Certain 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 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,” explains the author.
However, upon excessive and prolonged activation, this basically protective pathway can cause chronic inflammation. “Hence, a fine-tuned regulation of these signalling processes is of great medical relevance, in order to prevent pathophysiological conditions caused by either inefficient or overshooting NF-κB activation.”
The new study has revealed that mitochondria play a crucial role in the regulation of the NF-κB signalling pathway. Within minutes after pathway activation, a signalling platform assembles at the outer mitochondrial membrane, resulting in the activation of NF-κB.
“This allows signal amplification, based on the large surface of mitochondria,” says the author. “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.”
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 signalling pathway; they also contribute to the deactivation and thus regulation of the signal. This is accomplished by an enzyme located at the outer mitochondrial membrane, which counteracts ubiquitination, a posttranslational modification required for NF-κB activation.
The authors show that TNF treatment induces the recruitment of HOIP, the catalytic component of the linear ubiquitin chain assembly complex (LUBAC), and its substrate NEMO to the outer mitochondrial membrane, where M1- and K63-linked ubiquitin chains are generated. NF-κB is locally activated and transported to the nucleus by mitochondria, leading to an increase in mitochondria-nucleus contact sites in a HOIP-dependent manner.
Two genes causally linked to Parkinson's disease are involved in the mitochondrial regulation of the NF-κB signalling pathway: PINK1 and Parkin.
“Our findings explain why mutations resulting in a loss of PINK1 or Parkin function promote neuronal cell death under stress conditions,” points out the author.
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.”
Mitochondria transmit signals in the immune and nervous systems
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