Fueling asthma inflammation via bioenergetic metabolic reprogramming

Metabolic and bioenergetic abnormalities are associated with asthma, yet the mechanisms linking these disruptions to disease pathophysiology remain unclear. We hypothesized that asthma arises from altered connectivity within metabolic networks. To test this, we employed a systems-level approach integrating platelet bioenergetic profiling with plasma metabolomics to map the bioenergetic-metabolite interactome. Fasting plasma metabolites and platelet bioenergetics were analyzed in individuals with asthma (n = 40) and healthy controls (n = 18). Among 119 altered metabolites, adenosine derivatives correlated with inflammation, and lung function, but did not fully distinguish asthma from controls. Platelet bioenergetic profiling revealed less ATP-linked oxygen consumption, and greater bioenergetic reserve capacity in asthma. Studies of primary human airway smooth muscle cells identify less mitochondrial glucose use in asthma as compared with controls. Integration of platelet bioenergetics and plasma metabolites shows a restructured network in asthma with fewer connections between metabolites and bioenergetic nodes, and new asthma-specific clusters enriched in lipid metabolism. These findings reveal a previously unrecognized bioenergetic phenotype of asthma, defined by greater oxidative reserve capacity, less mitochondrial glucose utilization, and a shift of the bioenergetic - metabolic network toward lipid pathways.