How do neural cells respond to ischemia?

A group of researchers from the Lomonosov Moscow State University in collaboration with their Irish colleagues from the University College Cork has studied the early response of cells to ischemia, which is a restriction in blood supply to tissues causing the death of the cell. The article describing the results of their studies is published in Genome Biology. It's impact factor is 10.5.

Dmitry Andreev, PhD, senior research fellow at the A.N. Belozersky Institute Of Physico-Chemical Biology and Ivan Shatsky, PhD, professor at the same institute, described the results.

"The study became possible due to the development of techniques Next-Generation Sequencing (NGS), which made a real revolution in the life sciences. In particular, we used the ribosome profiling technique which allows the capture of a "snapshot" of all protein synthesis in the cell at a given time. The protein synthesis in the cell is driven by ribosomes, which are huge macromolecular machines capable of reading the information encoded in the messenger RNA and synthetizing corresponding proteins. At any time thousands of various proteins, are being synthesized by ribosomes. When a change in external conditions occurs, ribosomes can quickly switch to the other messenger RNA and begin to synthesize the proteins necessary for adaptation to new conditions.

"We decided to use this method to study the changes in gene expression in the cells upon oxygen and glucose deprivation, - Dmitry Andreev explains, - "This is a model for studying ischemia".

Prolonged exposure to ischemia always leads to irreversible tissue damage, and as a consequence to the cell death. However, within a short time after the stress cells are still viable, what means they can rescued and thereby prevent the devastating effects of ischemia. That is why understanding of the processes occurring in a cell in the early hours, or even minutes after ischemia, can have a very important fundamental and practical significance.

We have studied the early response to ischemia in the first hour after stress. It appeared that within 20 minutes after the stress significant changes in the synthesis of proteins occur. It is interesting that the most significant changes occur in the synthesis of proteins involved in mitochondrial respiratory chain. Apparently, the cell tries dramatically to adapt to new conditions and to switch to "alternative" energy sources in order to avoid death.

The main paradigm of regulation of respiration in the cell signaling pathway is a family of transcription factors known as HIF (Hypoxia Inducible Factor). This transcription factor activates expression of several genes involved, for example, in glucose transport or in the formation of new blood vessels. Under normal conditions, when the oxygen in the cell is sufficient, specific prolyl hydroxylase enzymes constantly modify regulatory subunits of HIF sending it to the destruction. Thereby HIF remains turned off. Once the oxygen level in the cell falls below a threshold, prolyl hydroxylase, which requires oxygen for activity, turns off, while HIF stabilizes and begins to work.