Discovery of a novel innate immune cell death pathway, mitoxyperilysis 2253951

Abstract Introduction Innate immune activation and metabolic dysregulation are common features of disease. Specifically, mitochondrial dysfunction and oxidative stress contribute to pathogenesis during infection, inflammation, and cancer. However, the molecular pathways that connect these processes to disease remain poorly understood. Methods Using complementary techniques under in vitro and in vivo experimental settings, we sought to investigate how the synergism of innate immune activation and metabolic dysregulation affects the cell fate mechanistically. Results We discovered a distinct form of lytic cell death induced by the synergism of innate immune activation and metabolic disruption, which was independent of caspase activity and known regulated cell death pathways. Instead, mitochondria that were damaged by oxidative stress persisted in contact with the plasma membrane, leading to localized membrane oxidation and rupture–a process we term mitoxyperilysis. Mechanistically, mTOR activity was required for cell death following mitochondrial damage, and mTOR inhibition restored cytoskeletal dynamics, enabling lamellipodia retraction and mitochondrial repositioning away from the plasma membrane to preserve membrane integrity. Upstream, we identified BAX/BAK and SLC7A11 as key mediators of this pathway. In tumor models, simultaneous activation of innate immune signaling and metabolic perturbation induced tumor cell death exhibiting hallmarks of mitoxyperilysis. Conclusion Collectively, our findings define a new cell death modality driven by mitochondrial oxidative damage and subcellular localization in response to immune—metabolic stress. Given the central role of mitochondrial stress, inflammation, and cell death in disease, characterization of this pathway offers new therapeutic strategies for cancer and inflammatory disorders. Funding Source n/a Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)