Mitochondrial Adenine Nucleotide Translocase Drives Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis

Chronic Obstructive Pulmonary disease (COPD) and Idiopathic Pulmonary Fibrosis (IPF) represent two ends of a spectrum of interstitial lung diseases. On one hand COPD is characterized by the destruction of alveolar walls and connective tissue, on the other hand IPF is characterized by the accumulation of extracellular matrix and aberrant wound healing response. Despite the seemingly opposite mechanisms of these disparate lung diseases, recent studies have revealed a critical role of mitochondrial dysfunction in driving both disorders. There are currently no efficacious treatments for COPD which can halt or reverse progression and current therapies are only supportive. Treatments for IPF remain limited in scale and have limited efficacy in reversing or preventing disease. Thus, it is critical to understand links between mitochondrial function and lung disease to develop potential new therapies which may improve the prognosis of these deadly chronic diseases. Here, we study the function of adenine nucleotide translocase 1 (ANT1) in both disease contexts. ANT1 is one of the most abundant proteins in the cell and acts as an ATP/ADP antiporter on the inner mitochondrial membrane. ANT1 has been demonstrated to play a critical role in maintaining total cellular ATP levels in a variety of different cell types. We found that ANT1 is reduced in monocytes and alveolar macrophages of early-stage COPD patients. We leverage a COPD smoking-mouse model using an Ant1-null mouse to study the effects of mitochondrial function in COPD macrophage and monocytes. Furthermore, we use a bleomycin-induced injury model of pulmonary fibrosis and identify key senescent pathways modulated by loss of Ant1. Taken together, these studies provide valuable mechanistic insight into the function of mitochondrial metabolism in the pathogenesis of COPD and IPF. Ant1 represents a promising therapeutic target for the future treatment of these diseases and may signify an important approach for future immunomodulatory therapeutics.