Mitochondrial dysfunction caused by outer membrane vesicles from Gram-negative bacteria activates intrinsic apoptosis and inflammation

Pankaj Deo, Seong H. Chow, Mei-Ling Han, Mary Speir, Cheng Huang, Ralf B. Schittenhelm, Subhash Dhital, Jack Emery, Jian Li, Benjamin T. Kile, James E. Vince, Kate E. Lawlor, Thomas Naderer

Research output: Contribution to journalArticleResearchpeer-review

98 Citations (Scopus)


Sensing of microbes activates the innate immune system, depending on functional mitochondria. However, pathogenic bacteria inhibit mitochondrial activity by delivering toxins via outer membrane vesicles (OMVs). How macrophages respond to pathogenic microbes that target mitochondria remains unclear. Here, we show that macrophages exposed to OMVs from Neisseria gonorrhoeae, uropathogenic Escherichia coli and Pseudomonas aeruginosa induce mitochondrial apoptosis and NLRP3 inflammasome activation. OMVs and toxins that cause mitochondrial dysfunction trigger inhibition of host protein synthesis, which depletes the unstable BCL-2 family member MCL-1 and induces BAK-dependent mitochondrial apoptosis. In parallel with caspase-11-mediated pyroptosis, mitochondrial apoptosis and potassium ion efflux activate the NLRP3 inflammasome after OMV exposure in vitro. Importantly, in the in vivo setting, the activation and release of interleukin-1β in response to N. gonorrhoeae OMVs is regulated by mitochondrial apoptosis. Our data highlight how innate immune cells sense infections by monitoring mitochondrial health.

Original languageEnglish
Pages (from-to)1418–1427
Number of pages10
JournalNature Microbiology
Issue number11
Publication statusPublished - Nov 2020


  • bacterial host response
  • bacterial pathogenesis
  • innate immunity

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