Cardiolipin coordinates inflammatory metabolic reprogramming through regulation of Complex II disassembly and degradation

Macrophage metabolic plasticity enables repurposing of electron transport from energy generation to inflammation and host defense. Altered respiratory complex II function has been implicated in cancer, diabetes, and inflammation, but regulatory mechanisms are incompletely understood. Here, we show t...

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Bibliographic Details
Published in:Science advances 2023-02, Vol.9 (5), p.eade8701-eade8701
Main Authors: Reynolds, Mack B, Hong, Hanna S, Michmerhuizen, Britton C, Lawrence, Anna-Lisa E, Zhang, Li, Knight, Jason S, Lyssiotis, Costas A, Abuaita, Basel H, O'Riordan, Mary X
Format: Article
Language:English
Subjects:
Biomedicine and Life Sciences
Cardiolipins - metabolism
Cell Biology
Humans
Inflammation - metabolism
Lipopolysaccharides - pharmacology
Mitochondria - metabolism
SciAdv r-articles
Succinate Dehydrogenase - metabolism
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Summary:Macrophage metabolic plasticity enables repurposing of electron transport from energy generation to inflammation and host defense. Altered respiratory complex II function has been implicated in cancer, diabetes, and inflammation, but regulatory mechanisms are incompletely understood. Here, we show that macrophage inflammatory activation triggers Complex II disassembly and succinate dehydrogenase subunit B loss through sequestration and selective mitophagy. Mitochondrial fission supported lipopolysaccharide-stimulated succinate dehydrogenase subunit B degradation but not sequestration. We hypothesized that this Complex II regulatory mechanism might be coordinated by the mitochondrial phospholipid cardiolipin. Cardiolipin synthase knockdown prevented lipopolysaccharide-induced metabolic remodeling and Complex II disassembly, sequestration, and degradation. Cardiolipin-depleted macrophages were defective in lipopolysaccharide-induced pro-inflammatory cytokine production, a phenotype partially rescued by Complex II inhibition. Thus, cardiolipin acts as a critical organizer of inflammatory metabolic remodeling.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.ade8701