Role of Cofilin-1 in Mitochondrial Quality Control Influencing Mechanisms of Airway Epithelial Dysfunction in Chronic Bronchitis

Chronic Obstructive Pulmonary Disease (COPD) afflicts 13% of the world’s population and causes 150,000 deaths annually in the United States. Patients with chronic bronchitis, a subgroup of COPD, suffer from lung function decline with significant symptoms. Chronic CS-exposed primary human airway epithelial cells differentiated on an air-liquid interface and COPD-patient-derived differentiated epithelia are unable to form a healthy epithelial monolayer. We have demonstrated that the airway epithelial cells with chronic bronchitis have lower levels of the actin-severing protein, cofilin-1, the loss of which is recapitulated in our in vitro models of chronic CS exposure. Decreasing polymerized actin and restoring cofilin-1 to optimal levels in both COPD and CS injured airway epithelia improves monolayer integrity. We propose that the loss of cofilin-1 and the resulting reduction in actin dynamics impact the mitochondrial quality control required for repair mechanisms with chronic injury and hypothesize that strategies to target this pathway will improve airway epithelial health. In Aim 1, we will dissect the role of cofilin-1 in mitochondrial dynamics. We will determine if the loss of cofilin-1 mitochondrial fission and fusion to maintain healthy mitochondria. In addition, we will determine if the loss of cofilin-1 impairs intercellular mitochondrial dynamics by preventing the transfer of healthy mitochondria between cells and assess the role of the actin dynamics and cofilin-1 on these regulatory pathways. We will determine if these processes regulate the mitochondrial dysfunction evident in COPD patient derived cells. In Aim 2, we will determine if the loss of cofilin-1, either through its role on actin or in an actin-independent fashion, impacts mitophagy and mitochondrial biogenesis. As we see transcriptional changes in critical nuclear-derived proteins required for the mitochondrial machinery, we will determine if cofilin-1 serves as a transcription factor to regulate nuclear transcription of these critical proteins. We will determine if nuclear translocation of cofilin-1 is required for maintaining transcription of the mitochondrial machinery. Aim 3 will investigate the critical role of loss of cofilin-1 in maintaining cell proliferation required for airway epithelial repair after chronic injury. We will determine if the loss of cofilin-1, through its impact on mitochondrial function, stalls progression through the cell cycle and whether this loss of proliferation is due to cell quiescence or senescence. Finally, we will determine if the loss of cofilin-1, via its effects on mitochondria, promotes the epithelial changes observed in chronic bronchitis. We are uniquely positioned to uncover novel mechanisms linking cofilin-1 loss with dysfunctional cellular energetics in the airway epithelium of patients with chronic bronchitis. These novel studies provide preclinical and translational data to better understand the mechanism leading to mitochondrial dysfunction in COPD and to target actin dynamics for therapeutic gains.