Transcriptomics combined with metabolomics to elucidate the mechanisms of bacterial otitis media infection: insights from mitochondrial dysfunction.

backgroundLipopolysaccharide (LPS) is a key pathogen-associated molecular pattern that triggers inflammatory diseases such as otitis media (OM). However, the core mechanisms by which LPS leads to epithelial cell damage, specifically through the regulation of cellular metabolism and mitochondrial function extending beyond canonical inflammatory signaling, remain incompletely understood.

resultsThis study employed an integrated approach combining transcriptomics and untargeted metabolomics to systematically analyze LPS-treated human middle ear epithelial cells. The results demonstrate that LPS induces significant metabolic reprogramming, characterized by disruptions in key energy metabolism pathways such as pyruvate metabolism and pantothenate/CoA biosynthesis. We identified a core regulatory axis comprising short-chain acyl-CoA synthetase (ACSS2) and cytochrome c oxidase assembly factors (COX10/COX17). Functional assays confirmed that LPS specifically inhibits the activity of electron transport chain Complex IV (cytochrome c oxidase), leading to mitochondrial membrane potential collapse, impaired oxidative phosphorylation, ATP synthesis deficiency, and the compensatory activation of mitophagy. This metabolic-mitochondrial dysfunction was conserved across different epithelial cell types.

conclusionsThis study is the first to reveal the critical role of the ACSS2-COX10/COX17 regulatory axis in LPS-induced inflammatory responses. This axis operates through a dual-action mechanism, linking metabolic reprogramming to mitochondrial functional failure, thereby systematically elucidating a novel mechanism of "metabolic inflammation" in middle ear epithelial cell injury. These findings provide a new theoretical foundation and identify potential therapeutic targets for intervening in mitochondrial metabolism to treat otitis media.