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A ground-breaking study on ferroptosis published in Nature Chemical Biology

obrazek: dr Karolina Mikulska-Rumińska [fot. Andrzej Romański]
dr Karolina Mikulska-Rumińska photo: Andrzej Romański

A multidisciplinary team of scientists, which includes dr. Karolina Mikulska-Rumińska from the Department of Biophysics of the Institute of Physics at the Nicolaus Copernicus University made a groundbreaking discovery regarding the ferroptosis process and indicate a key role of nitric oxide (NO) in the cell death regulation of ferroptosis process in pro-inflammatory conditions. The results of the study were published in the prestigious Nature Chemical Biology journal.

The research team, in which Dr. Karolina Mikulska-Rumińska was participating, investigated the process of ferroptosis. The team started collaboration in 2016 and since then published several groundbreaking papers on this subject in CELL, Journal of Clinical Investigation and JACS. The team consists of several experimental and theoretical groups, independent laboratories from various scientific disciplines including chemistry, physics, biology or medicine. One of the team members is a prominent world’s authority in the field of medicine and biology of free radicals, Valerian Kagan. As a result of collaboration with doctors from the UP Medical Center hospital in Pittsburgh, the group has access to patients which is a strong advantage.

Ferroptosis is a recently (2012) discovered form of cell death, different from better-known apoptosis or necrosis. The Ferroptosis characteristic feature is an increasing level of lipid peroxides. Therefore, free radicals take electrons from the lipids causing the cell damage. Ferroptosis was identified as the mechanism of cell death in Parkinson and Huntington’s diseases, and sepsis. It plays a critical role in the treatment of cancers and may contribute to the degradation of tissue in brain trauma, kidney diseases, and asthma. Although a lot of interest in that process can be seen among scientists, the explanation remains unclear.

Molecules are the most critical elements in every living organism. They control life functions, performing a lot of complex operations, such as the transmission of signals between cells. In particular important in this respect are proteins.

In ferroptosis, the key role is played by two proteins, PEBP1 and lipoxygenase, which, as a result of the interaction, form a complex that initiates lipid peroxidation which leads to the ferroptotic cell death signal. The existence of this complex was first discovered in 2017 (publication by the mentioned team at CELL).

The mechanism that triggers the ferroptotic cell death signal can be disturbed as a result of the nitric oxide interactions with the PEBP1-lipoxygenase substrate. Studies with NO-deficient mice in pro-inflammatory conditions of brain trauma or tumor microenvironment shows resistance to pharmacologically induced ferroptosis.

The latest study on this topic was reported in the recent article Redox lipid reprogramming commands susceptibility of macrophages and microglia to ferroptotic death which is published in the Nature Chemical Biology.


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Computational model of PEBP1-lypoxygenase complex (PEBP1-15LOX, coordinates for both proteins obtained from X-ray) with catalytic site which consist of iron ion (denoted as the pink sphere) that is covalently bonded to histidines and isoleucine from lipoxygenase (green residues). Residues in blue belong to the entrance of the tunnel localized in the lipoxygenase. As a result of the interactions with nitric oxide the tunnel is opening. Residues that stabilize the interactions with nitric oxide in the catalytic site are displayed in orange. Yellow, dashed line indicates the nitric oxide pathway in lipoxygenase structure. [fot. dr Karoluna Mikulska-Rumińska]