Compulsion to commit suicide

Mitochondrial protein may become a target of drugs,
inducing apoptosis of cancer cells

LifeSciencesToday based on IRB materials: A protein that can mean life or death for cellsEach cell of any organism has a sensor that evaluates the state of its internal environment.

This "panic button" is located in the endoplasmic reticulum, which is able to "feel" cellular stress and initiate reactions either saving the cell or leading to its death. A group of scientists from the Institute for Research in Biomedicine (IRB), Barcelona, found that the Mitofusin 2 protein (Mitofusin 2, Mfn2) plays a crucial role in the correct assessment of stress levels, and its activity is a guarantee that the intended goals – apoptosis or recovery – will be guaranteed to be achieved.

Researchers describe some of the molecular mechanisms linking Mfn2 to endoplasmic reticulum stress in the EMBO Journal, a scientific journal published by the European Molecular Biology Organization (Munoz et al., Mfn2 modulates the UPR and mitochondrial function via repression of PERK).

The endoplasmic reticulum responds to the removal of Mfn2 under conditions of cellular stress by hyperactivating repair pathways. At the same time, it functions worse, reducing the ability of cells to overcome stress and contributing to apoptosis to a lesser extent.

"When Mfn2 is removed, the cell's stress response pathways are completely disrupted," comments the results of the study by its leader Antonio Sorzano, coordinator of the IRB Molecular Medicine program and head of the heterogeneous and polygenic diseases group, professor of the Department of Biochemistry and Molecular Biology at the School of Biology of the University of Barcelona (Universitat de Barcelona).

Mfn2 is a mitochondrial protein whose deficiency is associated with diabetes. In an earlier publication in the Proceedings of the National Academy of Sciences, Professor Sorsano's group demonstrated that without Mfn2, tissues become resistant to insulin, which is characteristic of diabetes and the so-called metabolic syndrome. In this study, it was found that cells deprived of Mfn2 also experience more pronounced stress of the endoplasmic reticulum.

Endoplasmic reticulum of a cell with and without Mfn2 protein (left).
On the right: ER forms vesicles indicating complete disorganization of the organelle
and the inability to respond adequately to cellular stress. (Photo: JP Munoz)

The study is devoted to the study of the relationship between the endoplasmic reticulum and mitochondria and shows that changes in mitochondria caused by the loss of the Mfn2 protein directly affect its function.

"We have shown the importance of Mfn2 for cell viability and its association with many diseases, in addition to diabetes, such as neurodegeneration, cancer, cardiovascular diseases," explains the first author of the article, postdoctoral researcher Juan Pablo Munoz.

"The fact that we can modulate the cell's response to damage using Mfn2 makes further study of the therapeutic potential of this protein a very promising direction," says Munoz.

Tumor cells do not undergo apoptosis in the way that normal cells do, and proliferate uncontrollably.

"It has already been noticed that the level of Mfn2 is low in cancer cells, and if we were able to increase it, we would give an additional impetus to the induction of apoptosis," the scientist continues.

Considering this, several research groups have already published articles in which increased expression of Mfn2 is considered as a factor in the induction of apoptosis.

To prove the significance of Mfn2 as a therapeutic target, researchers now need to find a low molecular weight compound that modulates its expression in animal cells.

"Our work on Mfn2 is a proof of concept, and the article we published highlights the importance of this mitochondrial protein for the normal state of the cell," concludes Professor Sorsano.

One of the immediate tasks of his group is to provide funding for further research. The scientists plan to conduct a large-scale screening of molecules with the ability to modulate Mfn2 expression and test their effect in experiments on mice.

Portal "Eternal youth" http://vechnayamolodost.ru30.09.2013