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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
PubMed

Insights

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.
Keywords:
Cell DeathInflammationMitochondriaNF-κBUbiquitin

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