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Production, Crystallization, and Structure Determination of the IKK-binding Domain of NEMO
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Production, Crystallization, and Structure Determination of the IKK-binding Domain of NEMO

Published on: December 28, 2019

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Damaged mitochondria recruit the effector NEMO to activate NF-κB signaling

Olivia Harding1, Elisabeth Holzer2, Julia F Riley1

  • 1Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA.

Molecular Cell
|September 8, 2023
PubMed

Insights

Damaged mitochondria trigger innate immune responses. Nuclear factor kappa B (NF-κB) effector molecule (NEMO) is recruited to damaged mitochondria, initiating inflammatory signaling pathways parallel to mitophagy.

Area of Science:

  • Cell Biology
  • Immunology
  • Neuroscience

Background:

  • Mitophagy, the clearance of damaged mitochondria, is crucial for cellular health.
  • Dysfunctional mitophagy can lead to inflammation, but the underlying mechanisms are not fully understood.
  • The intersection between mitochondrial damage signaling and innate immunity requires further elucidation.

Purpose of the Study:

  • To investigate the molecular mechanisms linking damaged mitochondria to inflammatory signaling.
  • To determine the role of Nuclear Factor kappa B (NF-κB) essential regulator NF-κB effector molecule (NEMO) in response to mitochondrial damage.
  • To explore the potential neuroinflammatory implications of this pathway.

Main Methods:

  • Utilized cell-based assays to track the recruitment of NEMO to damaged mitochondria.
  • Employed mitophagy adaptors like optineurin (OPTN) and p62/SQSTM1 for comparative analysis.
  • Investigated the activation of the inhibitor of kappa B kinase (IKK) complex and subsequent NF-κB signaling.
  • Examined mitochondrial recruitment of NEMO in primary astrocytes under oxidative stress.

Main Results:

  • NEMO is recruited to damaged mitochondria in a Parkin-dependent manner, paralleling optineurin (OPTN) recruitment.
  • NEMO forms distinct phase-separated condensates on damaged mitochondria, colocalizing with p62/SQSTM1.
  • NEMO recruitment leads to the activation of phospho-IKKβ, initiating NF-κB signaling and cytokine upregulation.
  • NEMO is recruited to mitochondria in astrocytes during oxidative stress, suggesting a neuroinflammatory role.

Conclusions:

  • Damaged mitochondria act as platforms for initiating innate immune signaling via NEMO recruitment.
  • Activated IKK complexes form on damaged mitochondria, sufficient to trigger NF-κB signaling.
  • Mitophagy and NF-κB signaling are proposed as parallel pathways activated by mitochondrial stress.
  • This pathway may contribute to neuroinflammation in response to mitochondrial dysfunction.
Keywords:
ALSNEMONF-κBNF-κB effector moleculeParkinParkinson’s diseaseSQSTM1/p62amyotrophic lateral sclerosiscell stressinnate immunitymitophagyneurodegenerationneuroinflammationoptineurin nuclear factor kappa Bphase separationubiquitin

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