Mitochondrial Derived Peptides in Chronic Obstructive Pulmonary Disease

Abstract Chronic obstructive pulmonary disease (COPD) is characterized by accelerated lung aging and tissue destruction. COPD affects approximately 16 million adults in the US with a prevalence of 6% and is the 6th leading cause of death. In COPD, the lungs develop chronic inflammation, abnormal epithelial repair and irreversible alveolar destruction called emphysema. Major risk factors for COPD include cigarette smoke (CS) exposure, air pollution and genetics, leading to millions of affected individuals worldwide with few effective treatments, which fail to reverse the disease course. COPD pathogenesis involves dysfunctional mitochondria that contribute to abnormal lung remodeling when confronted with an injury. Mitochondria are key metabolic organelles that mediate overall cellular responses to stress and are signaling hubs through mitochondrial-derived peptides (MDPs). Several MDPs that normally have protective roles have been shown to be depleted in neurological disease. We seek to better understand which MDPs are dysregulated in COPD and how they contribute to mechanisms of lung aging to develop therapies that will halt or reverse COPD development. We will utilize the NHLBI BioLINCC repository to test plasma and lung tissue for MDPs to characterize pathogenic changes in COPD across disease severity. We will combine experimental assays with novel bioinformatic discovery tools, specifically mitochondria-wide association scans (MiWAS) and mitochondria- wide interaction scans (MiWIS), to identify new MDPs related to COPD. Bioinformatic analyses will be conducted using the NHLBI-funded COPDGene (Genetic Epidemiology of COPD) and TOPMed SPIROMICS study cohorts. This research proposal will provide novel insights into understanding accelerated lung aging in COPD by providing: 1) a comprehensive analysis of MDPs and related SNPs in human COPD, 2) defining how these peptides correlate with clinical factors such as lung function and 3) a scaffold for future studies defining the mechanistic and therapeutic potential of MDPs to improve lung repair in COPD.