Pneumococcal H 2 O 2 Reshapes Mitochondrial Function and Reprograms Host Cell Metabolism
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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 Spn-mediated stress. These findings elucidate a novel mechanism by which Spn manipulates host metabolism to facilitate infection, highlighting potential therapeutic targets for pneumococcal diseases.
Highlights
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Spn-derived SpxB-generated H 2 O 2 directly inhibits TCA cycle enzymes ACO2, GDH, and OGDHC.
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Spn-H 2 O 2 disrupts mitochondrial respiration, increases citrate levels, and enhances glucose consumption with elevated lactate and acetate production.
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SpxB-dependent H 2 O 2 induces transcriptional dysregulation, upregulating HK2 and PFKP while reducing pyruvate entry into the TCA cycle.
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H 2 O 2 -mediated reprogramming shifts host cells to a Warburg-like metabolic phenotype.
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Spn-H 2 O 2 triggers limited apoptosis and maintains mitochondrial membrane potential, supporting bacterial survival.
