Fueling asthma inflammation via bioenergetic metabolic reprogramming

Area of Science:

• Biochemistry
• Systems Biology
• Metabolomics

Background:

• Metabolic and bioenergetic abnormalities are linked to asthma.
• The precise mechanisms connecting these disruptions to asthma pathophysiology are not fully understood.

Purpose of the Study:

• To investigate the hypothesis that asthma arises from altered connectivity within metabolic networks.
• To map the bioenergetic-metabolite interactome in asthma using a systems-level approach.

Main Methods:

• Integrated platelet bioenergetic profiling and plasma metabolomics.
• Analyzed fasting plasma metabolites and platelet bioenergetics in individuals with asthma (n=40) and healthy controls (n=18).
• Studied primary human airway smooth muscle cells.

Main Results:

• Identified 119 altered metabolites, with adenosine derivatives correlating with inflammation and lung function.
• Observed reduced ATP-linked oxygen consumption and greater bioenergetic reserve capacity in asthma.
• Found decreased mitochondrial glucose utilization in asthma airway smooth muscle cells.
• Revealed a restructured metabolic network in asthma with fewer connections and new clusters enriched in lipid metabolism.

Conclusions:

• Asthma exhibits a distinct bioenergetic phenotype characterized by increased oxidative reserve capacity.
• Reduced mitochondrial glucose utilization and a shift towards lipid metabolism pathways are key features of asthma.
• The study highlights a restructured bioenergetic-metabolite network in asthma, offering new insights into disease mechanisms.