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Mitochondrial outer membrane integrity regulates a ubiquitin-dependent and NF-κB-mediated inflammatory response
Esmee Vringer1,2, Rosalie Heilig1,2, Joel S Riley1,2,3
1Cancer Research UK Scotland Institute, Switchback Road, Glasgow, G61 1BD, UK.
The EMBO Journal
|February 10, 2024
Summary
Mitochondrial outer membrane permeabilisation (MOMP) triggers inflammation by ubiquitylating proteins, recruiting NEMO, and activating NF-κB signaling. This study reveals how mitochondrial integrity controls inflammatory responses.
Area of Science:
- Cell Biology
- Immunology
- Molecular Biology
Background:
- Mitochondrial outer membrane permeabilisation (MOMP) is crucial for apoptosis and emerging roles in anti-tumour immunity.
- The precise mechanisms by which MOMP initiates inflammation and its regulation are not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanisms linking MOMP to pro-inflammatory signaling.
- To identify how cells regulate the inflammatory response initiated by mitochondrial damage.
Main Methods:
- Investigated protein ubiquitylation on mitochondrial membranes following MOMP.
- Assessed the recruitment of NEMO and activation of NF-κB signaling pathways.
- Examined the consequences of disrupting mitochondrial outer membrane integrity.
Main Results:
- MOMP leads to promiscuous ubiquitylation of mitochondrial proteins.
- Ubiquitylated proteins recruit the adaptor molecule NEMO, activating NF-κB signaling.
- Disruption of mitochondrial integrity consistently engages this pro-inflammatory pathway.
Conclusions:
- Mitochondrial integrity directly governs inflammatory responses.
- Permeabilised mitochondria act as a trigger for NF-κB-mediated inflammation.
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