Mitochondria-Associated Inflammasome Activation and Its Impact on Aging and Age-Related Diseases

Abstract

Oxidative phosphorylation is a mitochondrial reaction chain that generates energy in the form of ATP (adenosine triphosphate) for cellular functions. As a by-product, it produces reactive oxygen species (ROS) that are essential, e.g., for cellular signaling and immune responses but in excessive amounts detrimental for cells. Aging is accompanied by reduced oxidative phosphorylation, decreased ATP production, increased ROS production, and diminished mitophagy that removes dysfunctional organelles by autophagy. Aged mitochondria are also prone to damages in their DNA (mtDNA). These changes create danger signals that are efficiently sensed by NLRP3, an intracellular pattern recognition receptor forming an intracellular protein complex for caspase-1-mediated activation of pro-inflammatory cytokines IL-1β and IL-18. Mitochondrial ROS and NLRP3 participate in the release of mtDNA into cytosol where its oxidized form further promotes inflammasome activation. The physical interaction of NLRP3 with mitochondria at the interface between the endoplasmic reticulum (ER) and mitochondria called mitochondria-associated ER membranes (MAMs) as well as with other mitochondria-related proteins connects NLRP3 closely to the functionality of mitochondria and provides a direct link from mitochondrial dysfunction to chronic age-related inflammation.