Adenine nucleotide translocase regulates airway epithelial metabolism, surface hydration and ciliary function.

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.

Why new biology must be uncovered to advance therapeutic strategies for chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is characterized by the destruction of alveolar tissue (in emphysema) and airway remodeling (leading to chronic bronchitis), which cause difficulties in breathing. It is a growing public health concern with few therapeutic options that can reverse disease progression or mortality. This is in part because current treatments mainly focus on ameliorating symptoms induced by inflammatory pathways as opposed to curing disease. Hence, emerging research focused on upstream pathways are likely to be beneficial in the development of efficient therapeutics to address the root causes of disease. Some of these pathways include mitochondrial function, cytoskeletal structure and maintenance, and airway hydration, which are all affected by toxins that contribute to COPD. Because of the complexity of COPD and unknown targets for disease onset, simpler model organisms have proved to be useful tools in identifying disease-relevant pathways and targets. This review summarizes COPD pathology, current treatments, and therapeutic discovery research, with a focus on the aforementioned pathways that can advance the therapeutic landscape of COPD.

Discovery and Quantitative Dissection of Cytokinesis Mechanisms Using Dictyostelium discoideum.

The social amoeba Dictyostelium discoideum is a versatile model for understanding many different cellular processes involving cell motility including chemotaxis, phagocytosis, and cytokinesis. Cytokinesis, in particular, is a model cell-shaped change process in which a cell separates into two daughter cells. D. discoideum has been used extensively to identify players in cytokinesis and understand how they comprise the mechanosensory and biochemical pathways of cytokinesis. In this chapter, we describe how we use cDNA library complementation with D. discoideum to discover potential regulators of cytokinesis. Once identified, these regulators are further analyzed through live cell imaging, immunofluorescence imaging, fluorescence correlation and cross-correlation spectroscopy, micropipette aspiration, and fluorescence recovery after photobleaching. Collectively, these methods aid in detailing the mechanisms and signaling pathways that comprise cell division.

Female juvenile play elicits Fos expression in dopaminergic neurons of the VTA.

Juveniles of many species engage in rough-and-tumble play behaviors, and these social encounters are important for the expression of typical social behaviors. Play is a highly motivated and rewarding behavior, which suggests that the mesocorticolimbic dopamine system is likely important for reinforcing the behavior. Indeed, systemic dopamine receptor antagonists decrease the expression of play behaviors, but the specific dopaminergic networks important for play are not known. In this study, we examined immediate-early gene expression in specific dopaminergic cell groups after juvenile male and female rats played or did not play. Subjects were housed with a same-sex sibling, and spontaneous play behavior (or lack thereof) was observed for 1 hr. Brains were harvested and immunohistochemistry was used to localize Fos and tyrosine hydroxylase. Cells expressing both proteins were counted in midbrain and forebrain dopaminergic cell groups. Females that played had more double-labeled cells in the ventral tegmental area (VTA) than females that did not play, but there was no effect of play on double-labeled cell counts in any brain region in males. Furthermore, many measures of play in females were positively correlated with the number of double-labeled cells in the VTA, including play duration and pin duration. Our results suggest that play in females likely induces dopamine release from mesocorticolimbic neurons to reinforce play behaviors. Our results also highlight a sex difference in the neural networks mediating play, thus emphasizing the importance of studying the neurobiology of play in both males and females.