ATF3 represses PINK1 gene transcription in lung epithelial cells to control mitochondrial homeostasis

Marta Bueno, Judith Brands, Lauren Voltz, Kaitlin Fiedler, Brenton Mays, Claudette St. Croix, John Sembrat, Rama K. Mallampalli, Mauricio Rojas, Ana L. Mora*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

26 Citations (Scopus)
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Abstract

PINK1 (PTEN-induced putative kinase 1) is a key regulator of mitochondrial homeostasis that is relatively depleted in aging lungs and in lung epithelial cells from patients with idiopathic pulmonary fibrosis (IPF), a disease linked with aging. Impaired PINK1 expression and accumulation of damaged mitochondria in lung epithelial cells from fibrotic lungs were associated with the presence of ER stress. Here, we show that ATF3 (activating transcription factor 3), a member of the integrated stress response (ISR), negatively regulates transcription of the PINK1 gene. An ATF3 binding site within the human PINK1 promoter is located in the first 150 bp upstream of the transcription start site. Induction of ER stress or overexpression of ATF3 inhibited the activity of the PINK1 promoter. Importantly, overexpression of ATF3 causes accumulation of depolarized mitochondria, increased production of mitochondrial ROS, and loss of cell viability. Furthermore, conditional deletion of ATF3 in type II lung epithelial cells protects mice from bleomycin-induced lung fibrosis. Finally, we observed that ATF3 expression increases in the lung with age and, specially, in lung epithelial cells from IPF lungs. These data provide a unique link between ATF3 and PINK1 expression suggesting that persistent stress, driven by ATF3, can dysregulate mitochondrial homeostasis by repression of PINK1 mRNA synthesis.

Original languageEnglish
Article numbere12720
JournalAging Cell
Volume17
Issue number2
DOIs
Publication statusPublished - Apr 2018
Externally publishedYes

Keywords

  • activating transcription factor 3
  • aging
  • ER stress
  • idiopathic pulmonary fibrosis
  • mitochondrial dysfunction
  • PTEN-induced putative kinase 1

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    Bueno, M., Brands, J., Voltz, L., Fiedler, K., Mays, B., St. Croix, C., ... Mora, A. L. (2018). ATF3 represses PINK1 gene transcription in lung epithelial cells to control mitochondrial homeostasis. Aging Cell, 17(2), [e12720]. https://doi.org/10.1111/acel.12720