1. Context-dependent roles of mitochondrial LONP1 in orchestrating the balance between airway progenitor versus progeny cells
- Author
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Xu, Le, Tan, Chunting, Barr, Justinn, Talaba, Nicole, Verheyden, Jamie, Chin, Ji Sun, Gaboyan, Samvel, Kasaraneni, Nikita, Elgamal, Ruth M, Gaulton, Kyle J, Lin, Grace, Afshar, Kamyar, Golts, Eugene, Meier, Angela, Alexander, Laura E Crotty, Borok, Zea, Shen, Yufeng, Chung, Wendy K, McCulley, David J, and Sun, Xin
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Chronic Obstructive Pulmonary Disease ,Lung ,Genetics ,Stem Cell Research ,Stem Cell Research - Nonembryonic - Non-Human ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,Respiratory ,ATF4 ,BOK ,COPD ,airway homeostasis ,differentiated progeny cells ,influenza infection ,integrated stress response ,lung epithelial cells ,mitochondria ,progenitor basal cells ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
While all eukaryotic cells are dependent on mitochondria for function, in a complex tissue, which cell type and which cell behavior are more sensitive to mitochondrial deficiency remain unpredictable. Here, we show that in the mouse airway, compromising mitochondrial function by inactivating mitochondrial protease gene Lonp1 led to reduced progenitor proliferation and differentiation during development, apoptosis of terminally differentiated ciliated cells and their replacement by basal progenitors and goblet cells during homeostasis, and failed airway progenitor migration into damaged alveoli following influenza infection. ATF4 and the integrated stress response (ISR) pathway are elevated and responsible for the airway phenotypes. Such context-dependent sensitivities are predicted by the selective expression of Bok, which is required for ISR activation. Reduced LONP1 expression is found in chronic obstructive pulmonary disease (COPD) airways with squamous metaplasia. These findings illustrate a cellular energy landscape whereby compromised mitochondrial function could favor the emergence of pathological cell types.
- Published
- 2024
