Oral Presentation 16th Lorne Infection and Immunity 2026

Mitochondrial fission mediates an evolutionarily conserved antibacterial defence response via the UPRmt and inducible lipid droplets (131148)

James EB Curson 1 , Ronan Kapetanovic 2 , Syeda Farhana Afroz 1 , Ina Kirmes 1 , Divya Ramnath 1 , Stephan Nothjunge 3 , Jinting Liu 1 , Karoline D Raven 1 , Marta Bosch 4 , Jordan D Atkinson 1 , Arnaud Ahier 1 , Bernhard Keller 1 , Grace MEP Lawrence 1 , Kaustav Das Gupta 1 , Melanie R Shakespear 1 , Charles Fergurson 1 , Claudia J Stocks 1 , Nilesh J Bokil 1 , Michael Koczerka 2 , Gabriele Matthias 3 , Tam TK Nguyen 1 , Zeinab G Khalil 1 , Robert C Reid 1 , Karl A Hansford 1 , Philip M Hansbro 5 , Matthew A Cooper 1 , Mark A Schembri 1 , Antje Blumenthal 1 , Kate Schroder 1 , David P Fairlie 1 , Albert Pol 4 , Patrick Matthias 3 , Robert G Parton 1 , Steven Zuryn 1 , Matthew J Sweet 1
  1. University of Queensland, Brisbane, QLD, Australia
  2. INRAE, Université de Tours, Infectiologie et Santé Publique , Tours
  3. Friedrich Miescher Institute for Biomedical Research, Basel
  4. Universitat de Barcelona, Barcelona
  5. School of Biomedical Sciences, The University of Newcastle, Callaghan

Animals engage pleiotropic immune defence mechanisms to survive infections. We discovered an unexpected function for mitochondrial fission in host defence. Challenge of macrophages with E. coli increases mitochondrial fission, with this response promoting bacterial killing in mammalian macrophages (human and mouse) and Caenorhabditis elegans. Upon sensing bacterial infection, macrophages undergo extensive metabolic rewiring and utilise the fission-promoting GTPase dynamin-related protein 1 (DRP1) to fragment their mitochondrial network. Manipulating macrophages to favour mitochondrial fission enhances bacterial killing whilst skewing towards fusion supports bacterial survival. Upon infection with E. coli, mitochondrial fission engages dual antibacterial responses via the mitochondrial unfolded protein response (UPRmt) and inducible lipid droplet (LD) production. Fission-triggered UPRmt, characterized by ATF transcription factor activation in mouse (ATF5) and C. elegans (ATFS-1), curtails inducible LDs for cross-regulation of these pathways. The intramacrophage pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) suppresses fission via SPI1-encoded virulence factors, leading to a concomitant reduction in inducible LD production. Restoring the fission response in S. Typhimurium-infected macrophages by genetic or pharmacological targeting of the mitochondrial fusion-promoting histone deacetylase 6 (HDAC6) reactivates LD production for bacterial clearance. In a mouse S. Typhimurium infection model, HDAC6 inhibition dramatically reduces bacterial dissemination to the liver and spleen, whilst simultaneously suppressing pathological inflammatory responses. Furthermore, we show that enhancing fission via HDAC6 inhibition is effective at restricting the growth of other human pathogens such as Mycobacterium tuberculosis and uropathogenic E. coli in macrophages from multiple mammalian species. We propose that mitochondrial fission serves to redirect LD function from energy supply to bacterial killing as part of an ancient and conserved host defence pathway, and that the fission-LD axis can be exploited for anti-infective design.