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Glutamate utilization fuels rapid production of mitochondrial ROS in dendritic cells and drives systemic inflammation following Francisella infection

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 intracellular pathogen Francisella tularensis exploiting host mitochondria. Shortly after internalization, Francisella associates with DC mitochondria which leads to rapid repurposing of their oxidative metabolism for production of mitochondrial reactive oxygen species (mtROS). Mitochondrial metabolic rewiring is orchestrated by intra-mitochondrial signaling mediated by protein acetylation and involves switching to glutamate as the primary substrate for DC tricarboxylic acid cycle. Rather than killing bacterium, glutamate-fueled mtROS production triggers p38-dependent proinflammatory gene expression and blocking of glutamate utilization prevents DC activation, bacterial dissemination, and alleviates immunopathology of severe infection. Our findings underscore the importance of metabolic plasticity in anti-bacterial DC response and open up new possibilities for therapies targeting host metabolism.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Primary Cell, Dendritic Cell

DISEASE(S): Tularemia

SUBMITTER: Ivo Fabrik

LAB HEAD: Ivo Fabrik

PROVIDER: PXD055084 | Pride | 2025-07-21

REPOSITORIES: Pride

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			Action	DRS
	20190321_IF021_R1_Ft-L_BMDC_AcK_Fr10_01.raw	Raw
	20190321_IF021_R1_Ft-L_BMDC_AcK_Fr1_02.raw	Raw
	20190321_IF021_R1_Ft-L_BMDC_AcK_Fr2_01.raw	Raw
	20190321_IF021_R1_Ft-L_BMDC_AcK_Fr3_01.raw	Raw
	20190321_IF021_R1_Ft-L_BMDC_AcK_Fr4_01.raw	Raw

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