell development, VDAC1 in the mitochondria unfolds part of its structure, connects to Bcl-xL and deactivates the inhibitor.
“Many research teams worldwide are working on the exciting topic of apoptosis and its targeted control,” said Prof. Franz Hagn from the Chair of Structural Membrane Biochemistry at TUM School of Natural Sciences. “The big advantage is that we are dealing with a highly efficient, evolutionarily developed regulatory mechanism. So, we don’t have to invent something completely new, but can use the appropriate structural methods to learn from nature’s optimized processes.”
Driving cancer cells to death
The newly understood regulatory mechanism opens possibilities for developing drugs with opposite effects depending on the disease. In cancer therapy, future medicines could enhance VDAC1 activation to drive cancer cells to death. In neurodegenerative diseases such as Alzheimer’s or Parkinson’s, treatments could block VDAC1 to prevent unwanted nerve cell death. Deactivation of VDAC1 could also help in certain heart diseases such as ischaemia-reperfusion injury.
“In our study, we used high-resolution structural methods such as nuclear magnetic resonance, X-ray crystallography, and cryo-electron microscopy to investigate how the VDAC1 protein changes under stress conditions,” said Dr. Umut Günsel and Dr. Melina Daniilidis, co-first authors of the study. “We also combined this data with biochemical functional experiments to show that VDAC1 actually binds to the brake protein Bcl-xL, thereby promoting apoptosis.”
However, researchers emphasised that clinical application remains far away. The search for appropriate active substances can now begin, but whether it will be successful is completely open and will become clear only after further experiments. The study was conducted at the Bavarian NMR Center, which is jointly supported by TUM and Helmholtz Munich.
