German Study Explains Inflammatory Response Triggered by Cell Death

Research from University of Cologne and Osnabrück University is shedding light on how messenger substances signal inflammation during removal of damaged cells. Better understanding of the process could lead to cancer treatments that are less harmful to the body.   

Normally, the body triggers apoptosis, a form of program cell death, to get rid of damaged cells, but how this mechanism works at the molecular level is not well understood.  The process is of particular interest in cancer research, where radiotherapy treatment is routinely used to kill cancer cells, but induces inflammation.

In this study, the research team from Cluster of Excellence for Aging Research at the University of Cologne (CECAD) and Center for Cellular Nanoanalytics (CellNanOs) at Osnabrück University used high-resolution microscopy methods to show that two proteins already known to regulate cell death mechanism in mitochondria—BAX and BAK—interact dynamically with each other to determine whether a dying cell triggers an inflammatory reaction in the body.  

Previously considered twin proteins because of their similarities, the team was the first to show that BAX and BAK differ in their mechanism of action. BAK proteins organize into smaller structures more quickly than BAX. The two proteins also influence each other.  “We could clearly observe under the microscope how both proteins interacted with each other to form a pore in the mitochondrion, so that the mitochondrial DNA exited through the pore to trigger inflammation,” says Andreas Jenner of the University of Cologne. The interplay between BAK and BAX regulates the formation of the pore and thus the amount of mitochondrial DNA released. This, in turn, determines whether an inflammatory response is triggered in the body.

“The relative availability of BAX and BAK proteins in cells determines the growth of the pore and the rate at which mitochondrial DNA is released. Possibly, our findings open up new perspectives to control inflammation during cancer treatments,” says Katia Cosentino of the Osnabrück University.

Further investigation is needed to determine whether additional molecules contribute to the dynamics of BAX and BAK pore formation and regulate pore growth and size.

The findings were published recently in Molecular Cell.