Sporoplasm Surface Protein SSP2 hijacks APP to trigger mitochondrial apoptosis in Microsporidian-infected cells

Microsporidia are intracellular eukaryotic pathogens that pose a substantial threat to both immunocompetent and immunocompromised hosts. They infect host cells and disrupt their normal function to promote parasite growth. However, the specific proteins that affect the host’s mitochondria are not well understood. In this study, we identified a novel microsporidian sporoplasm surface protein, SSP2, which interacts with the host’s amyloid precursor protein (APP) through the “GXXXG” motif shared by both proteins. This interaction, along with a previously identified protein SSP1, forms a new pathway involving APP and mitochondrial channels. This pathway damages the mitochondria, triggering cell death and helping the parasite release mature spores. Our results show that SSP2 promotes the breakdown of APP, leading to the production of harmful amyloid-β peptides that disrupt mitochondrial function and cause apoptosis. These findings provide new insights into the mechanisms of microsporidian infection and suggest potential therapeutic approaches targeting mitochondrial pathways to treat these infections.