Ruhr University Bochum on 17 November 2022
Mitochondria are best known as the powerhouses of cells. However, these cell organelles are not only important for providing energy: Prof. Dr. Konstanze Winklhofer from the Medical Faculty of the Ruhr University Bochum proved that mitochondria also play an important role in the transmission of signaling processes in the innate immune system. They regulate a signaling pathway that leads to the elimination of pathogens, but if activated for too long, they can cause damage through chronic inflammation. The research team reports in the EMBO Journal on November 17, 2022.
Protection against bacteria and viruses
Some mediators, but also so-called intracellular pathogens, such as viruses and some bacteria, activate the NF-κB transcription factor. It regulates the expression of various genes. “Depending on the triggering stimulus and the cell type, the cells are protected from cell death and more proteins are produced that contribute to the elimination of bacteria and viruses,” explains Konstanze Winklhofer. However, excessive and long-term activation of this actually protective signaling pathway can lead to chronic inflammation. “Therefore, effective regulation of these signaling processes is of great medical importance to prevent pathological processes resulting from ineffective or excessive activation of NF-κB.”
Two advantages of mitochondria: they are mobile and have a large surface area
The current study shows for the first time that mitochondria are involved in the regulation of the NF-κB signaling pathway. Within minutes of activation of this signaling pathway, a signaling complex is formed on the outer mitochondrial membrane that activates NF-κB. “Due to the large surface area of the mitochondria, the signal is amplified,” explains Konstanze Winklhofer. “In addition, mitochondria have another property that predisposes them as signal transduction organelles: they are mobile and can anchor to motor proteins in the cell’s nucleus, thereby facilitating uptake into the cell’s nucleus.”
However, mitochondria are not only involved in the efficient activation of the NF-κB signaling pathway; they also contribute to switching off and thus signal regulation. This is ensured by an enzyme on the outer membrane of the mitochondria. It reverses the change in certain proteins that is necessary for activation.
Why are Parkinson’s patients more susceptible to certain infections?
Two genes whose mutation leads to Parkinson’s disease are involved in the mitochondrial regulation of the NF-κB signaling pathway: PINK1 and Parkin. “Our data explain why loss of PINK1 or Parkin function leads to increased cell death of nerve cells under stressful conditions,” says Konstanze Winklhofer. “It is remarkable to find that Parkinson’s disease patients with mutations in the Parkin or PINK1 gene are more susceptible to various infections caused by intracellular pathogens. Our findings also contribute to a better understanding of the interface between the nervous system and the immune system.”