The role of mitochondrial cations homeostasis in the control of inflammatory response

The immune system is activated upon pathogens infections, in particular the innate immune system represents the first line of defense. In detail, the assembly of NLRP3 inflammasome releases IL-1β/IL-18 and promotes pyroptosis. Recent studies suggest the role of ion fluxes, in particular K+ and Ca2+, in NLRP3 inflammasome activation. It is known that mitochondria are necessary for the induction and maintenance of innate and adaptative immune cell responses, acting as signaling platforms and mediators in effector responses. In particular, they play a fundamental role by participating in ion (Ca2+ and K+) homeostasis. In detail, calcium enters mitochondria matrix through mitochondria calcium uniporter complex (MCU complex) where it regulates metabolism, autophagy and cell death. In addition, K+ fluxes across the inner mitochondrial membrane determine the organelle water content, thus regulating matrix volume. In this scenario, MitoK-ATP channel plays an essential role. Thus, understanding the role of mitochondrial cation homeostasis in the regulation of NLRP3 inflammasome activation paves the way to the discovery of new molecular targets, whose manipulation can attenuate or prevent inflammation. Here, we characterize MCU+/- and MitoK mouse models to validate the role of cation fluxes in the control of inflammation response. In particular, we demonstrated that the alteration in mitochondrial K+ and Ca2+ homeostasis attenuates the inflammatory response.