Adenine Nucleotide translocase 1 (ANT1) Deficiency Impairs Macrophage Metabolism and Migration, Protecting Against Emphysema in COPD [6 months]

Macrophage-mediated inflammation drives various lung diseases, including chronic obstructive pulmonary disease (COPD). COPD macrophages have dysfunctional mitochondrial metabolism and function which lead to a chronic inflammatory lung environment. However, the factors regulating this altered metabolism have not been elucidated. Adenine nucleotide translocase 1 (ANT1) is a mitochondrial ATP transporter critical to mitochondrial metabolism. We demonstrate that human alveolar macrophages from patients with moderate COPD (GOLD stage 2) have reduced ANT1 expression while macrophages from very severe COPD (GOLD stage 4) has elevated ANT1 compared to normal control subjects. Ant1-deficient mice were protected against cigarette smoke (CS)-induced emphysema with failure of recruited immune cells to migrate into alveoli. Ant1-null alveolar macrophages had reduced ATP production and mitochondrial respiration, upregulated fewer inflammatory pathways after CS and reduced migratory capacity. Conditional Ant1 knockout in Cx3cr1-positive monocytes and adoptive transfer of Ant1-deficient bone marrow into CS-treated mice phenocopied the migratory defect in the lung. Our data indicate that ANT1 is a critical regulator of lung macrophage inflammatory signaling and CS-triggered cell migration in the lung, suggesting that metabolic modulation may be a promising therapeutic avenue for COPD C57BL WT or Ant1 null mice (gift from Douglas Wallace, Children's Hospital of Philadelphia) (female mice at 10-12 weeks of age, n = 3-4 per group) were subjected to the smoke of 4 unfiltered cigarettes per day (lot# 3R4F; University of Kentucky), 5 days a week for a duration of 6 months, using a smoking apparatus that delivers targeted cigarette smoke to single mice isolated in individual chambers. The controls in each group were exposed to room-air alone. Whole lung single cell suspensions were created and single cell RNA seq was performed.