Mir22hg facilitates ferritinophagy-mediated ferroptosis in sepsis by recruiting the m6A reader YTHDC1 and enhancing Angptl4 mRNA stability.

Autor: Deng W; Emergency of Department, SSL Central Hospital of Dongguan City, No.1 Xianglong Road, Shilong Town, Dongguan, 523326, China. Dengwenlong2020@163.com., Zhong L; Emergency of Department, SSL Central Hospital of Dongguan City, No.1 Xianglong Road, Shilong Town, Dongguan, 523326, China., Ye S; Emergency of Department, SSL Central Hospital of Dongguan City, No.1 Xianglong Road, Shilong Town, Dongguan, 523326, China., Luo J; Emergency of Department, SSL Central Hospital of Dongguan City, No.1 Xianglong Road, Shilong Town, Dongguan, 523326, China., Ren G; Emergency of Department, SSL Central Hospital of Dongguan City, No.1 Xianglong Road, Shilong Town, Dongguan, 523326, China., Huang J; Emergency of Department, SSL Central Hospital of Dongguan City, No.1 Xianglong Road, Shilong Town, Dongguan, 523326, China., Zhuang X; Emergency of Department, SSL Central Hospital of Dongguan City, No.1 Xianglong Road, Shilong Town, Dongguan, 523326, China.
Jazyk: angličtina
Zdroj: Journal of bioenergetics and biomembranes [J Bioenerg Biomembr] 2024 Aug; Vol. 56 (4), pp. 405-418. Date of Electronic Publication: 2024 Jun 06.
DOI: 10.1007/s10863-024-10022-1
Abstrakt: Background: Ferritinophagy-mediated ferroptosis plays a crucial role in fighting pathogen aggression. The long non-coding RNA Mir22hg is involved in the regulation of ferroptosis and aberrantly overexpression in lipopolysaccharide (LPS)-induced sepsis mice, but whether it regulates sepsis through ferritinophagy-mediated ferroptosis is unclear.
Methods: Mir22hg was screened by bioinformatics analysis. Ferroptosis was assessed by assaying malondialdehyde (MDA), reactive oxygen species (ROS), and Fe 2+ levels, glutathione (GSH) activity, as well as ferroptosis-related proteins GPX4 and SLC3A2 by using matched kits and performing western blot. Ferritinophagy was assessed by Lyso tracker staining and FerroOrange staining, immunofluorescence analysis of Ferritin and LC-3, and western blot analysis of LC-3II/I, p62, FTH1, and NCOA4. The bind of YTH domain containing 1 (YTHDC1) to Mir22hg or angiopoietin-like-4 (Angptl4) was verified by RNA pull-down and/or immunoprecipitation (RIP) assays.
Results: Mir22hg silencing lightened ferroptosis and ferritinophagy in LPS-induced MLE-12 cells and sepsis mouse models, as presented by the downregulated MDA, ROS, Fe 2+ , NCOA4, and SLC3A2 levels, upregulated GPX4, GSH, and FTH1 levels, along with a decrease in autophagy. Mir22hg could bind to the m6A reader YTHDC1 without affecting its expression. Mechanistically, Mir22hg enhanced Angptl4 mRNA stability through recruiting the m6A reader YTHDC1. Furthermore, Angptl4 overexpression partly overturned Mir22hg inhibition-mediated effects on ferroptosis and ferritinophagy in LPS-induced MLE-12 cells.
Conclusion: Mir22hg contributed to in ferritinophagy-mediated ferroptosis in sepsis via recruiting the m6A reader YTHDC1 and strengthening Angptl4 mRNA stability, highlighting that Mir22hg may be a potential target for sepsis treatment based on ferroptosis.
(© 2024. The Author(s).)
Databáze: MEDLINE
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