Mitochondria play an important role in signal transduction in innate immune pathways

Mitochondria are primarily known as the powerhouse of the cell. However, these cell organelles are not only necessary for providing energy: Professor Konstanze Winklhofer and her group at the Ruhr University Bochum Medical School in Germany recently discovered that mitochondria play an important role in signal transduction in innate immune pathways. They regulate a signaling pathway that helps eliminate pathogens, but when overactivated can cause damage by inflammation. The research team published their findings in the November 17, 2022 issue of the EMBO Journal.

Some cytokines, but also intracellular pathogens such as viruses and some bacteria, activate the transcription factor NF-κB, which regulates the expression of various genes.

Depending on the stimulus and cell type, NF-κB activation results in protection against cell death and increased synthesis of proteins needed to kill bacteria or viruses.”

Konstanze Winklhofer, Professor at the Faculty of Medicine, Ruhr University Bochum

However, with excessive and prolonged activation, this essentially protective pathway can cause chronic inflammation. “Finely tuned regulation of these signaling processes is of great medical importance to prevent pathophysiological conditions caused by either inefficient or overshooting NF-κB activation.”

A new study has revealed that mitochondria play a key role in regulating the NF-κB signaling pathway. Within minutes of activation of the pathway, a signaling platform is assembled on the outer mitochondrial membrane, leading to NF-κB activation. “This enables signal amplification based on the large surface area of ​​the mitochondria,” says Konstanze Winklhofer. “In addition, mitochondria have another capacity that qualifies them as signal transduction organelles: they are mobile and can attach to motor proteins in the cell.” The research team observed that mitochondria escort the activated transcription factor NF-κB to the nuclear membrane, thus facilitating the translocation of NF-κB into the nucleus.

However, mitochondria are not only involved in the efficient activation of the NF-κB signaling pathway; they also contribute to deactivation and thus signal regulation. This is accomplished by an enzyme located on the outer mitochondrial membrane that counteracts ubiquitination, a post-translational modification required for NF-κB activation.

Two genes causally associated with Parkinson’s disease are involved in the mitochondrial regulation of the NF-κB signaling pathway: PINK1 and Parkin. “Our findings explain why mutations leading to loss of PINK1 or Parkin function promote neuronal cell death under stressful conditions,” emphasizes Konstanze Winklhofer. “Notably, our findings show that Parkinson’s disease patients with mutations in PINK1 or the Parkin gene show an increased vulnerability to various infections caused by intracellular pathogens. Thus, our study also helps to better understand the interface between the nervous and immune systems.” .”