Mitochondria are best known for providing our cells with energy. These “cellular power plants” also appear to play an important role in signaling in the innate immune system: a new study shows that 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 cellular respiration in the cells of our body and are therefore considered the power plants of the cells. However, recent research suggests that their function goes beyond energy provision: they are involved in the regulation of programmed cell death, among other things, and may also use various signaling pathways to inform the other components of the cell. about his own state. In addition, there is increasing evidence that they also influence immune system processes.
“Until now, however, the mechanisms by which mitochondria influence signal transduction were not sufficiently understood,” reports a team led by Zhixiao Wu from the Ruhr University in Bochum. To find out more precisely what role mitochondria play in our immune system, the researchers used human and mouse cell lines to analyze how mitochondria and associated proteins affect important signaling pathways. They discovered that the cell’s power plants 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 the cell type, NF-κB protects cells from cell death and produces more proteins that help kill bacteria and viruses,” explains Wu’s colleague Konstanze Winklhofer. However, if activated over a longer period of time, this truly protective signaling pathway can also cause chronic inflammation. “Therefore, the efficient regulation of these signaling processes is of great medical relevance to avoid pathological processes derived from an inefficient or excessive activation of NF-κB”, says Winklhofer.
large surface mobile
The NF-κB signaling pathway is activated, among other things, by the signaling substance TNF. Wu and his team added this signaling substance to cell cultures and isolated the mitochondria a few minutes later. They found that, as a result of the treatment, a signaling complex had been formed on the mitochondrial membrane that is important for the activation of NF-κB. This was stabilized, among other things, by the mitochondrial protein PINK1. “Due to the large surface area of the mitochondria, this amplifies the signal,” explains Winklhofer. “In addition, mitochondria have another property that predestines them as signaling organelles: they are mobile and can couple to motor proteins in the cell.”
In fact, in subsequent experiments, the research team found that the contact area between mitochondria and the cell nucleus was increased in cells with an activated NF-κB signaling pathway. Mitochondria apparently transport the activated transcription factor NF-κB close to the cell nucleus and thus facilitate its delivery to its site of action on DNA. According to the study, in addition to this signal-amplifying effect, mitochondria also have a down-regulating function: Wu and his team also identified an enzyme on the surface of mitochondria that reverses changes in certain proteins that are necessary for activation. and thus it surpasses them the reactions prevented.
Interface between the nervous system and the immune system
The involvement of the mitochondrial protein PINK1 is also relevant with respect to neurological diseases such as Parkinson’s, the team explains. Through its stabilizing function, it normally prevents controlled cell death from initiating. In Parkinson’s, however, the corresponding gene is mutated, so PINK1 is not functional. “Our data explain why a loss of PINK1 function 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. Therefore, our insights also contribute to a better understanding of the interfaces 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