Mitochondrial dysfunction promotes alternative gasdermin D-mediated inflammatory cell death and susceptibility to infection

Abstract

SUMMARYHuman mutations in mitochondrial-associated genes are associated with inflammatory diseases and susceptibility to infection. However, their mechanistic contributions to immune outcomes remain ill-defined. We discovered that the disease-associated gain-of-function allele Lrrk2G2019S (leucine-rich repeat kinase 2) promotes mitochondrial hyper-fission, depolarization, and oxidative stress in macrophages. In the presence of Lrrk2G2019S-dependent mitochondrial perturbations, AIM2 inflammasome activation promotes more cell death but not more pyroptotic IL-1b release. Instead, inflammasome activation in Lrrk2G2019S macrophages triggers gasdermin D (GSDMD)-mediated mitochondrial pores, driving up ROS-mediated RIPK1/RIPK3/MLKL dependent necroptosis. Consequently, infection of Lrrk2G2019S mice with Mycobacterium tuberculosis elicits hyperinflammation and immunopathology via enhanced neutrophil infiltration. By uncovering that GSDMD promotes non-pyroptotic cell death in Lrrk2G2019S macrophages, our findings demonstrate that altered mitochondrial function can reprogram cell death modalities to elicit distinct immune outcomes. This provides mechanistic insights into why mutations in LRRK2 are associated with susceptibility to chronic inflammatory and infectious diseases.HIGHLIGHTSAltered mitochondrial homeostasis reprograms cell death modalitiesGSDMD associates with and depolarizes mitochondrial membranes following AIM2 activationGSDMD initiates a shift from pyroptotic to necroptotic cell death in Lrrk2G2019S macrophagesLrrk2G2019S elicits hyperinflammation and susceptibility to infection in flies and mice

Host‐pathogen dialogues in different cell death modes during Mycobacterium tuberculosis infection

“…In Lrrk2G2019S macrophages, mtROS promotes pyroptosis shift toward RIPK1/RIPK3/MLKL-dependent necroptosis, thereby causing severe inflammatory and pathological consequences. 120 This study suggests that the switch between pyroptosis and necrosis may be associated with mitochondrial homeostasis.…”

“…57 Moreover, the gainof-function allele Lrrk2G2019S (leucine-rich repeat kinase 2) promotes mitochondrial ROS release, which can bind to GSDMD and cause perforation of the mitochondrial membrane, contributing to necroptosis. 120 The gainof-function allele Lrrk2G2019S alters cell death pathways by disrupting mitochondrial homeostasis in macrophages. These findings suggest that mitochondria could be a potential target for shifting different host cell death modes and regulating cell death outcomes.…”

Baicalin Ameliorates Defective Decidualization in URSA by Regulating Mitochondrial Fission Induced Necroptosis

“…This indicated that mitochondrial fission was significantly active in URSA. Moreover, given that mitochondrial fission is increased in URSA, and that mitochondrial fission is closely related to necroptosis (21)(22)(23), we further explored the effect of mitochondrial fission on necroptosis and decidualization in vitro. First, TA9 was applied to successfully induce mitochondrial fission, characterized by the increased expression of (western blot: Drp1 P<0.05; Fis1 P<0.01. immunofluorescence: Drp1 and Fis1 P<0.05) (Figure 4A-D).…”

The emerging role of LRRK2 in tauopathies

“…The inhibition of the NLRP3 inflammasome prevents tau aggregation and disease progression in a mouse model of tauopathies [ 56 ]. LRRK2 has been implicated in inflammasome activation; however, no direct role in NLRP3 inflammasome activation and IL-1β/IL-18 production has been reported so far [ 57 , 58 ]. It is of interest to note, however, that the commonly used NLRP3 inflammasome activator Nigericin activates LRRK2 [ 59 ].…”