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Image: Verian Bader, Konstanze Winklhofer and Zhixiao Wu (from left) working
together on the study.
Image credit: Marquard
Protects against bacteria and viruses
Certain cytokines and intracellular pathogens, such as viruses and some bacteria, activate the transcription factor NF-κB, which regulates the expression
of various genes.
Konstanze Winklhofer explains: "Depending on the stimulus and cell type, NF-κB activation prevents cell death and increases the protein synthesis
needed to eliminate bacteria or viruses.
" However, once activated excessively and for a long time, this basic protective pathway can lead to chronic inflammation
.
"Therefore, fine-tuning these signaling processes is medically important to prevent pathophysiological conditions
caused by insufficient or excessive NF-κB activation.
"
Mitochondria have two advantages: one is mobile, and the other is large surface area
New research shows that mitochondria play a crucial role
in regulating the NF-κB signaling pathway.
Within minutes of pathway activation, the signaling platform assembles the outer mitochondrial membrane, resulting in NF-κB activation
.
Konstanze Winklhofer said: "This allows signal amplification, based on the large surface
of mitochondria.
" "In addition, mitochondria have the ability to make them organelles for signal transduction: they are mobile and can dock on
motor proteins in cells.
" The team observed that mitochondria escort activated transcription factor NF-κB to the nuclear membrane, thereby 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 help with inactivation, thereby modulating the signal
.
This is done by an enzyme located in the outer mitochondrial membrane, which counteracts ubiquitination, a post-translational modification
required for NF-κB activation.
Why people with Parkinson's disease are more susceptible to certain infections
Two genes associated with Parkinson's disease are involved in mitochondrial regulation of the NF-κB signaling pathway: PINK1 and Parkin
.
Konstanze Winklhofer noted: "Our findings explain why mutations that cause loss of function in PINK1 or Parkin promote neuronal cell death
under stress conditions.
" "Notably, our findings suggest that Parkinson's disease patients with mutations in the PINK1 or Parkin genes have increased
vulnerability to various infections caused by intracellular pathogens.
" Therefore, our research also contributes to a better understanding of the interface between the nervous system and the
immune system.
”
LUBAC assembles a ubiquitin signaling platform at mitochondria for signal amplification and transport of NF-? B to the nucleus