The NSUN5-FTH1/FTL pathway mediates ferroptosis in bone marrow-derived mesenchymal stem cells

• Published in: Cell death discovery Vol. 8; no. 1; p. 99
• Main Authors: Liu, Jie, Ren, Zhenxing, Yang, Lin, Zhu, Lulu, li, Yi, Bie, Caiqun, Liu, Helu, Ji, Yichun, Chen, Dongfeng, Zhu, Meiling, Kuang, Weihong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.03.2022; Nature Publishing Group
• Subjects: 631/532/2074; 631/80/82; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Life Sciences; Stem Cells
• ISSN: 2058-7716; 2058-7716
• DOI: 10.1038/s41420-022-00902-z

Ferroptosis is a type of cell death induced by the iron-dependent accumulation of lipid hydroperoxides and reactive oxygen species (ROS) in cells. Inhibiting ferroptosis is important for improving the survival of transplanted bone marrow-derived mesenchymal stem cells (BMSCs). Although it is known that NOP2/Sun RNA methyltransferase 5 (NSUN5) post-transcriptionally regulates ferroptosis in BMSCs through RNA methylation, the precise mechanisms underlying these effects have not been reported. In this study, we demonstrate that NSUN5 is downregulated in erastin-induced ferroptosis in BMSCs. Ferroptosis was inhibited by the overexpression of NSUN5 or ferritin heavy chain/light-chain (FTH1/FTL) and was enhanced by NSUN5 knockdown. RNA immunoprecipitation experiments revealed that NSUN5 binds to FTH1/FTL, while NSUN5 depletion reduced the levels of 5-methylcytosine in FTH1 / FTL RNA and increased intracellular iron concentrations, resulting in the downregulation of glutathione peroxidase 4 (GPX4) and the accumulation of ROS and lipid peroxidation products. Co-immunoprecipitation experiments demonstrated that the recognition of FTH1 and FTL by NSUN5 is dependent on the recruitment of tumor necrosis factor receptor-associated protein 1 (TRAP1). These results suggested that the NSUN5-FTH1/FTL pathway mediates ferroptosis in BMSCs and that the therapeutic targeting of components of this pathway may promote resistance to ferroptosis and improve the survival of transplanted BMSCs.