Oxidative stress: How protein recycling protects against cell death

Controlled cell death protects the body against cancer and other diseases. A team of researchers led by Professor Alexander Bartelt from the Institute for Prophylaxis and Epidemiology of Circulatory Diseases (IPEK) has now deciphered a new mechanism of how oxidative stress influences cell death. The researchers hope that this will lead to new approaches for combating cancer cells and other diseases. The results were recently published in the journal Cell Death & Differentiation .

When cells die and the plasma membrane is attacked, this is known as ferroptosis. In a chain reaction, the fat molecules of the membrane are destroyed and the cell literally disintegrates. "Ferroptosis is a new type of cell death and we are looking for ways to control its progression," says Bartelt. The team has focused on the proteasome, a kind of recycling garbage can of the cell. Old or damaged proteins are broken down via the proteasome and made available to the cell again.

Using the latest mass spectrometry methods, the team investigated whether the recycling of proteins is disrupted during ferroptosis. The researchers were able to determine that the proteasome is virtually blocked, which accelerates cell death. At the same time, they identified the enzyme DDI2, which boosts recycling and protects against cell death. "DDI2 is a protease and this type of enzyme can be therapeutically influenced," says Anahita Ofoghi, who carried out the study.

The results show a new way in which cell death can be manipulated. On the one hand, this may be relevant for new cancer therapies, and on the other, it indicates how healthy cells can be protected from death. "We have contributed a small piece to the fascinating puzzle of ferroptosis," says Bartelt. The authors hope that this molecular mechanism can now be used therapeutically.

Anahita Ofoghi et al.: Activating the NFE2L1-ubiquitin-proteasome system by DDI2 protects from ferroptosis. Cell Death & Differentiation 2024