Journal
JOURNAL OF CELL SCIENCE
Volume 134, Issue 4, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.257162
Keywords
Adenine nucleotide translocase; Airway epithelium; Cigarette smoke; Mitochondria; SLC25A4; SLC25A5
Categories
Funding
- National Institutes of Health (NIH): National Heart, Lung, and Blood Institute (NHLBI) [F32HL129660, K08HL141595, R01HL124099, R01HL108882]
- National Institute of General Medical Sciences (NIGMS) [R01GM66817]
- Biochemistry, Cellular, and Molecular Biology Program Training Grant [T32GM007445]
- Burroughs Wellcome Fund CAMs Award
- Parker B Francis Pulmonary Fellowship
- Johns Hopkins Bauernschmidt Fellowship Foundation
- Thomas Wilson Foundation
- American Heart Association [12PRE11910004]
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- CFF RDP
- [P30 DK072506]
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Airway hydration and ciliary function are critical to airway homeostasis and dysregulated in chronic obstructive pulmonary disease (COPD), and members of the mitochondrial ADP/ATP transporter family adenine nucleotide translocase (ANT) play a protective role against cigarette smoke, highlighting a potential for upregulation of ANT proteins in COPD protection.
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. This article has an associated First Person interview with the first author of the paper.
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