Pneumococcal H(2)O(2) Reshapes Mitochondrial Function and Reprograms Host Cell Metabolism.

Streptococcus pneumoniae (Spn) is a primary cause of pneumonia, induces acute lung parenchymal infection, damaging through a unique metabolic pathway that generates hydrogen peroxide (H(2)O(2)) as a byproduct. This study reveals that Spn-derived H(2)O(2), primarily produced by pyruvate oxidase (SpxB), inhibits the tricarboxylic acid (TCA) cycle in lung epithelial cells by targeting aconitase, glutamate dehydrogenase, and α-ketoglutarate dehydrogenase. This inhibition leads to citrate accumulation and reduced NADH production for oxidative phosphorylation, while RNA sequencing shows SpxB-dependent upregulation of glycolytic genes (e.g., HK2, PFKP), limiting pyruvate entry into the TCA cycle. Consequently, glucose consumption and lactate/acetate production increase, resembling a Warburg-like metabolic shift that supports bacterial survival. Despite TCA cycle suppression, mitochondrial membrane potential remains largely unaffected, with minimal apoptosis induced by Spnmediated stress. These findings elucidate a novel mechanism by which Spn manipulates host metabolism to facilitate infection, highlighting potential therapeutic targets for pneumococcal diseases.