Mitochondrial fission mediates an evolutionarily conserved antibacterial defense response

Abstract

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.