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Adenine Nucleotide Translocase regulates the airway epithelium, mitochondrial metabolism and ciliary function

Corrine R. Kliment, Jennifer M. K. Nguyen, Mary Jane Kaltreider, YaWen Lu, Steven M. Claypool, Josiah E. Radder, Frank C. Sciurba, Yingze Zhang, Alyssa D. Gregory, View ORCID ProfilePablo A. Iglesias, View ORCID ProfileVenkataramana K. Sidhaye, Douglas N. Robinson
doi: https://doi.org/10.1101/2020.05.18.101378
Corrine R. Kliment
1Department of Cell Biology, Johns Hopkins University School of Medicine
2Department of Medicine, Division of Pulmonary and Critical Care, Johns Hopkins University School of Medicine
3Department of Medicine, Division of Pulmonary and Critical Care, University of Pittsburgh, Pittsburgh, PA 15260
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  • For correspondence: ckliment@pitt.edu dnr@jhmi.edu
Jennifer M. K. Nguyen
2Department of Medicine, Division of Pulmonary and Critical Care, Johns Hopkins University School of Medicine
4Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine
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Mary Jane Kaltreider
3Department of Medicine, Division of Pulmonary and Critical Care, University of Pittsburgh, Pittsburgh, PA 15260
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YaWen Lu
5Department of Physiology, Johns Hopkins University School of Medicine
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Steven M. Claypool
5Department of Physiology, Johns Hopkins University School of Medicine
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Josiah E. Radder
3Department of Medicine, Division of Pulmonary and Critical Care, University of Pittsburgh, Pittsburgh, PA 15260
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Frank C. Sciurba
3Department of Medicine, Division of Pulmonary and Critical Care, University of Pittsburgh, Pittsburgh, PA 15260
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Yingze Zhang
3Department of Medicine, Division of Pulmonary and Critical Care, University of Pittsburgh, Pittsburgh, PA 15260
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Alyssa D. Gregory
3Department of Medicine, Division of Pulmonary and Critical Care, University of Pittsburgh, Pittsburgh, PA 15260
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Pablo A. Iglesias
6Department of Electrical and Computer Engineering Johns Hopkins University
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  • ORCID record for Pablo A. Iglesias
Venkataramana K. Sidhaye
2Department of Medicine, Division of Pulmonary and Critical Care, Johns Hopkins University School of Medicine
8Department of Environmental Health Sciences and Engineering, Johns Hopkins University School of Public Health
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Douglas N. Robinson
1Department of Cell Biology, Johns Hopkins University School of Medicine
2Department of Medicine, Division of Pulmonary and Critical Care, Johns Hopkins University School of Medicine
4Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine
7Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21205
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  • For correspondence: ckliment@pitt.edu dnr@jhmi.edu
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Abstract

Airway hydration and ciliary function are critical to airway homeostasis and dysregulated in chronic obstructive lung disease (COPD). COPD is the 4th leading cause of death in the US and is impacted by cigarette smoking with no therapeutic options. We utilized a genetic selection approach in the amoeba Dictyostelium discoideum as a comparative discovery tool in lung biology to identify genetic protectors from cigarette smoke (CS). Adenine nucleotide translocase (ANT), a mitochondrial ADP/ATP transporter, was protective against CS in Dictyostelium and human bronchial epithelial cells. ANT2 gene expression is reduced in lung tissue from COPD patients and in a mouse smoking model. ANT1 and ANT2 overexpression resulted in enhanced oxidative respiration and ATP flux. In addition to ANT’s presence in the mitochondria, ANT1 and ANT2 reside at the plasma membrane in airway epithelial cells and this localization plays a role in how ANTs regulate airway homeostasis. ANT2 overexpression stimulates airway surface liquid hydration by ATP and maintains ciliary beating after CS exposure, which are key functions of the airway. Our study highlights the potential of ANT modulation in protecting from dysfunctional mitochondrial metabolism, airway hydration, and ciliary motility in COPD.

Competing Interest Statement

The authors have declared no competing interest.

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  • The authors have declared no conflicts of interest exist.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 19, 2020.
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Adenine Nucleotide Translocase regulates the airway epithelium, mitochondrial metabolism and ciliary function
Corrine R. Kliment, Jennifer M. K. Nguyen, Mary Jane Kaltreider, YaWen Lu, Steven M. Claypool, Josiah E. Radder, Frank C. Sciurba, Yingze Zhang, Alyssa D. Gregory, Pablo A. Iglesias, Venkataramana K. Sidhaye, Douglas N. Robinson
bioRxiv 2020.05.18.101378; doi: https://doi.org/10.1101/2020.05.18.101378
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Adenine Nucleotide Translocase regulates the airway epithelium, mitochondrial metabolism and ciliary function
Corrine R. Kliment, Jennifer M. K. Nguyen, Mary Jane Kaltreider, YaWen Lu, Steven M. Claypool, Josiah E. Radder, Frank C. Sciurba, Yingze Zhang, Alyssa D. Gregory, Pablo A. Iglesias, Venkataramana K. Sidhaye, Douglas N. Robinson
bioRxiv 2020.05.18.101378; doi: https://doi.org/10.1101/2020.05.18.101378

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