2. Academic Validation
  3. Glutamate utilization fuels rapid production of mitochondrial ROS in dendritic cells and drives systemic inflammation during tularemia

Glutamate utilization fuels rapid production of mitochondrial ROS in dendritic cells and drives systemic inflammation during tularemia

  • Sci Adv. 2025 Aug 29;11(35):eadu6271. doi: 10.1126/sciadv.adu6271.
Ivo Fabrik 1,  Petra Spidlova 2,  Lukas Prchal 1,  Daniela Fabrikova 1,  Ina Viduka 3,  Valentina Marecic 3,  Vlada Filimonenko 4 5,  Radek Sleha 6,  Marie Vajrychova 1,  Rudolf Kupcik 1,  Ondrej Soukup 1,  Tomas Rousar 7,  Anetta Härtlova 8 9,  Marina Santic 3 10,  Jiri Stulik 2
Affiliations

Affiliations

  • 1 Biomedical Research Center, University Hospital Hradec Kralove, 500 05 Hradec Kralove, Czechia.
  • 2 Department of Molecular Pathology and Biology, Military Faculty of Medicine, University of Defence, 500 01 Hradec Kralove, Czechia.
  • 3 Department of Microbiology and Parasitology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia.
  • 4 Electron Microscopy Core Facility, Institute of Molecular Genetics, Czech Academy of Sciences, 142 20 Prague, Czechia.
  • 5 Laboratory of Biology of the Cell Nucleus, Institute of Molecular Genetics, Czech Academy of Sciences, 142 20 Prague, Czechia.
  • 6 Department of Epidemiology, Military Faculty of Medicine, University of Defence, 500 01 Hradec Kralove, Czechia.
  • 7 Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, 532 10 Pardubice, Czechia.
  • 8 Wallenberg Centre for Molecular and Translational Medicine, Department of Microbiology and Immunology at Institute of Biomedicine, University of Gothenburg, 405 30 Gothenburg, Sweden.
  • 9 Institute of Medical Microbiology and Hygiene, Medical Center-University of Freiburg, Faculty of Medicine, 79104 Freiburg, Germany.
  • 10 Department of Environmental Health, Teaching Institute of Public Health of Primorje-Gorski Kotar County, Rijeka, Croatia.
PMID: 40880474 DOI: 10.1126/sciadv.adu6271
Abstract

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 Francisella tularensis exploiting host mitochondrial anaplerosis. Shortly after internalization, Francisella 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.

Figures
Products