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ResearchIn-Press PreviewInflammationMetabolism Open Access | 10.1172/JCI200067

Mitochondrial metabolic dysfunction in airway epithelial cells promotes goblet cell metaplasia and more severe asthma

Xiuxia Zhou,1 Krithika S. Rao,2 Sruti Shiva,3 Catharina van Heusden,4 Qi Wei,1 Nobuhiko Fukuda,1 Mayoko Tsuji,1 Angelina Kendi,2 Laura R. Bradley,1 Jinming Zhao,1 John B. Trudeau,1 Anuradha Ray,5 Richard C. Boucher,4 and Sally E. Wenzel1

1Department of Environmental and Occupational Health, School of Public Health, University of Pittsburgh, Pittsburgh, United States of America

2Vascular Medicine Institute, Division of Cardiology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

3Vascular Medicine Institute, Division of Classical Hematology, Department o, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

5Pulmonary, Allergy, Critical Care, and Sleep Medicine Division, Department , School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

Find articles by Zhou, X. in: PubMed | Google Scholar

1Department of Environmental and Occupational Health, School of Public Health, University of Pittsburgh, Pittsburgh, United States of America

2Vascular Medicine Institute, Division of Cardiology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

3Vascular Medicine Institute, Division of Classical Hematology, Department o, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

5Pulmonary, Allergy, Critical Care, and Sleep Medicine Division, Department , School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Environmental and Occupational Health, School of Public Health, University of Pittsburgh, Pittsburgh, United States of America

2Vascular Medicine Institute, Division of Cardiology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

3Vascular Medicine Institute, Division of Classical Hematology, Department o, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

5Pulmonary, Allergy, Critical Care, and Sleep Medicine Division, Department , School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Environmental and Occupational Health, School of Public Health, University of Pittsburgh, Pittsburgh, United States of America

2Vascular Medicine Institute, Division of Cardiology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

3Vascular Medicine Institute, Division of Classical Hematology, Department o, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

5Pulmonary, Allergy, Critical Care, and Sleep Medicine Division, Department , School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Environmental and Occupational Health, School of Public Health, University of Pittsburgh, Pittsburgh, United States of America

2Vascular Medicine Institute, Division of Cardiology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

3Vascular Medicine Institute, Division of Classical Hematology, Department o, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

5Pulmonary, Allergy, Critical Care, and Sleep Medicine Division, Department , School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Environmental and Occupational Health, School of Public Health, University of Pittsburgh, Pittsburgh, United States of America

2Vascular Medicine Institute, Division of Cardiology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

3Vascular Medicine Institute, Division of Classical Hematology, Department o, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

5Pulmonary, Allergy, Critical Care, and Sleep Medicine Division, Department , School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

Find articles by Fukuda, N. in: PubMed | Google Scholar

1Department of Environmental and Occupational Health, School of Public Health, University of Pittsburgh, Pittsburgh, United States of America

2Vascular Medicine Institute, Division of Cardiology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

3Vascular Medicine Institute, Division of Classical Hematology, Department o, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

5Pulmonary, Allergy, Critical Care, and Sleep Medicine Division, Department , School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Environmental and Occupational Health, School of Public Health, University of Pittsburgh, Pittsburgh, United States of America

2Vascular Medicine Institute, Division of Cardiology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

3Vascular Medicine Institute, Division of Classical Hematology, Department o, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

5Pulmonary, Allergy, Critical Care, and Sleep Medicine Division, Department , School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Environmental and Occupational Health, School of Public Health, University of Pittsburgh, Pittsburgh, United States of America

2Vascular Medicine Institute, Division of Cardiology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

3Vascular Medicine Institute, Division of Classical Hematology, Department o, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

5Pulmonary, Allergy, Critical Care, and Sleep Medicine Division, Department , School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Environmental and Occupational Health, School of Public Health, University of Pittsburgh, Pittsburgh, United States of America

2Vascular Medicine Institute, Division of Cardiology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

3Vascular Medicine Institute, Division of Classical Hematology, Department o, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

5Pulmonary, Allergy, Critical Care, and Sleep Medicine Division, Department , School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

Find articles by Zhao, J. in: PubMed | Google Scholar

1Department of Environmental and Occupational Health, School of Public Health, University of Pittsburgh, Pittsburgh, United States of America

2Vascular Medicine Institute, Division of Cardiology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

3Vascular Medicine Institute, Division of Classical Hematology, Department o, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

5Pulmonary, Allergy, Critical Care, and Sleep Medicine Division, Department , School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

Find articles by Trudeau, J. in: PubMed | Google Scholar |

1Department of Environmental and Occupational Health, School of Public Health, University of Pittsburgh, Pittsburgh, United States of America

2Vascular Medicine Institute, Division of Cardiology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

3Vascular Medicine Institute, Division of Classical Hematology, Department o, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

5Pulmonary, Allergy, Critical Care, and Sleep Medicine Division, Department , School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

Find articles by Ray, A. in: PubMed | Google Scholar

1Department of Environmental and Occupational Health, School of Public Health, University of Pittsburgh, Pittsburgh, United States of America

2Vascular Medicine Institute, Division of Cardiology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

3Vascular Medicine Institute, Division of Classical Hematology, Department o, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

5Pulmonary, Allergy, Critical Care, and Sleep Medicine Division, Department , School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

Find articles by Boucher, R. in: PubMed | Google Scholar

1Department of Environmental and Occupational Health, School of Public Health, University of Pittsburgh, Pittsburgh, United States of America

2Vascular Medicine Institute, Division of Cardiology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

3Vascular Medicine Institute, Division of Classical Hematology, Department o, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

4Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

5Pulmonary, Allergy, Critical Care, and Sleep Medicine Division, Department , School of Medicine, University of Pittsburgh, Pittsburgh, United States of America

Find articles by Wenzel, S. in: PubMed | Google Scholar |

Published October 6, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI200067.
Copyright © 2026, Zhou et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 6, 2026 - Version history
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Abstract

Type 2 (T2) inflammation is a defining feature of asthma and associated with epithelial dysfunction, including goblet cell metaplasia and ciliary loss. Here, we investigated whether T2 inflammation and associated 15 lipoxygenase-1 (15LO1) activity alters mitochondrial metabolism in airway epithelial cells (AECs) and contributes to disease pathophysiology. Freshly isolated AECs from T2-high asthmatic participants exhibited increased oxygen consumption rates (OCR), including elevated basal respiration and proton leak, alongside reduced coupling efficiency compared to T2-low participants. These functional changes were accompanied by increased expression of electron transport chain (ETC) proteins, worse lung function and epithelial phenotypic changes. In vitro, IL-13 stimulation of differentiated AECs recapitulated these findings, inducing higher OCR, increased ETC protein levels, and enhanced proton leak while paradoxically reducing intracellular ATP. These metabolic alterations are associated with increased uncoupling protein 2 (UCP2) expression and goblet cell differentiation. Mechanistically, 15LO1 emerged as a key regulator, as ALOX15 knockdown or pharmacologic inhibition reduced OCR parameters, ETC protein expression, UCP2, and goblet cell markers, without effect on ATP levels, suggesting additional regulatory mechanisms. Collectively, these findings identify a metabolic axis linking T2 inflammation, mitochondrial dysfunction, and airway epithelial metabolism, while highlighting 15LO1-driven mitochondrial uncoupling as a potential therapeutic target in asthma. 

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