Helicobacter pylori VacA-induced mitochondrial damage in the gastric pit cells of the antrum and therapeutic rescue
Investigating the specific ways in which host cells are affected, the mechanisms by which disease develops, and the detailed molecular processes of the vacuolating cytotoxin A, or VacA, secreted by the bacterium Helicobacter pylori, often abbreviated as Hp, represents a critical area of research for the creation of innovative treatment approaches. VacA exerts its influence on events occurring within cells, with a notable impact on mitochondria, and this influence varies depending on the specific type of cell. Nevertheless, our comprehension of the intricate networks of mitochondria within a living human stomach is currently limited by the absence of dependable models that accurately replicate the damage to subcellular structures caused by VacA. These limitations also hinder the effective screening of new drugs that could be clinically relevant.
In this study, human antrum gastric organoids, referred to as hAGOs, along with tissue samples obtained from patients infected with Hp, were utilized to demonstrate the detrimental effects of mitochondrial damage induced by VacA. These effects were observed predominantly in mucus-producing gastric pit cells through the application of analyses at the transcriptional, translational, and functional levels. Within hAGOs that were exposed to VacA or infected with Hp, a significant fragmentation of mitochondria was observed specifically in the gastric pit cells. This mitochondrial fragmentation led to a reduction in the production of adenosine triphosphate, or ATP, during cellular respiration. Furthermore, the experimental evidence presented here provides the first demonstration of the loss of integrity of the mucosal barrier as a consequence of VacA exposure or Hp infection in these organoid models.
By employing the hAGO model, a screening process was conducted to evaluate the effectiveness of small molecules that hold clinical relevance. This screening identified MLN8054, an inhibitor of Aurora kinase A, as a compound capable of reversing the mitochondrial damage and the loss of gastric epithelium integrity induced by VacA. The effectiveness of MLN8054 was confirmed in hAGOs treated with VacA, hAGOs infected with Hp, and in a mouse model. These findings underscore the potential of hAGOs as a valuable model for drug screening purposes. Taken together, these results suggest that the regulation of mitochondrial quality may represent a promising avenue for therapeutic intervention against the toxicity mediated by Hp VacA and the progression of associated diseases.