Mitochondria are best known for providing our cells with energy. Apparently, these “cell power plants” also fulfill an important function in signal transmission in the innate immune system: a new study shows that the cell 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 cell respiration in our body cells and are therefore considered the power plants of the cells. However, recent research suggests that their function goes beyond the provision of energy: They are involved in the regulation of programmed cell death, among other things, and can also use various signaling pathways to inform the other components of the cell about their own status. In addition, there is increasing evidence that they also influence processes of the immune system.
Efficient regulation
“Until now, however, the mechanisms by which mitochondria influence signal transduction were only insufficiently understood,” reports a team led by Zhixiao Wu from the Ruhr University in Bochum. In order to find out more precisely what role the mitochondria play in our immune system, the researchers used cell lines from humans and mice to analyze how the mitochondria and associated proteins affect important signaling pathways. They discovered that the cell’s power plants are involved in regulating 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 the cells from cell death and produces more proteins that help eliminate bacteria and viruses,” explains Wu’s colleague Konstanze Winklhofer. However, if activated for a longer period of time, this actually protective signaling pathway can also cause chronic inflammation. “Therefore, efficient regulation of these signaling processes is of great medical relevance in order to avoid pathological processes resulting from inefficient or excessive NF-κB activation,” says Winklhofer.
Mobile with a large surface
The NF-κB signaling pathway is activated, among other things, by the signaling substance TNF. Wu and her team added this signaling substance to the cell cultures and isolated the mitochondria a few minutes later. They found that as a result of the treatment, a signaling complex that is important for the activation of NF-κB had formed on the membrane of the mitochondria. This was stabilized, among other things, by the mitochondrial protein PINK1. “Because of the large surface area of mitochondria, this amplifies the signal,” explains Winklhofer. “In addition, mitochondria have another property that predestines them as organelles for signal transmission: They are mobile and can dock to motor proteins in the cell.”
In fact, in further experiments, the research team found that the contact area between mitochondria and cell nucleus increased in cells with an activated NF-κB signaling pathway. The mitochondria apparently transport the activated transcription factor NF-κB close to the cell nucleus and in this way make it easier for it to reach its site of action on the DNA. According to the study, in addition to this signal-amplifying effect, the mitochondria also have a down-regulating function: Wu and her team also identified an enzyme on the surface of the mitochondria that reverses the changes in certain proteins that are necessary for activation and thus overshoots them reactions prevented.
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, the team explains. Through its stabilizing function, it normally prevents controlled cell death from being initiated. In Parkinson’s, however, the corresponding gene is mutated, so that PINK1 is not functional. “Our data explain why a loss of function of PINK1 leads to increased cell death of nerve cells under stress conditions,” says Winklhofer. “The finding that Parkinson’s patients with mutations in the PINK1 gene are more susceptible to various infections caused by intracellular pathogens is remarkable. Thus, our insights also contribute to a better understanding of interfaces between the nervous system and the immune system.”
Source: Zhixiao Wu (Ruhr-Universität Bochum) et al., EMBO Journal, in press, doi: 10.1101/2022.05.27.493704