Role of mitochondrial K+ homeostasis in the control of the inflammatory process

The immune system defends the organism in different ways: one of these is innate immunity. In macrophages, the assembly of the NLRP3 inflammasome is a crucial step in the inflammation process: it mediates the release of different cytokines like Il-1β, promoting pyroptosis. The inflammasome activation is a two-step mechanism that involves many different signals. According to recent data, the homeostasis of cations fluxes, particularly K+ and Ca2+, may have a role in its activation. Mitochondrial Ca2+ signalling regulates different pathways inside the cells, in particular autophagy, metabolism, and cell death. Ca2+ enters the mitochondrial matrix thanks to the presence of the mitochondrial calcium uniporter complex (MCU). Moreover, the MitoKATP channel regulates K+ flux across the inner mitochondrial membrane and controls the matrix water intake. Taking for granted the influence of these ions in the inflammatory process, the aim of this work is to demonstrate the role of mitochondrial Ca2+ and K+ homeostasis in the control of NLRP3 inflammasome induction. We characterized macrophages of MitoK-/- mouse model to unveil the influence of MitoKATP in the control of inflammasome induction. In addition, we took advantage of a chemical inhibitor of mitochondrial Ca2+ uptake to verify whether mitochondrial K+ and Ca2+ fluxes could act synergistically in the control of inflammasome formation. Our experiments demonstrate that alterations in mitochondrial K+ and Ca2+ homeostasis modulate inflammasome response.