Diversity Supplement (PA-23-189) Parent Award: R01HL168050-01 Project Title: The Role of Adenine Nucleotide Translocase in Mitochondrial Dysfunction Associated Senescence in Chronic Obstructive Pulmonary Disease (COPD) PI: Corrine Kliment, MD, PhD Applicant Trainee: Ugonna Mbaekwe, B.S. Abstract: COPD is a prevalent disease characterized by chronic inflammation, abnormal epithelial repair and alveolar destruction (emphysema). Major risk factors for COPD include cigarette smoke (CS) exposure, air pollution and genetics [1,2], leading to millions of affected individuals worldwide with few effective treatments. We seek to better understand mechanisms of disease pathogenesis to develop therapies that will halt or reverse COPD development. The objective of this research project is to determine how adenine nucleotide translocase 2 (ANT2), a prominent mitochondrial ATP transporter, alters mitochondrial function to influence lung epithelial cell repair and senescence in smoking-induced lung injury and COPD. The research performed under this diversity supplement is an integral part of the approved, ongoing research under the parent R01. The parent R01 has 3 primary aims: 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; and 3) To test the hypothesis that therapeutic restoration of ANT2 or removal of senescent cells can protect against emphysema. This diversity supplement will specifically focus on the mechanism of senescence and ferroptosis, a form of cell death, in lung repair. The connection between ferroptosis and senescence in lung disease remains unknown. Research under this supplement will evaluate novel links between the senescence and ferroptosis pathways in the context of the parent R01 studies. This is an exciting and logical extension of the studies outlined in the R01.