Selective 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

作者：Congcong Li, Debin Ma, Yan Chen, Wei Liu, Faguang Jin, Liyan Bo · 发表于：International Journal of Molecular Medicine · 年份：2022 · DOI：10.3892/ijmm.2022.5141 · 被引用次数：19 · 研究领域：Autophagy in Disease and Therapy、Endoplasmic Reticulum Stress and Disease、Mitochondrial Function and Pathology

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. T...