Mitochondria play a crucial role in the regulation of the NF-κB signaling pathway

Mitochondria are highly regarded as the cell's powerhouse. However, these cellular organelles are essential for more than only energy production: Professor Konstanze Winklhofer and her colleagues at Ruhr University Bochum’s Faculty of Medicine have found that mitochondria play an essential role in signal transduction in innate immune pathways.

Mitochondria play a crucial role in the regulation of the NF-κB signaling pathway
Verian Bader, Konstanze Winklhofer, and Zhixiao Wu (from left) worked together on the study. © RUB, Marquard

They control a signaling pathway that aids in the elimination of infections but can cause serious damage through inflammation if overactivated. The findings were reported on November 17th, 2022, in the EMBO Journal.

Protection from bacteria and viruses

Some cytokines, as well as intracellular pathogens like viruses and bacteria, trigger the transcription factor NF-κB, which governs gene expression.

Depending on the stimulus and the cell type, NF-κB activation results in protection from cell death and increased synthesis of proteins required for the elimination of bacteria or viruses.

Konstanze Winklhofer, Professor, Ruhr-University Bochum

However, when activated over an extended period of time, this normally protective pathway can induce chronic inflammation.

Konstanze Winklhofer adds, “Hence, a fine-tuned regulation of these signaling processes is of great medical relevance, in order to prevent pathophysiological conditions caused by either inefficient or overshooting NF-κB activation.”

Two advantages of mitochondria: They are mobile and have a large surface area

Recent research found that mitochondria perform an important role in the control of the NF-κB signaling pathway. Within minutes of pathway activation, a signaling platform develops at the outer mitochondrial membrane, activating NF-κB.

This allows signal amplification, based on the large surface of mitochondria. Moreover, mitochondria have another capacity that qualifies them as organelles for signal transduction: they are mobile and can dock onto motor proteins in the cell.”

Konstanze Winklhofer, Professor, Ruhr-University Bochum

The researchers discovered that active transcription factor NF-κB is guided to the nuclear membrane by mitochondria, promoting NF-κB translocation into the nucleus.

However, mitochondria are not only engaged in the effective activation of the NF-κB signaling pathway; they also play a role in signal deactivation and hence signal control. This is performed by a mitochondrial enzyme that inhibits ubiquitination, a posttranslational change essential for NF-κB activation.

Why Parkinson’s disease patients are more susceptible to some infections

PINK1 and Parkin, two genes normally connected to Parkinson’s disease, are implicated in the mitochondrial regulation of the NF-κB signaling pathway.

Our findings explain why mutations resulting in a loss of PINK1 or Parkin function promote neuronal cell death under stress conditions. Remarkably, our findings show that Parkinson’s disease patients with mutations in the PINK1 or Parkin gene show an increased vulnerability to various infections caused by intracellular pathogens. Thus, our study also helps to gain a better understanding of the interfaces between the nervous and immune system.”

Konstanze Winklhofer, Professor, Ruhr-University Bochum

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