Metabolic stress promotes NLRP3 inflammasome activation
  • Jong-Seok Moon Ph.D.
  • SLS Colloquia / Nov 22th 04:00 pm / BLDG 110 ROOM N104
Abstract
 

Mitochondria have been linked to inflammation as critical organelle in immunity. NADPH oxidase 4 (NOX4), a source of cellular superoxide anions, has multiple biological functions that may be of importance in inflammation and in the pathogenesis of human metabolic diseases, including diabetes. However, the mechanisms by which NOX4-dependent metabolic regulation affect the innate immune response remain unclear. Our results suggest Mitochondrial protein NADPH oxidase 4 (NOX4)-dependent metabolic pathway is critical for NLRP3 inflammasome activation. Notably, NOX4-dependent fatty acid oxidation (FAO) promotes NLRP3 inflammasome activation in macrophages.

Beyond its role in inflammation, mitochondria play a central role in the regulation of several forms of cell death, including apoptosis and necrosis. Recently, necroptosis, programed necrosis, is the best-characterized form of regulated necrosis by receptor interacting protein kinase-1 and -3 (RIPK1 and RIPK3). The RIPK1-RIPK3 complex recruits the mixed lineage kinase domain-like protein (MLKL), a key regulator of necroptosis. The phosphorylation of MLKL by necrosome formation is regarded as the critical step in the initiation of necroptosis. Our results suggest impaired mitochondrial oxidative phosphorylation (OXPHOS) provides a critical metabolic mechanism for the activation of necroptosis in human epithelial cells. These results suggest that mitochondria are critical regulator of inflammation and cell death.