PDF(Pubmed)
Abstract：
Localization of phosphorylated (p)‑JNK to the mitochondria can lead to functional mitochondrial disorder, resulting in a decrease in energy supply and membrane potential, as well as an increase in reactive oxygen species production and apoptosis. JNK is involved in the occurrence of acute lung injury (ALI), and activation of the JNK pathway is one of the crucial factors resulting in injury. The aim of the present study was to investigate whether the JNK‑mitochondria (mitoJNK) location participated in the occurrence of ALI and acute respiratory distress syndrome (ALI/ARDS). The present study examined the activation of the JNK pathway, the content of JNK located on the mitochondria and the treatment effects of a cell‑permeable peptide Tat‑SabKIM1, which can selectively inhibit the location of JNK on mitochondria. The expression levels of proteins were detected by western blot analysis. Lung injuries were evaluated by histological examination, wet‑to‑dry weight ratios, and H2O2 and malondialdehyde concentrations in the lung tissues. Lung cells apoptosis was evaluated using TUNEL assay. The results demonstrated that JNK was phosphorylated and activated during seawater inhalation‑induced ALI/ARDS, not only in the routine JNK pathway but also in the mitoJNK pathway. It was also found that Tat‑SabKIM1 could specifically inhibit JNK localization to mitochondria and the activation of mitoJNK signaling. Furthermore, Tat‑SabKIM1 could inhibit Bcl‑2‑regulated autophagy and mitochondria‑mediated apoptosis. In conclusion, mitoJNK localization disrupted the normal physiological functions of the mitochondria during ALI/ARDS, and selective inhibition of JNK and mitochondrial SH3BP5 (also known as Sab) binding with Tat‑SabKIM1 can block deterioration from ALI/ARDS.
摘要：
磷酸化（p）-JNK到线粒体的定位可导致功能性线粒体疾病，导致能量供应和膜电位下降，以及活性氧产生和细胞凋亡的增加。JNK参与急性肺损伤（ALI）的发生，JNK通路的激活是导致损伤的关键因素之一。本研究的目的是调查JNK-线粒体（mitoJNK）位置是否参与了ALI和急性呼吸窘迫综合征（ALI/ARDS）的发生。本研究检查了JNK途径的激活，位于线粒体上的JNK的含量以及细胞渗透性肽Tat‑SabKIM1的治疗效果，该肽可选择性地抑制JNK在线粒体上的位置。通过蛋白质印迹分析检测蛋白质的表达水平。通过组织学检查评估肺损伤，湿干重量比，以及肺组织中的H2O2和丙二醛浓度。使用TUNEL测定评价肺细胞凋亡。结果表明，JNK在海水吸入诱导的ALI/ARDS过程中被磷酸化和激活，不仅在常规JNK途径中，而且在mitoJNK途径中。还发现Tat‑SabKIM1可以特异性抑制JNK定位于线粒体和mitoJNK信号的激活。此外，Tat‑SabKIM1可抑制Bcl‑2调节的自噬和线粒体介导的细胞凋亡。总之,mitoJNK定位破坏了ALI/ARDS期间线粒体的正常生理功能，选择性抑制JNK和线粒体SH3BP5（也称为Sab）与Tat‑SabKIM1的结合可以阻断ALI/ARDS的恶化。
