Pro-inflammatory macrophages produce mitochondria-derived superoxide by reverse electron transport at complex I that regulates IL-1β release during NLRP3 inflammasome activation.

ABSTRACT: Macrophages stimulated by lipopolysaccharide (LPS) generate mitochondria-derived reactive oxygen species (mtROS) that act as antimicrobial agents and redox signals; however, the mechanism of LPS-induced mitochondrial superoxide generation is unknown. Here we show that LPS-stimulated bone-marrow-derived macrophages produce superoxide by reverse electron transport (RET) at complex I of the electron transport chain. Using chemical biology and genetic approaches, we demonstrate that superoxide production is driven by LPS-induced metabolic reprogramming, which increases the proton motive force (∆p), primarily as elevated mitochondrial membrane potential (Δψ_m) and maintains a reduced CoQ pool. The key metabolic changes are repurposing of ATP production from oxidative phosphorylation t

SUBMITTER: Casey AM 

PROVIDER: S-EPMC11946910 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature