Glutamate utilization fuels rapid production of mitochondrial ROS in dendritic cells and drives systemic inflammation during tularemia
Dendritic cells (DCs) hijacked by intracellular bacteria contribute to pathogen dissemination and immunopathology. How bacteria achieve DC subversion remains largely unknown. Here, we describe the mechanism used by tularemia agent <i>Francisella tularensis</i> exploiting host mitochondrial anaplerosis. Shortly after internalization, <i>Francisella</i> associates with DC mitochondria, which leads to the rapid repurposing of their oxidative metabolism for production of mitochondrial reactive oxygen species (mtROS). Mitochondrial metabolic rewiring is orchestrated by the intramitochondrial signaling mediated by protein acetylation and involves switching to glutamate as the primary substrate for DC tricarboxylic acid cycle. Rather than killing the bacterium, glutamate-fueled mtROS production activates p38-dependent proinflammatory gene expression. Blocking of glutamate utilization prevents DC activation and bacterial dissemination and alleviates inflammation in vivo. Our findings underscore the importance of metabolic plasticity in antibacterial DC response and open up potential avenues for therapies targeting host metabolism.
Authors
- Tomáš Roušar (ORCID: https://orcid.org/0000-0002-6893-821X)
- Ondřej Soukup (ORCID: https://orcid.org/0000-0001-6376-8701)
- Marina Šantić (ORCID: https://orcid.org/0000-0003-4138-3581)
- Daniela Fabriková (ORCID: https://orcid.org/0000-0001-9598-4978)
- Petra Špidlová (ORCID: https://orcid.org/0000-0002-9417-636X)
- Lukáš Prchal (ORCID: https://orcid.org/0000-0001-9698-4478)
- Ina Viduka (ORCID: https://orcid.org/0000-0002-5176-5850)
- Ivo Fabrik (ORCID: https://orcid.org/0000-0002-3027-1253)
- Rudolf Kupčík (ORCID: https://orcid.org/0000-0002-4199-6321)
- Jiří Stulík (ORCID: https://orcid.org/0000-0002-4790-2365)
- Marie Vajrychová (ORCID: https://orcid.org/0000-0002-9495-8046)
- Anetta Härtlová (ORCID: https://orcid.org/0000-0002-8152-4361)
- Valentina Marečić (ORCID: https://orcid.org/0000-0001-6246-8547)
- Radek Sleha (ORCID: https://orcid.org/0000-0001-7359-9147)
- Vlada Filimonenko (ORCID: https://orcid.org/0000-0002-7939-5572)
Institutions
- University of Pardubice (CZ)
- University of Rijeka (HR)
- University of Freiburg (DE)
- Institute of Public Health Bengaluru (IN)
- Wallenberg Wood Science Center (SE)
- Institute of Molecular Genetics (RU)
- University Hospital Hradec Králové (CZ)
- Czech Academy of Sciences, Institute of Molecular Genetics (CZ)
- Institute of Medical Microbiology and Hygiene (DE)
- University of Defence (RS)
- University of Gothenburg (SE)
- University of Defence (CZ)
Publication Details
- Journal
- Science Advances
- Published
- 2025-08-29
- DOI
- https://doi.org/10.1126/sciadv.adu6271
- Citations
- 1
- Primary Topic
- Bacillus and Francisella bacterial research
- Type
- article
- Field-Weighted Citation Impact
- 0.81