University of Pittsburgh scientists unravel the complexities of a newly discovered cell death process that plays a key role in health and disease, with new findings linking it to asthma, kidney damage and brain injury. The results are the first steps in drug development that could transform emergency care.
Damaged cells can wreak havoc in the body, so they need to be destroyed and disposed of safely and effectively. One way to achieve this is with ferroptosis , a type of regulated cell death program that uses iron, which was first discovered in 2012.
To function harmoniously, the billions of cells in the body use a complex and coordinated language to communicate. Last year, two papers were published that revealed the signaling language that cells use to initiate ferroptosis . The communication process that has been discovered requires a group of naturally occurring oxidized phospholipids called OOH- phosphatidylethanolamines (OOH-PE). Phospholipids are the basic building blocks that make up cell membranes, separating what’s inside the cell from everything else outside. However, if too many of these phospholipid signals are generated and too many cells die, the organs and tissues of the body cannot function properly.
The discovery of ferroptosis was just the tip of the iceberg, it is important to learn how to keep this process under control, scientists say. To do this, you need to understand how it works. Several key proteins have been found to interact with phospholipid molecules to induce ferroptosis . It is now possible to move forward and look for ways to limit ferroptosis and prevent massive cell death.
In the new work, the team used various methods to discover that OOH-PE production is the main “crossroads” at which the cell decides whether to initiate ferroptosis .
Previous studies have shown that OOH-PEs were produced due to enzymes known as 15-lipoxygenases (15LOs). In the course of the study, the team found that a protein called PEBP1 acts as a “watchman” that controls whether the 15LO enzymes made either OOH-PE or another type of membrane building block. When the cell increased OOH-PE, it initiated ferroptosis .
The researchers also used several cell culture experiments to demonstrate that PEBP1 and other key players in this pathway play a role in controlling ferroptosis in several diseases, such as kidney failure, neurons in brain injury, and airway cells in asthma. Preventing PEBP1 from binding to 15LOs could be a way to prevent ferroptosis , the scientists say.
Treatment of traumatic brain injury and acute kidney injury is essential, and gaining an understanding of these processes at the molecular level is extremely important for the development of new treatments. In brain injury and acute renal failure, the area of cell death tends to continually expand, indicating that ferroptosis is not abated even after the cells involved in the original injury have been cleared.
Future therapies targeting ferroptosis may have different effects on asthma. With asthma, it is important not only to stop attacks, but also to prevent them. The study revealed how ferroptotic death signals can damage the cells lining the airways. Targeting these pathways may lead to preventive and curative measures for asthma exacerbations.