Oxidative stress: how protein recycling protects against cell death

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Programmed cell death protects the body against cancer and other diseases. A team of researchers led by Professor Alexander Bartelt from the Institute for Cardiovascular Prevention (IPEK) has decoded a new mechanism by which oxidative stress influences cell death. The researchers hope this discovery will lead to novel approaches for targeting cancer cells and other diseases. Their findings were recently published in the journal Cell Death & Differentiation.

When the lipids in the plasma are attacked, it is referred to as ferroptosis. In a chain reaction, the lipid molecules that make up the membrane are being destroyed and the cell literally dissolves. “Ferroptosis is a recently discovered form of cell death and we’re searching for ways to control the process,” says Bartelt. The team concentrated on the proteasome, which functions as a sort of recycling bin for the cell. Through the operations of the proteasome, old or damaged proteins are broken down and made available to the cell again.

Using state-of-the-art methods of mass spectrometry, the team investigated whether the recycling of proteins is disrupted during ferroptosis. In this way, the researchers found that the proteasome is effectively clogged up, accelerating cell death. At the same time, they identified the enzyme DDI2, which cranks up the recycling again and protects against cell death. “DDI2 is a protease – a type of enzyme it’s possible to therapeutically influence,” says Anahita Ofoghi, who carried out the study.

The findings point to a new way of manipulating cell death. This could be relevant not only for new cancer therapies, but also indicates how we might be able to protect healthy cells against death. “We’ve contributed a small piece to the fascinating puzzle of ferroptosis,” says Bartelt. The authors now hope to exploit this molecular mechanism for therapies.

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