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 Mycobacterium tuberculosis elicits hyperinflammation 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.

尽管线粒体相关基因的突变与炎症和感染易感性有关，但它们对免疫结果的机制贡献仍然不明确。我们发现与疾病相关的功能获得等位基因Lrrk2 ^G2019S（富含亮氨酸重复激酶 2）会扰乱线粒体稳态并重新编程巨噬细胞中的细胞死亡途径。当Lrrk2 ^G2019S巨噬细胞中的炎症小体被激活时，升高的线粒体 ROS (mtROS) 会引导成孔蛋白gasdermin D (GSDMD) 与线粒体膜结合。线粒体 GSDMD 孔形成随后释放 mtROS，促进向 RIPK1/RIPK3/MLKL 依赖性坏死性凋亡的转变。与坏死性凋亡增强一致，Lrrk2 ^G2019S小鼠感染结核分枝杆菌会引起过度炎症和严重的免疫病理学。我们的研究结果表明 GSDMD 作为多种细胞死亡途径的执行者发挥着关键作用，并证明线粒体功能障碍可以通过细胞死亡方式转换来指导免疫结果。这项工作提供了关于 LRRK2 突变如何表现或加剧人类疾病的见解，并将 GSDMD 依赖性坏死性凋亡确定为限制Lrrk2 ^G2019S介导的免疫病理学的潜在靶点。