Reduced Mitochondrial Adenine Nucleotide Translocase 1 (ANT1) Correlates With Aging-Associated Airway Remodeling

Aging generates a variety of phenotypes in the lungs with increased alveolar airspaces or emphysema, decreased surface area, and increased disease susceptibility. Senescence, oxidative stress, and mitochondrial dysfunction are known contributory factors. However, the underlying mechanisms promoting unhealthy aging remain unclear. Adenine nucleotide Translocase 1 (ANT1), a mitochondrial ADP/ATP transporter, is important for mitochondrial metabolism. Loss of ANT1 has been implicated in the development of pulmonary fibrosis, a disease characterized by accelerated lung aging, through mitochondrial dysfunction and senescence. To determine the role of ANT1 in normal lung aging, we analyzed aged human lung data from the Human Lung Cell Atlas and evaluated the ANT1-related mechanism in an aged genetic mouse and in vitro models. Analysis of SLC25A4 (ANT1) gene expression in the Human Lung Cell Atlas data from healthy adults (ages 20-80) revealed an age-associated reduction in SLC25A4 in alveolar type 2 pneumocytes (AT2), and airway ciliated and basal cells. Using an Ant1-deficient mouse model, aged Ant1-null mice developed increased airway thickening and airway resistance on lung function testing compared to aged wildtype mice. In human airway epithelial cells, ANT1 knockdown resulted in upregulation of senescence and tissue remodeling genes, including COL8A1. Aged Ant1-null mice and aged human airways similarly had increased p21 expression in AT2 and airway club cells, increased SASP markers, and increased COL8A1 expression in the airways. We demonstrate for the first time that ANT1, an important multifunctional mitochondrial protein, plays a significant role in the pathogenesis of lung aging by regulating senescence and airway matrix remodeling.