Mitochondrial ROS promotes susceptibility to infection via gasdermin D-mediated necroptosis

Although mutations in mitochondrial-associated genes are linked to inflammation and susceptibility to infec-tion, their mechanistic contributions to immune outcomes remain ill-defined. We discovered that the disease -associated gain-of-function allele Lrrk2(G2019S) (leucine-rich repeat kinase 2) perturbs mitochondrial homeo-stasis and reprograms cell death pathways in macrophages. When the inflammasome is activated in Lrrk2(G2019S) macrophages, elevated mitochondrial ROS (mtROS) directs association of the pore-forming pro-tein gasdermin D (GSDMD) to mitochondrial membranes. Mitochondrial GSDMD pore formation then re-leases mtROS, promoting a switch to RIPK1/RIPK3/MLKL-dependent necroptosis. Consistent with enhanced necroptosis, infection of Lrrk2(G2019)S mice with Mycobacterium tuberculosis elicits hyperinflamma-tion and severe immunopathology. Our findings suggest a pivotal role for GSDMD as an executer of multiple cell death pathways and demonstrate that mitochondrial dysfunction can direct immune outcomes via cell death modality switching. This work provides insights into how LRRK2 mutations manifest or exacerbate human diseases and identifies GSDMD-dependent necroptosis as a potential target to limit Lrrk2(G2019S)-mediated immunopathology.