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Published on: March 15, 2024
The NSUN5-FTH1/FTL pathway mediates ferroptosis in bone marrow-derived mesenchymal stem cells
Jie Liu1, Zhenxing Ren2, Lin Yang1
1Traditional Chinese Medicine Innovation Research Center, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, China.
Abstract:
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.
Insights
NSUN5 regulates ferroptosis in mesenchymal stem cells by methylating FTH1/FTL RNA. Targeting this pathway can enhance cell survival and improve transplanted stem cell efficacy.
Area of Science:
- Cell Biology
- Biochemistry
- Stem Cell Biology
Background:
- Ferroptosis, an iron-dependent cell death, impacts mesenchymal stem cell survival.
- NOP2/Sun RNA methyltransferase 5 (NSUN5) is implicated in ferroptosis regulation via RNA methylation.
- The precise mechanisms of NSUN5 in ferroptosis of BMSCs are not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanisms by which NSUN5 regulates ferroptosis in bone marrow-derived mesenchymal stem cells (BMSCs).
- To investigate the role of NSUN5 in the context of iron metabolism and oxidative stress in BMSCs.
- To explore the therapeutic potential of targeting the NSUN5 pathway for improving transplanted BMSC survival.
Main Methods:
- Investigated NSUN5 expression levels in erastin-induced ferroptosis in BMSCs.
- Utilized overexpression and knockdown of NSUN5 and FTH1/FTL to modulate ferroptosis.
- Performed RNA immunoprecipitation and co-immunoprecipitation assays to identify molecular interactions.
- Quantified 5-methylcytosine levels, intracellular iron, ROS, and lipid peroxidation products.
Main Results:
- NSUN5 expression was downregulated during ferroptosis in BMSCs.
- Overexpression of NSUN5 or FTH1/FTL inhibited ferroptosis, while NSUN5 knockdown enhanced it.
- NSUN5 directly binds to FTH1/FTL RNA, and its depletion reduces FTH1/FTL methylation.
- NSUN5-mediated FTH1/FTL recognition involves TRAP1 recruitment, impacting iron levels and GPX4 expression.
Conclusions:
- The NSUN5-FTH1/FTL pathway is a key regulator of ferroptosis in BMSCs.
- NSUN5 controls intracellular iron levels through methylation of FTH1/FTL RNA.
- Targeting the NSUN5-FTH1/FTL pathway offers a potential strategy to enhance ferroptosis resistance and improve transplanted BMSC survival.
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