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Next ground-breaking study of the ferroptotic cell death signal published in Nature Chemical Biology

obrazek: [fot. Andrzej Romański]
photo: Andrzej Romański

A multidisciplinary team of scientists, which includes Dr. Karolina Mikulska-Ruminska from the Department of Biophysics of the Institute of Physics at the Nicolaus Copernicus University, made a groundbreaking discovery regarding to the ferroptosis process and indicate a key role of protein called iPLA2β in the cell death regulation of ferroptosis process. 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 (2017, impact factor = 38.6), Nature Chemical Biology (2020), Redox Biology (2021, joint paper with the ferroptosis discoverer), 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 most prominent team member is 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. Ferroptosis characteristic feature is 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 of that process can be seen among scientists, the explanation still remains unclear. Recently, on the basis of observations of basic science studies and clinical researches on COVID-19, there is a hypothesis that ferroptosis may be an important cause of multiple organ involvement in COVID-19.

Living organisms are composed of all kinds of specialized cells and each of them is made from proteins. Out of the total dry body weight, ¾ are made up of proteins. They are crucial elements in almost every vital process in living organisms. 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. During that process OOH group is added to the carbon atom of ETE-PE. Due to this process peroxidized phospholipids called 15-HpETE-PE are forming and affect the integrity of membrane bilayer that leads to the ferroptotic cell death signal. The existence of this complex was first discovered in 2017 (publication by the mentioned team at CELL).

This time the team discovered another important protein in ferroptosis process – iPLA2β which can hydrolyze 15-HpETE-PE and may averts the accumulation of lipid peroxidation, and thus eliminate the ferroptotic cell death signal. Moreover, experiments on mice with iPLA2β mutant exhibited progressive parkinsonian motor deficits and 15-HpETE-PE accumulation.

Computational model of iPLA2β dimer presented below display protein interactions with the products of PEBP1-lipoxygense action, 15-HpETE-PE, which are localized in a membrane.

The latest study on this topic was reported in the recent article Phospholipase iPLA2β averts ferroptosis by eliminating a redox lipid death signal which is published in the Nature Chemical Biology (2021). The studies were i.a. supported by the National Science Centre (Poland) and National Institutes of Health (NIH).

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