Organelle stress in NLRP3 inflammasome: a central mediator of neurodegenerative diseases

Abstract Organelle stress and NLRP3 inflammasome activation have been established as pivotal contributors to inflammatory responses and play a significant role in the pathogenesis of neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD) and Parkinson’s disease (PD). However, the involvement of multiple organelles and their interorganellar signaling in NLRP3 inflammasome activation has not yet been systematically elucidated. The causal mechanisms by which these organelles promote NLRP3 activation and subsequently drive the progression of NDDs remain unclear. Furthermore, therapeutic interventions targeting this pathway require urgent and comprehensive investigation. This article comprehensively reviews the mechanisms by which organelle-derived stress signals, such as mitochondrial reactive oxygen species (mtROS), cathepsin B (CTSB), and calcium ions (Ca2+), induce NLRP3 inflammasome activation. It further examines the pivotal role of organelle-specific NLRP3 localization and post-translational modifications in the activation of the NLRP3 inflammasome. Finally, we outline NLRP3-mediated inflammatory processes in NDDs, focusing on events directly induced by organelle stress and interactions. These processes are not merely consequences of NDD progression but also critical factors accelerating disease deterioration. Potential therapeutic strategies targeting the organelle-NLRP3 axis are proposed, which may provide novel theoretical foundations and promising avenues for the prevention and treatment of NDDs. Graphical Abstract