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Bcl-2 蛋白通过 PINK1/Parkin 信号通路调节脂多糖诱导的急性肺损伤中的线粒体自噬。

Bcl-2 Proteins Regulate Mitophagy in Lipopolysaccharide-Induced Acute Lung Injury via PINK1/Parkin Signaling Pathway.

机构信息

Department of Anesthesiology, Shenzhen Hospital, Southern Medical University, No. 1333, Xinhu Road, Baoan District, Shenzhen, Guangdong Province, 518110, China.

Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Renmindadao Road, Xiashan District, Zhanjiang, Guangdong Province, 524002, China.

出版信息

Oxid Med Cell Longev. 2020 Feb 20;2020:6579696. doi: 10.1155/2020/6579696. eCollection 2020.

DOI:10.1155/2020/6579696
PMID:32148654
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7054785/
Abstract

Mitophagy is involved in sepsis-induced acute lung injury (ALI). Bcl-2 family proteins play an important role in mitochondrial homeostasis. However, whether targeting Bcl-2 proteins (Bcl-2 and Bad) could influence mitophagy in ALI remains unclear. In this study, lipopolysaccharide (LPS) was used to induce injury in A549 cells and ALI in mice. LPS treatment resulted in elevated cell apoptosis, enhanced mitophagy, decreased Bcl-2 expression, increased Bad expression, and activation of PINK1/Parkin signaling in cells and lung tissues. Both Bcl-2 overexpression and Bad knockdown attenuated LPS-induced injury, inhibited cell apoptosis and mitophagy, and improved survival. Atg5 knockout (KO) inhibited LPS-induced cell apoptosis. Furthermore, Bcl-2 proteins regulated mitophagy by modulating the recruitment of Parkin from the cytoplasm to mitochondria via direct protein-protein interactions. These results were further confirmed in Park2 KO cells and Park2 mice. This is the first study to demonstrate that Bcl-2 proteins regulated mitophagy in LPS-induced ALI via modulating the PINK1/Parkin signaling pathway, promoting new insights into the mechanisms and investigation of therapeutic strategies for a septic patient with ALI.

摘要

自噬参与了脓毒症诱导的急性肺损伤（ALI）。Bcl-2 家族蛋白在维持线粒体稳态方面发挥着重要作用。然而，靶向 Bcl-2 蛋白（Bcl-2 和 Bad）是否会影响 ALI 中的自噬仍不清楚。在这项研究中，脂多糖（LPS）被用于诱导 A549 细胞损伤和小鼠 ALI。LPS 处理导致细胞凋亡增加、自噬增强、Bcl-2 表达减少、Bad 表达增加以及 PINK1/Parkin 信号通路激活。Bcl-2 过表达和 Bad 敲低均减轻 LPS 诱导的损伤，抑制细胞凋亡和自噬，提高存活率。Atg5 敲除（KO）抑制 LPS 诱导的细胞凋亡。此外，Bcl-2 蛋白通过直接蛋白-蛋白相互作用调节 Parkin 从细胞质到线粒体的募集来调节自噬。这些结果在 Park2 KO 细胞和 Park2 小鼠中得到进一步证实。这是第一项研究表明，Bcl-2 蛋白通过调节 PINK1/Parkin 信号通路来调节 LPS 诱导的 ALI 中的自噬，为脓毒症合并 ALI 患者的机制研究和治疗策略提供了新的思路。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b937/7054785/cf3a27995845/OMCL2020-6579696.007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b937/7054785/1fb35d2596f1/OMCL2020-6579696.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b937/7054785/abd75cec48fd/OMCL2020-6579696.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b937/7054785/adfe1e77b334/OMCL2020-6579696.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b937/7054785/fb0c681ba014/OMCL2020-6579696.004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b937/7054785/1fcfe76ee2cf/OMCL2020-6579696.005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b937/7054785/25a59616fd10/OMCL2020-6579696.006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b937/7054785/cf3a27995845/OMCL2020-6579696.007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b937/7054785/1fb35d2596f1/OMCL2020-6579696.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b937/7054785/abd75cec48fd/OMCL2020-6579696.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b937/7054785/adfe1e77b334/OMCL2020-6579696.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b937/7054785/fb0c681ba014/OMCL2020-6579696.004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b937/7054785/1fcfe76ee2cf/OMCL2020-6579696.005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b937/7054785/25a59616fd10/OMCL2020-6579696.006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b937/7054785/cf3a27995845/OMCL2020-6579696.007.jpg

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