Journal article

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

Nature Microbiology | NATURE PUBLISHING GROUP | Published : 2020

Abstract

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 apoptosi..

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Grants

Awarded by National Health and Medical Research Council


Funding Acknowledgements

We thank A. Strasser, D. Huang and S. Masters (Walter and Eliza Hall Institute of Medical Research) and V. Dixit (Genentech) for providing the genetically modified mice; I. D. Hay (University of Auckland) for the ClearColi and uropathogenic E. coli bacterial strains; M. Ryan (Monash University) for the antibodies; D. Creek (Monash Proteomics and Metabolomics Facility) for liquid chromatography-mass spectrometry support; the Monash Micro Imaging Facility for expert advice on live cell imaging microscopy; and the Monash Animal Research Platform for providing mice. This research was supported by grants from the National Health and Medical Research Council (grant nos. 1145788, 1183070 and 1141466 to J.E.V.; 1162765 and 1181089 to K.E.L.; and 1183848 and 1163556 to T.N.). J.L. and J.E.V. are Australian National Health and Medical Research Council Principal Research and Career Development fellows. K.E.L. and T.N. are Australian Research Council (ARC) Future fellows (FT190100266 and FT170100313).