Mitochondrial fission mediates an evolutionarily conserved innate defense response against bacterial infection

Animals must be able to engage pleiotropic immune defense mechanisms against microorganisms to survive infection. Here we reveal an unexpected function for mitochondrial fission in innate immunity, showing this process mediates host defense through antimicrobial lipid droplet production. Bacterial infection activates fission, enabling microbial clearance in mammalian macrophages and Caenorhabditis elegans. The mechanism involves the mitochondrial unfolded protein response (UPRmt), characterized by activation of Atf transcription factor family members in mouse (Atf5) and C. elegans (ATFS-1). Fission and the UPRmt initiate bacterial killing through inducible production of lipid droplets, organelles with antimicrobial properties. Salmonella enterica serovar Typhimurium blocks inducible fission but inhibiting the fusion-promoting enzyme histone deacetylase 6 (Hdac6) overcomes this host subversion, enabling bacterial clearance. We propose that mitochondrial fission has similarities to intracellular bacterial replication, forewarning the host of impending infection. Awakening this ancient pathway in bacterial pathogen-compromised cells could be exploited for host-directed anti-infective strategies. Overall design: Mouse BMM activated with LPS for 6h before performing Cut&Run for ATF5, H3K27Ac and Control (DRP1)