Role of Iron in Initiating Programmed Cell Death

Health care professionals from I.M. Sechenov Moscow State Medical University published a review of scientific articles to illustrate how the atoms of iron initiate ferroptosis - programmed cell death. The article was published in the Free Radical Biology and Medicine journal.

Iron is a part of many biological processes where it acts as a catalyst or oxidizer. Many biologically active structures also contain atoms of iron, for example, the haem of haemoglobin where they play the role of oxygen binders. However, besides vitally important processes, the atoms of iron can also catalyze damaging reactions and cause cell death.

When iron accumulates in a cell it induces the peroxidation of fats (lipids) causing the formation of reactive oxygen species ROS also known as free radicals. These particles are oxygen atoms with one electron on their outer level. This gives ROS high oxidizing capacity and the ability to damage cell organelles and walls. The process of cell death caused by iron accumulation is called ferroptosis.

The above-mentioned mechanism of ferroptosis is not the only one. Scientists also know the second way: reduction of the activity of glutathione peroxidase 4 - a ferment that removes peroxidized compounds, the sources of ROS, from the cell. 

Until now, the influence of each mechanism on ferroptosis has been unclear. To understand it, a group of authors including the scientist from Sechenov University and his colleagues from the USA and Austria published an extensive review of numerous scientific works dated back to different years. The scientists discovered that the reduction of the activity of glutathione peroxidase 4 plays the biggest role in ferroptosis. Previously, the process of lipid oxidation catalyzed by iron and leading to the formation of ROS was considered as the key element of ferroptosis, as well as other programmed cell death processes - apoptosis and necroptosis.

According to the authors of the new review, a reliable proof the lipid oxidation influence on cell death existed only for apoptosis. Studies show that two other programmed cell death processes are caused by different fermentative reactions that take place in the cell. Namely, ferroptosis is likely to be determined by the reduction of the activity of glutathione peroxidase 4.

“Numerous experimental data shows the important role of strictly controlled “looped” iron-dependent cell growth processes and increased cell survival. There are also results illustrating the role of iron in ferroptosis. We suggested a solution combining these two apparently opposite processes. The answer to this puzzle to a great extent depends on the identification of the proteins causing ferroptosis, i.e. those in charge for cell membrane destruction and cell death,” says Sergey Bolevich, MD, a co-author of the work, head of the Department of Human Pathology at Sechenov University.

This article has been republished from materials provided by Sechenov University. Note: material may have been edited for length and content. For further information, please contact the cited source.

Reference:

Stoyanovsky, D., Tyurina, Y., Shrivastava, I., Bahar, I., Tyurin, V., Protchenko, O., . . . Kagan, V. (2018). Iron catalysis of lipid peroxidation in ferroptosis: Regulated enzymatic or random free radical reaction? Free Radical Biology and Medicine. doi:10.1016/j.freeradbiomed.2018.09.008