Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0034069 (
pulmonary fibrosis
)
7,050
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Although endoplasmic reticulum (ER) unfolded protein response (UPR
ER
) is well known, mitochondrial unfolded protein response (UPR
mt
) has not been recognized in alveolar epithelial cells. Furthermore, ER stress and mitochondrial dysfunction are frequently encountered in alveolar epithelial cells from an array of lung disorders. However, these two scenarios have been often regarded as separate mechanisms contributing to the pathogeneses. It is unclear whether there is interplay between these two phenomena or an integrator that couples these two signaling cascades in the stressed alveolar epithelial cells from those pathologies. In this study, we defined UPR
mt
in alveolar epithelial cells and identified ATF4 (activating transcription factor 4), but not
ATF5
, as the key regulator of UPR
mt
. We found that UPR
ER
led to UPR
mt
and mitochondrial dysfunction in an ATF4-dependent manner. In contrast, mitochondrial stresses did not activate UPR
ER
. We found that alveolar epithelial ATF4 and UPR
mt
were induced in aged mice with experimental
pulmonary fibrosis
as well as in patients with idiopathic pulmonary fibrosis. Finally, we found that the inducible expression of ATF4 in mouse alveolar epithelial cells aggravated pulmonary UPR
mt
, lung inflammation, body weight loss, and death upon bleomycin-induced lung injury. In conclusion, ER stress induces ATF4-dependent UPR
mt
and mitochondrial dysfunction, indicating a novel mechanism by which ER stress contributes to the pathogeneses of a variety of pulmonary disorders.
...
PMID:ATF4 Mediates Mitochondrial Unfolded Protein Response in Alveolar Epithelial Cells. 3271 42
