Cell-type-specific ATF6α programs regulate epithelial mitochondrial homeostasis and pericyte remodeling during physiological and exposure-accelerated lung aging

Proteostasis declines with lung aging, while the role of the Unfolded Protein Response (UPR) in lung aging and age–associated pulmonary diseases remains understudied. We investigated how deficiency in the UPR sensor ATF6α affects physiological and smoke exposure–accelerated lung aging. ATF6α –deficient mice exhibited accelerated alveolar simplification, a sign of lung parenchymal aging, which was exacerbated by smoking. Nevertheless, small airway vascular fibrotic remodeling, a prominent smoking induced pathology, was not evident in smoke–exposed ATF6α –deficient mice. Mechanistically, these divergent phenotypes arose from cell–type–specific ATF6α programs. In alveolar epithelial type 2 cells (AEC2s), the facultative progenitors of the lung parenchyma, ATF6α maintained mitochondrial bioenergetics and sustained efficient re-differentiation into alveolar epithelial type 1 cells (AEC1s). In lung pericytes, ATF6α promoted extravasation, re-differentiation into myofibroblast–like cells, and production of collagens 1 and 3. These findings identify ATF6α as a cell–type–specific regulator of differentiation programs during lung aging and highlight the need to study ATF6α under defined physiological and pathological contexts before therapeutically targeting this pathway.