Mechanism of lncRNA gadd7 regulating mitofusin 1 expression by recruiting LSD1 to down-regulate H3K9me3 level, and mediating mitophagy in alveolar type II epithelial cell apoptosis in hyperoxia-induced acute lung injury.
Guoyue Liu, Guiyang Jia, Yingcong Ren, Cunzhi Yin, Xuan Xiao, Hang Wu, Jun Liu, Miao Chen
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Abstract
Objective: Hyperoxic exposure induces acute lung injury (ALI). We analyzed the mechanism of long non-coding RNA (lncRNA) growth-arrested DNA damage-inducible gene 7 (gadd7) regulating mitofusin 1 (MFN1) in Hyperoxia-induced ALI (HALI) type II alveolar epithelial cell (AEC II) apoptosis.
Methods: The HALI rat model was generated using hyperoxic induction and treated with shRNA-gadd7 and rapamycin (Rapa), with ALI, apoptotic level, total protein concentration and total cell, neutrophil and macrophage counts assessed. The HALI cell model was developed on hyperoxia-induced RLE-6TN cells and processed with oe-MFN1, si-gadd7 and Rapa. Cell viability, apoptosis, TOM20/LC3BII co-localization, mitochondrial membrane potential (MMP), superoxide dismutase activity, malonaldehyde, reactive oxygen species (ROS), tumor necrosis factor-α, interleukin (IL)-10, IL-6, IL-1β, gadd7, MFN1, Cleaved caspase-3, Cleaved poly (ADP-ribose) polymerase, B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X, LC3BI/II, lysine-specific demethylase 1 (LSD1), p62, and H3K9me3 protein levels were measured. gadd7-LSD1 interaction was predicted and verified by RPISeq database, RIP, and RNA pull-down assay.
Results: In HALI rats, gadd7 was up-regulated in lung tissues, and gadd7 silencing alleviated oxidative stress, ALI and apoptosis. gadd7 knockdown inhibited oxidative stress and apoptosis though MFN1, and mediated mitophagy (evidenced by diminished LC3BII/LC3BI ratio, TOM20/LC3BII co-localization and ROS level, and elevated p62 level and MMP), which were reversed by mitophagy activation. By recruiting LSD1 to down-regulate H3K9me3 level and promote MFN1 expression, gadd7-mediated mitophagy affected ALI and apoptosis in HALI rats.
Conclusion: LncRNA gadd7 regulated MFN1 expression by recruiting LSD1 to down-regulate H3K9me3 level and mediate mitophagy, thereby promoting AEC II apoptosis in HALI.
期刊介绍：
Cell Biology and Toxicology (CBT) is an international journal focused on clinical and translational research with an emphasis on molecular and cell biology, genetic and epigenetic heterogeneity, drug discovery and development, and molecular pharmacology and toxicology. CBT has a disease-specific scope prioritizing publications on gene and protein-based regulation, intracellular signaling pathway dysfunction, cell type-specific function, and systems in biomedicine in drug discovery and development. CBT publishes original articles with outstanding, innovative and significant findings, important reviews on recent research advances and issues of high current interest, opinion articles of leading edge science, and rapid communication or reports, on molecular mechanisms and therapies in diseases.
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