Open AccessSelective inhibition of JNK located on mitochondria protects against mitochondrial dysfunction and cell death caused by endoplasmic reticulum stress in mice with LPS‑induced ALI/ARDS
Author(s) -
Congcong Li,
Debin Ma,
Yan Chen,
Wei Liu,
Fang Jin,
Liyan Bo
Publication year - 2022
Publication title -
international journal of molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.048
H-Index - 90
eISSN - 1791-244X
pISSN - 1107-3756
DOI - 10.3892/ijmm.2022.5141
Subject(s) - ards , endoplasmic reticulum , mitochondrion , apoptosis , microbiology and biotechnology , unfolded protein response , programmed cell death , p38 mitogen activated protein kinases , mitochondrial permeability transition pore , western blot , kinase , biology , chemistry , medicine , protein kinase a , lung , biochemistry , gene
Few pharmacological interventions are able to improve the mortality rate of acute lung injury and acute respiratory distress syndrome (ALI/ARDS). The aim of this research was to elucidate whether endoplasmic reticulum (ER) stress and c‑Jun‑N‑terminal kinase (JNK)‑mitochondria pathways serve important roles in ALI/ARDS and to determine whether the key component Sab is a potential treatment target. The current study investigated the activation of ER stress and the JNK pathway, the content of JNK located on the mitochondria during ER stress and lipopolysaccharide (LPS)‑induced ALI/ARDS by western blot analysis. The treatment effects of Tat‑Sab KIM1 , a selective inhibitor of JNK located on mitochondria were explored by multiple methods including histopathological evaluation, lung cell apoptosis tested by TUNEL assay, mitochondrial membrane permeability and survival analysis. The results verified that ER stress was enhanced during LPS‑induced ALI/ARDS and could induce activation of the JNK pathway and JNK‑mitochondrial localization as well as mitochondrial dysfunction and cell death. Tat‑Sab KIM1 alleviated LPS injection‑induced lung injury and improved mouse survival rates by specifically inhibiting JNK localization to mitochondria and mito‑JNK signal activation without affecting cytosolic/nuclear JNK activation. The protective effect of Tat‑Sab KIM1 against ALI/ARDS was partly caused by inhibition of the excessive activation of mitochondria‑mediated apoptosis and autophagy. These results showed the important role of Sab as a treatment target of ALI/ARDS and the potential treatment effect of Tat‑Sab KIM1 . In conclusion, abnormal activation of the JNK‑mitochondrial pathway could significantly disrupt the normal physiological function of lung cells, resulting in the occurrence of ALI/ARDS and selective inhibit of JNK located on mitochondria by Tat‑Sab KIM1 had a protective effect against the mitochondrial dysfunction and cell death caused by endoplasmic reticulum stress in mice with LPS‑induced ALI/ARDS.