From Dictyostelium to human airway epithelium: adenine nucleotide translocase enhances cellular respiration and ciliary function disrupted by cigarette smoke

Chronic obstructive pulmonary disease (COPD), a leading cause of death worldwide, currently has no cure. Development of treatments has been stagnant in part from the difficulty of finding new causal pathways in the complex human lung. Hence, we leveraged the social amoeba Dictyostelium discoideum to find new pathways by exposing them to cigarette smoke (CS), a major cause of COPD. Adenine nucleotide translocase (ANT) was discovered to be protective in Dictyostelium and interestingly, in immortalized human bronchial epithelial cells (HBE) exposed to CS. ANT resides at the inner mitochondrial membrane and functions as an ATP/ADP transporter. Using the Seahorse FluxAnalyzer system, we found that ANT1 and ANT2 overexpression (OE) increases cellular metabolism in HBE. ANT1-2 OE also prevented the decrease in metabolism induced by CS. Surprisingly, while examining ANT localization in human lung tissue, we found that the mitochondrial protein also resides at cilia in airway epithelium. We found unique functions of ANT2 in primary normal human bronchial epithelial cells (NHBE). Confocal images of the airway surface liquid (ASL) stained with Texas Red dextran reveal that ANT2 OE increases ASL height. This effect is blocked by a cell impermeable ANT inhibitor, which indicates this function occurs at the cell surface. In NHBE, CS inhibited ciliary beating, reflected in reduced ciliary beat frequency (CBF). However, ANT2 OE protected the CBF from CS. Overall, ANT improves metabolic activity and at the airway surface, enhances ASL and protects ciliary function against CS. These observations will likely have significant impact for COPD.