Host cell sensing and restoration of mitochondrial function and metabolism within Helicobacter pylori VacA intoxicated cells

Ami Y Seeger, Faisal Zaidi, Sammy Alhayek, Rachel M Jones, Huzaifa Zohair, Robin L Holland, Ik-Jung Kim, Steven R Blanke

Research output: Contribution to journalArticlepeer-review


Helicobacter pylori vacuolating cytotoxin A (VacA) is an intracellular-acting protein exotoxin that induces mitochondrial dysfunction and energy depletion within host cells. Although exposure to VacA results in mitochondrial dysfunction, one recent study revealed that, following limited exposure to VacA, mitochondrial function and cellular ATP levels were restored in a time-dependent manner. Studies performed to address the mechanism by which host cells detect and respond to intracellular VacA identified the adenosine monophosphate (AMP)-activated protein kinase (AMPK) as a sensor of toxin-dependent alterations in cellular energy status. Activation of AMPK in response to VacA was demonstrated to orchestrate alterations in mitochondrial dynamics which resulted in restoration of mitochondrial function. Specifically, upregulation of dynamin-related protein 1 (Drp-1)-dependent mitochondrial fission resulted in reversible fragmentation of filamentous mitochondria and time-dependent reduction in mitochondrial-associated VacA, suggesting that fragmentation is important for removal of VacA from mitochondria. Cells with reduced levels of Drp-1 were more susceptible to VacA-dependent cell death, suggesting that mitochondrial dynamics is important for maintaining cell viability through the reduction in mitochondrial-associated toxin. Collectively, these studies support a model that cellular recovery and survival in response to VacA-dependent mitochondrial dysfunction is linked to host cell modulation of mitochondrial dynamics. This study provides new insights into cellular recognition and responses to intracellular-acting toxin modulation of host cell function, which could be relevant for the growing list of pathogenic microbes and viruses identified that target mitochondria as part of their virulence strategies.
Original languageEnglish (US)
Article number02117-23
Issue number5
StateE-pub ahead of print - Oct 2023


  • VacA
  • vacuolating cytotoxin
  • Helicobacter pylori
  • dynamin-related protein 1
  • AMPK
  • mitochondrial dysfunction
  • mitochondrial depolarization
  • transmembrane potential
  • proton motive force
  • mitochondrial dynamics

ASJC Scopus subject areas

  • Virology
  • Microbiology


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