Mitochondria as an important mediator in host-microbe interactions Holland, R.L.1, Phillips, H.1, Blanke, S.R.1,2 1College of Veterinary Medicine, 2School of Molecular and Cellular Biology, University of Illinois, Urbana Illinois, USA
As cellular powerhouses, mitochondria are critical for homeostasis. Interestingly, the diversity of mitochondrial functions has been continuing to expand in recent decades, with evidence that mitochondria play a major role in immunity and host-microbe interactions. Although numerous microbes are reported to target mitochondria, little is known on the importance, mechanism, and full extent of host responses to microbe mediated mitochondrial stress. The human gastric pathogen Helicobacter pylori disrupts host cell function through the actions of the secreted mitochondrial targeted toxin VacA. We hypothesized that host cells would respond to VacA mediated mitochondrial damage by activating a quality control response. By measuring mitochondrial structure and function with metabolism assays and fluorescence microscopy, our studies revealed that subsequent to VacA localization to mitochondria and induction of mitochondrial depolarization, fragmentation, and ATP depletion, a quality control response was activated, with restoration of mitochondrial function. Furthermore, the recovery of mitochondrial function was sufficient to prevent the induction of mitochondrial based cell death. Surprisingly, the results of an extensive analysis of mitochondrial mass and mitophagic machinery activation in response to VacA did not support a model of mitophagy induction, but rather activation of mitochondrial derived vesicles (MDVs). VacA exposure concurrently increased the formation of, and associated with, MDVs that further trafficked VacA from mitochondria to intracellular vacuoles. In order to evaluate the importance of VacA-mitochondria interactions in vivo, we developed a novel mouse intragastric toxin infusion model, which revealed VacA to induce parietal cell vacuolation, collapse of gastric pit structure, and inhibition of mucous cell secretion, processes that are dependent upon functional mitochondria. We propose that a disruption of mitochondrial dynamics by VacA, coupled with activation of quality control, creates a suitable microenvironment whereby host cells are viable, but unable to respond to clear H pylori infection. We posit that this toxin-mitochondria interaction facilitates persistent, chronic infections of H. pylori within the human stomach.
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