The Role of Adenine Nucleotide Translocase in Mitochondrial Dysfunction Associated Senescence in Chronic Obstructive Pulmonary Disease (COPD)

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PROJECT SUMMARY Chronic Obstructive Pulmonary Disease (COPD) is the fourth leading cause of death in the United States with no current therapies that significantly alter disease progression. Cigarette smoke (CS) is a major causative factor in COPD that results in mitochondrial dysfunction and reactive oxygen species (ROS). Alveolar epithelial type 2 cells (AEC2s) are essential progenitor cells for normal lung homeostasis (cell renewal) and epithelial repair after CS injury and in COPD. Mitochondrial dysfunction and cell senescence, a state of cell cycle arrest, have been implicated in COPD and may reduce AEC2 cell progenitor function and epithelial repair. The causative mechanisms and functional consequences of mitochondrial dysfunction on AEC2 senescence and epithelial repair in COPD remain major knowledge gaps and may provide new insights for the development of therapeutic approaches. The major goal of this proposal is to determine how mitochondrial dysfunction mediated by adenine nucleotide translocase 2 (ANT2) contributes to cellular senescence and abnormal epithelial cell repair in chronic obstructive pulmonary disease (COPD). Adenine nucleotide translocase 2 (ANT2) is a mitochondrial ATP transporter critical for cell metabolism and fate. We have shown that ANT2 gene expression is reduced in lung tissue from patients with COPD and that ANT2 knockdown in human bronchial epithelial cells results in reduced mitochondrial respiration (Kliment et al, J Cell Sci 2021). Our preliminary data show that human ANT2 is specifically reduced in AEC2s from COPD lungs. Knockdown of ANT2 in epithelial cells in vitro results in increased p21 and p16 (markers of senescence). In a mouse CS model of COPD, loss of ANT2 in alveolar epithelial cells results in enhanced lung destruction (emphysema), increased p21 and p16 in AEC2s, and increased ROS. This proposal will determine how ANT2 protects against emphysema by modulating ROS production, mitochondrial metabolism and senescence in AEC2 cells and epithelial repair after CS. Our study will determine the following: 1) To test the hypothesis that loss of ANT2 in AEC2 cells drives senescence by increasing ROS and the DNA damage response (DDR). 2) To test the hypothesis that loss of ANT2 shifts AEC2 metabolism and decreases repair capacity to promote COPD. 3) To test the hypothesis that therapeutic restoration of ANT2 or removal of senescent cells can protect against emphysema. The outcome of this proposal will define the mechanisms by which mitochondrial dysfunction and shifts towards glycolytic metabolism due to loss of ANT2 drives senescence and dysregulated epithelial repair in AEC2 cells in COPD. Elucidation of ANT2 as a major regulator of lung epithelial repair and senescence through mitochondrial dysfunction provides critical knowledge connecting these processes and will inform the discovery of new COPD therapies.