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

Authors

Huang, X., Bard, J. E., Tumenbayar, B.-I., Vedagiri, K., Nelson, C. E., Kenche, H., Reynolds, C. E., Leme, A. S., Moore, S. J., Perry, N. A., Shapiro, S. D., Perry, Y., Bae, Y., Blumental-Perry, A.

Abstract

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 ATF6 affects physiological and smoke exposure-accelerated lung aging. ATF6 -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 ATF6 -deficient mice. Mechanistically, these divergent phenotypes arose from cell-type-specific ATF6 programs. In alveolar epithelial type 2 cells (AEC2s), the facultative progenitors of the lung parenchyma, ATF6 maintained mitochondrial bioenergetics and sustained efficient re-differentiation into alveolar epithelial type 1 cells (AEC1s). In lung pericytes, ATF6 promoted extravasation, re-differentiation into myofibroblast-like cells, and production of collagens 1 and 3. These findings identify ATF6 as a cell-type-specific regulator of differentiation programs during lung aging and highlight the need to study ATF6 under defined physiological and pathological contexts before therapeutically targeting this pathway.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 11 Jul 2026.

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