ANT1 Deficiency Impairs Macrophage Metabolism and Migration, Protecting Against Emphysema in Chronic Obstructive Pulmonary Disease.

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. ANT1 (adenine nucleotide translocase 1) is a mitochondrial ATP transporter critical to mitochondrial metabolism. We demonstrate that human alveolar macrophages from patients with moderate COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 2) have reduced ANT1 expression, whereas macrophages from very severe COPD (GOLD stage 4) have elevated ANT1 compared with 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.