Mitochondria: diversity in the regulation of the NLRP3 inflammasome

Abstract

Recent studies have identified new roles for mitochondria in the regulation of autoinflammatory processes. Emerging data suggests that the release of danger signals from mitochondria in response to stress and infection promotes the formation of the inflammatory signaling platform known as inflammasomes. Activation of inflammasomes by damaged mitochondria results in caspase-1-dependent secretion of the inflammatory cytokines IL-1β and IL-18, and an inflammatory form of cell death referred to as pyroptosis. Here, we review recently described mechanisms that have been proposed to be involved in mitochondria-mediated regulation of inflammasome activation and inflammation. In addition, we highlight how aberrant regulation of mitochondria-induced inflammasome activation centrally contributes to the inflammatory process that are responsible for obesity and associated metabolic diseases.

Potassium Bisperoxo(1,10-phenanthroline)oxovanadate (bpV(phen)) Induces Apoptosis and Pyroptosis and Disrupts the P62-HDAC6 Protein Interaction to Suppress the Acetylated Microtubule-dependent Degradation of Autophagosomes

“…Both oxidative stress and lysosomal rupture, in turn, activate the NLRP3 inflammasome, which results in direct activation of caspase 1 (36). Activation of caspase 1 subsequently induces the secretion of potent pro-inflammatory cytokines and, eventually, an inflammatory form of cell death referred to as pyroptosis of the cell and other cells in the environment (21,(37)(38)(39)(40)(41). Although bpV-(phen) has been suggested as a drug for different types of diseases, it is necessary to consider the potential side effects caused by its impact on autophagy, apoptosis, and pyroptosis.…”

Molecular mechanisms regulating NLRP3 inflammasome activation

“…These include pore formation and potassium (K 1 ) efflux, 7,8 lysosomal destabilization and rupture, 9,10 and mitochondrial reactive oxygen species (ROS) generation. [10][11][12] Evidence supports that the aberrant activation of the NLRP3 inflammasome is associated with the pathogenesis of various autoinflammatory, autoimmune, and chronic inflammatory and metabolic diseases, including gout, atherosclerosis, and type 2 diabetes. [13][14][15] Thus, activation of the NLRP3 inflammasome should be tightly regulated to prevent unwanted host damage and excessive inflammation.…”

AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity

“…Potassium efflux, mitochondria dysfunction, and lysosomal disruption have been reported to mediate the activation of NLRP3, leading to the hypothesis that this inflammasome is a guardian of cellular integrity (11,12). In addition to detecting mitochondrial perturbations, NLRP3 was found to be activated by endoplasmic reticulum (ER) stress in different tissues including macrophages (13,14), liver (15), and insulin-producing β cells (16,17).…”