Repair of airway epithelia requires metabolic rewiring towards fatty acid oxidation

被引:24
作者
Crotta, Stefania [1 ]
Villa, Matteo [2 ]
Major, Jack [1 ]
Finsterbusch, Katja [1 ]
Llorian, Miriam [3 ]
Carmeliet, Peter [4 ,5 ,6 ,7 ]
Buescher, Joerg [2 ]
Wack, Andreas [1 ]
机构
[1] Francis Crick Inst, Immunoregulat Lab, London, England
[2] Max Planck Inst Immunobiol & Epigenet, Freiburg, Germany
[3] Francis Crick Inst, Bioinformat, London, England
[4] Katholieke Univ Leuven, Ctr Canc Biol, VIB, Lab Angiogenesis & Vasc Metab, Leuven, Belgium
[5] Katholieke Univ Leuven, Dept Oncol, Leuven, Belgium
[6] Aarhus Univ, Dept Biomed, Lab Angiogenesis & Vasc Heterogene, Aarhus, Denmark
[7] Khalifa Univ Sci & Technol, Ctr Biotechnol BTC, POB 127788, Abu Dhabi, U Arab Emirates
基金
英国医学研究理事会; 英国惠康基金; 欧洲研究理事会;
关键词
BETA-OXIDATION; STEM-CELLS; LUNG; GLYCOSYLATION; REGENERATION; COA; INFLAMMATION; HOMEOSTASIS; CARNITINE; MECHANISM;
D O I
10.1038/s41467-023-36352-z
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Airway epithelial repair, a key process in the recovery from lung injury, requires a metabolic shift from glycolysis to fatty acid oxidation (FAO). Pharmacological FAO promotion enhances epithelial differentiation, suggesting new therapeutic options. 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.
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页数:15
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