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

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.

doi:10.64898/2026.07.09.737329

bioRxiv · 10.64898/2026.07.09.737329

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

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.

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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 redifferentiation into alveolar epithelial type 1 cells (AEC1s). In lung pericytes, ATF6 promoted extravasation, redifferentiation 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.

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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.. 2026-07-10. Cell-type-specific ATF6α programs regulate epithelial mitochondrial homeostasis and pericyte remodeling during physiological and exposure-accelerated lung aging. https://doi.org/10.64898/2026.07.09.737329

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