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

ABSTRACT: Although mutations in mitochondrial-associated genes are linked to inflammation and susceptibility to infection, 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 homeostasis 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 protein gasdermin D (GSDMD) to mitochondrial membranes. Mitochondrial GSDMD pore formation then releases mtROS, promoting a switch to RIPK1/RIPK3/MLKL-dependent necroptosis. Consistent with enhanced necroptosis, infection of Lrrk2^G2019S mice with Myc

SUBMITTER: Weindel CG 

PROVIDER: S-EPMC9531054 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature