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Pro-inflammatory macrophages produce mitochondria-derived superoxide by reverse electron transport at complex I that

Alva M Casey1, Dylan G Ryan1, Hiran A Prag2

  • 1MRC Mitochondrial Biology Unit, Biomedical Campus, University of Cambridge, Cambridge, UK.

Nature Metabolism
|February 19, 2025
PubMed

Insights

Lipopolysaccharide (LPS) triggers macrophages to produce superoxide via reverse electron transport (RET) at mitochondrial complex I. This mechanism, driven by metabolic shifts, regulates inflammatory cytokine release.

Area of Science:

  • Immunology
  • Mitochondrial Biology
  • Cellular Metabolism

Background:

  • Macrophages utilize mitochondria-derived reactive oxygen species (mtROS) for antimicrobial functions and redox signaling.
  • The precise mechanism of superoxide generation in LPS-stimulated macrophages remains unclear.

Purpose of the Study:

  • To elucidate the mechanism of LPS-induced mitochondrial superoxide generation in macrophages.
  • To investigate the role of metabolic reprogramming in this process.
  • To determine the functional consequences of mtROS production via RET.

Main Methods:

  • Utilized chemical biology and genetic approaches in LPS-stimulated bone-marrow-derived macrophages.
  • Analyzed mitochondrial membrane potential (Δψm) and proton motive force (Δp).
  • Assessed the CoQ pool redox state and ATP production pathways.

Main Results:

  • Demonstrated that LPS stimulation induces superoxide production through reverse electron transport (RET) at complex I.
  • Showed that metabolic reprogramming, favoring glycolysis over oxidative phosphorylation, increases Δp and maintains a reduced CoQ pool, driving superoxide generation.
  • Confirmed that mtROS produced by RET regulates IL-1β release during NLRP3 inflammasome activation.

Conclusions:

  • LPS-induced mtROS production in macrophages occurs via RET at mitochondrial complex I.
  • Metabolic reprogramming is critical for driving this superoxide generation.
  • Mitochondrial ROS generated by RET act as key signaling molecules regulating macrophage inflammatory responses, specifically IL-1β release.

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