Mitochondrial fission mediates an evolutionarily conserved antibacterial defense response

Animals engage pleiotropic immune defense mechanisms to survive infections. Here, we present a function for mitochondrial fission in host defense. Challenge of macrophages with Escherichia coli increased mitochondrial fission, with this response promoting bacterial clearance in mammalian macrophages and Caenorhabditis elegans . E. coli –induced mitochondrial fission engaged dual antibacterial responses via the mitochondrial unfolded protein response (UPR mt ) and inducible lipid droplet production. Mitochondrial fission–triggered UPR mt , characterized by activation of activating transcription factor 5 (ATF5) in mouse macrophages and the paralog ATFS-1 in C. elegans , curtailed inducible lipid droplets to cross-regulate these pathways. The intramacrophage pathogen Salmonella enterica suppressed antibacterial mitochondrial fission, but restoring this response by inhibiting mitochondrial fusion–promoting histone deacetylase 6 (HDAC6) reactivated lipid droplet production and bacterial clearance. Therefore, we propose that mitochondrial fission is an ancient host defense pathway that can be exploited for anti-infective design.