Repair of airway epithelia requires metabolic rewiring towards fatty acid oxidation

Stefania Crotta (), Matteo Villa, Jack Major, Katja Finsterbusch, Miriam Llorian, Peter Carmeliet, Joerg Buescher and Andreas Wack ()
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Stefania Crotta: Francis Crick Institute
Matteo Villa: Max Planck Institute of Immunobiology and Epigenetics
Jack Major: Francis Crick Institute
Katja Finsterbusch: Francis Crick Institute
Miriam Llorian: Francis Crick Institute
Peter Carmeliet: KU Leuven
Joerg Buescher: Max Planck Institute of Immunobiology and Epigenetics
Andreas Wack: Francis Crick Institute

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Epithelial tissues provide front-line barriers shielding the organism from invading pathogens and harmful substances. In the airway epithelium, the combined action of multiciliated and secretory cells sustains the mucociliary escalator required for clearance of microbes and particles from the airways. Defects in components of mucociliary clearance or barrier integrity are associated with recurring infections and chronic inflammation. The timely and balanced differentiation of basal cells into mature epithelial cell subsets is therefore tightly controlled. While different growth factors regulating progenitor cell proliferation have been described, little is known about the role of metabolism in these regenerative processes. Here we show that basal cell differentiation correlates with a shift in cellular metabolism from glycolysis to fatty acid oxidation (FAO). We demonstrate both in vitro and in vivo that pharmacological and genetic impairment of FAO blocks the development of fully differentiated airway epithelial cells, compromising the repair of airway epithelia. Mechanistically, FAO links to the hexosamine biosynthesis pathway to support protein glycosylation in airway epithelial cells. Our findings unveil the metabolic network underpinning the differentiation of airway epithelia and identify novel targets for intervention to promote lung repair.

Date: 2023
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DOI: 10.1038/s41467-023-36352-z

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