METTL3-m6A-SLC25A11 Axis Promotes Chronic Hypoxia-Induced Cardiomyocyte Ferroptosis

Chronic hypoxia is commonly associated with various cardiovascular diseases, with cardiomyocyte death being the most frequently observed alteration. Mitochondrial dysfunction is another consequence seen in the hypoxic heart. However, the mechanistic linkage between mitochondrial dysfunction and cardiomyocyte death in the hypoxic heart remains unclear. Solute carrier family 25 member 11 (SLC25A11) is essential for mitochondrial function via transporting glutathione to mitochondria and is possibly involved in ferroptosis. However, the role of SLC25A11 in chronic hypoxia-induced cardiomyocyte ferroptosis remains unknown.

SLC25A11 overexpression and short hairpin RNA vector were constructed and introduced into the AC16 cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes exposed to chronic hypoxia, and the cell viability, mitochondrial function, and ferroptosis were evaluated. Myocardial injury and cardiac function were also assessed in hypoxic mouse models.

Our findings reveal that chronic hypoxia induced ferroptosis and mitochondrial dysfunction and decreased cell viability and SLC25A11 expression. SLC25A11 overexpression inhibited chronic hypoxia-induced ferroptosis and mitochondrial dysfunction. SLC25A11 silencing-induced ferroptosis is reversed by iron chelator deferoxamine. Chronic hypoxia-induced increased the N6-methyladenosine (m6A) level of SLC25A11 3'UTR and decreased expression of SLC25A11 were reversed by methyltransferase-like 3 inhibitor STM2457. m6A-binding protein YTH domain family 2 binds to the SLC25A11 3'UTR. STM2457 reversed chronic hypoxia-induced cardiomyocyte ferroptosis and mitochondrial dysfunction, while SLC25A11 knockdown abolished the effects of STM2457. The ameliorative effect of STM2457 in cardiomyocyte injury was proved in the hypoxia mouse model.

This study is the first to demonstrate the protective effect of methyltransferase-like 3 inhibition, via SLC25A11 m6A modification, against chronic hypoxia-induced cardiomyocyte ferroptosis and reveals the possibility that inhibiting activation of methyltransferase-like 3-m6A-SLC25A11 may provide cardioprotective therapy for chronic hypoxia-induced cardiovascular diseases.