Mitochondria transmit signals to the immune system

Mitochondria are best known for providing energy to our cells. These “cellular powerhouses” apparently also fulfill an important function in signal transduction in the innate immune system: a new study shows that the cellular organelles regulate the so-called NF-κB signaling pathway. It helps fight pathogens, causes inflammation and is also involved in various processes in the central nervous system.

Mitochondria are responsible for cellular respiration in our body cells and are therefore considered the powerhouses of cells. However, recent research suggests that their function goes beyond providing energy: Among other things, they are involved in the regulation of programmed cell death and can also inform other components of the cell about their own state using various signaling pathways. In addition, there is increasing evidence that they also affect the processes of the immune system.

Effective regulation

“Until now, however, the mechanisms by which mitochondria influence signal transduction have been poorly understood,” reports the team led by Zhixiao Wu from Ruhr University Bochum. To find out more precisely what role mitochondria play in our immune system, researchers used cell lines from humans and mice to analyze how mitochondria and related proteins influence important signaling pathways. They discovered that cellular powerhouses are involved in the regulation of the so-called NF-κB signaling pathway. NF-κB is a transcription factor that regulates the expression of many different genes in our body. In the central nervous system, it is involved in synaptic plasticity, among other things. This signaling pathway is also an important part of our innate immune system.

“Depending on the triggering stimulus and cell type, NF-κB protects cells from cell death and produces more proteins that help eliminate bacteria and viruses,” explains Wu’s colleague Konstanze Winklhofer. However, with prolonged activation, this actually protective signaling pathway can also cause chronic inflammation. “Effective regulation of these signaling processes is therefore of great medical importance to prevent pathological processes resulting from ineffective or excessive activation of NF-κB,” says Winklhofer.

Mobile with a large surface area

The NF-κB signaling pathway is activated, among other things, by the signaling substance TNF. Wu and her team added this signaling substance to cell cultures and minutes later isolated the mitochondria. They found that the treatment resulted in the formation of a signaling complex on the mitochondrial membrane that is important for the activation of NF-κB. This was stabilized by, among other things, the mitochondrial protein PINK1. “Because of the large surface area of ​​the mitochondria, this amplifies the signal,” explains Winklhofer. “Mitochondria also have another property that predisposes them to signal transduction organelles: They are mobile and can anchor to motor proteins in the cell.”

In fact, in further experiments, the research team found that the contact area between mitochondria and the cell nucleus increased in cells with an activated NF-κB signaling pathway. Mitochondria seem to transport the activated transcription factor NF-κB close to the cell nucleus and thereby facilitate its reaching the site of action on DNA. According to the study, in addition to this signal-amplifying effect, mitochondria also have a down-regulation function: Wu and her team also identified an enzyme on the surface of mitochondria that reverses changes in certain proteins that are necessary for activation. and thus the firefights prevented them from reacting.

The interface between the nervous system and the immune system

The involvement of the mitochondrial protein PINK1 is also relevant with regard to neurological diseases such as Parkinson’s disease, the team explains. Due to its stabilizing function, it normally prevents the initiation of controlled cell death. However, in Parkinson’s disease, the corresponding gene is mutated so that PINK1 is not functional. “Our data explain why loss of PINK1 function leads to increased cell death of nerve cells under stress conditions,” says Winklhofer. “The finding that Parkinson’s disease patients with mutations in the PINK1 gene are more susceptible to various infections caused by intracellular pathogens is remarkable. Our findings also contribute to a better understanding of the interface between the nervous system and the immune system.”

Source: Zhixiao Wu (Ruhr University Bochum) et al., EMBO Journal, in press, doi: 10.1101/2022.05.27.493704

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