Abstract
Targeting mitochondria is a powerful strategy for pathogens to subvert cell physiology and establish infection. Helicobacter pylori is a bacterial pathogen associated with gastric cancer development that is known to target mitochondria directly and exclusively through its pro-apoptotic and vacuolating cytotoxin VacA. By in vitro infection of gastric epithelial cells with wild-type and VacA-deficient H. pylori strains, treatment of cells with purified VacA proteins and infection of a mouse model, we show that H. pylori deregulates mitochondria by two novel mechanisms, both rather associated with host cell survival. First, early upon infection VacA induces transient increase of mitochondrial translocases and a dramatic accumulation of the mitochondrial DNA replication and maintenance factors POLG and TFAM. These events occur when VacA is not detected intracellularly, therefore do not require the direct interaction of the cytotoxin with the organelle, and are independent of the toxin vacuolating activity. In vivo, these alterations coincide with the evolution of gastric lesions towards severity. Second, H. pylori also induces VacA-independent alteration of mitochondrial replication and import components, suggesting the involvement of additional H. pylori activities in mitochondria-mediated effects. These data unveil two novel mitochondrial effectors in H. pylori-host interaction with links on gastric pathogenesis.
Highlights
Mitochondria are essential organelles responsible for energy production and involved in apoptosis, calcium homeostasis, lipids and amino acids metabolism
We show that H. pylori promotes an early and transitory alteration of mitochondrial import translocases, TOM22 and TIM23, and a dramatic up-regulation of POLG and TFAM
Immunofluorescence of TOM22, a component of the mitochondrial translocase outer membrane (TOM) complex[25], which is indicative of the organelle content[26], increased at 6 months pi, but decreased at 12 months pi, raising the question whether mitochondrial translocases were affected upon infection
Summary
Mitochondria are essential organelles responsible for energy production and involved in apoptosis, calcium homeostasis, lipids and amino acids metabolism. Their relevance to disease remain to a great extent unresolved Virulence factors of both intracellular and extracellular bacteria are secreted in the host cells and may interact with mitochondria, leading to modulation of mitochondrial function and promoting pathogenesis[3,4,5]. We show that H. pylori promotes an early and transitory alteration of mitochondrial import translocases, TOM22 and TIM23, and a dramatic up-regulation of POLG and TFAM. These effects are not exclusively VacA-dependent, and are compatible with host cell survival. Compatible mitochondrial alterations, including the deregulation of mtDNA replication and transcription factors and the depletion of mtDNA during chronic infection, occur during the progressive evolution of gastric inflammatory lesions toward severity in mice, pointing to their potential role in infection-associated pathogenicity
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