Handling Editor: David Stephens
ABSTRACT
Airway hydration and ciliary function are critical to airway homeostasis and dysregulated in chronic obstructive pulmonary disease (COPD), which is impacted by cigarette smoking and has no therapeutic options. We utilized a high-copy cDNA library genetic selection approach in the amoeba Dictyostelium discoideum to identify genetic protectors to cigarette smoke. Members of the mitochondrial ADP/ATP transporter family adenine nucleotide translocase (ANT) are protective against cigarette smoke in Dictyostelium and human bronchial epithelial cells. Gene expression of ANT2 is reduced in lung tissue from COPD patients and in a mouse smoking model, and overexpression of ANT1 and ANT2 resulted in enhanced oxidative respiration and ATP flux. In addition to the presence of ANT proteins in the mitochondria, they reside at the plasma membrane in airway epithelial cells and regulate airway homeostasis. ANT2 overexpression stimulates airway surface hydration by ATP and maintains ciliary beating after exposure to cigarette smoke, both of which are key functions of the airway. Our study highlights a potential for upregulation of ANT proteins and/or of their agonists in the protection from dysfunctional mitochondrial metabolism, airway hydration and ciliary motility in COPD.
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Footnotes
Competing interests
The authors declare no competing or financial interests.
Author contributions
Conceptualization: C.R.K., S.M.C., V.K.S., D.N.R.; Methodology: C.R.K., J.M.N., M.K., Y.L., V.K.S., D.N.R.; Software: P.A.I.; Validation: C.R.K., J.M.N., M.K., P.A.I., D.N.R.; Formal analysis: C.R.K., J.M.N., J.E.R., P.A.I., D.N.R.; Investigation: C.R.K., J.M.K.N., M.K., Y.L., J.E.R., A.D.G.; Resources: C.R.K., S.M.C., F.C.S., Y.Z., A.D.G., V.K.S., D.N.R.; Data curation: C.R.K., F.C.S., Y.Z.; Writing - original draft: C.R.K.; Writing - review & editing: C.R.K., J.M.K.N., S.M.C., V.K.S., D.N.R.; Visualization: C.R.K., D.N.R.; Supervision: C.R.K., D.N.R.; Project administration: C.R.K., D.N.R.; Funding acquisition: C.R.K., D.N.R.
Funding
We thank the National Institutes of Health (NIH): National Heart, Lung, and Blood Institute (NHLBI) (F32HL129660 and K08HL141595 to C.R.K.; R01HL124099 to R.S. and D.N.R.; R01HL108882 to S.M.C.); National Institute of General Medical Sciences (NIGMS) (R01GM66817 to D.N.R.); Other funding was obtained through a Biochemistry, Cellular, and Molecular Biology Program Training Grant T32GM007445 (to Y.L.); the Burroughs Wellcome Fund CAMs Award, Parker B Francis Pulmonary Fellowship, and Johns Hopkins Bauernschmidt Fellowship Foundation (to C.R.K.); the Thomas Wilson Foundation (to D.N.R.); the American Heart Association (12PRE11910004 to Y.L.); and the Airway Cell and Tissue Core supported by P30 DK072506 (Mike Meyerberg), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the CFF RDP (to Y.Z. at the University of Pittsburgh) for funding support. Deposited in PMC for release after 12 months.
Supplementary information
Supplementary information available online at https://jcs.biologists.org/lookup/doi/10.1242/jcs.257162.supplemental
- Received November 12, 2020.
- Accepted January 13, 2021.
- © 2021. Published by The Company of Biologists Ltd
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