Dynamic O-GlcNAcylation coordinates ferritinophagy and mitophagy to activate ferroptosis

• Published in: Cell discovery Vol. 8; no. 1; p. 40
• Main Authors: Yu, Fan, Zhang, Qianping, Liu, Hanyu, Liu, Jinming, Yang, Song, Luo, Xiaofan, Liu, Wei, Zheng, Hao, Liu, Qiqi, Cui, Yunxi, Chen, Guo, Li, Yanjun, Huang, Xinglu, Yan, Xiyun, Zhou, Jun, Chen, Quan
• Format: Journal Article
• Language: English
• Published: Singapore Springer Nature Singapore 03.05.2022; Springer Nature B.V; Nature Publishing Group
• Subjects: 631/80/458/1524; 631/80/82; Amino acids; Apoptosis; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Cycle Analysis; Cell death; Cell Physiology; Decision making; Diabetes; Enzymes; Ferritin; Ferroptosis; Homeostasis; Iron; Laboratories; Life Sciences; Lipid peroxidation; Lipids; Metabolism; Mitochondria; Mitophagy; O-GlcNAcylation; Proteins; Stem Cells
• ISSN: 2056-5968; 2056-5968
• DOI: 10.1038/s41421-022-00390-6

Ferroptosis is a regulated iron-dependent cell death characterized by the accumulation of lipid peroxidation. A myriad of facets linking amino acid, lipid, redox, and iron metabolisms were found to drive or to suppress the execution of ferroptosis. However, how the cells decipher the diverse pro-ferroptotic stress to activate ferroptosis remains elusive. Here, we report that protein O -GlcNAcylation, the primary nutrient sensor of glucose flux, orchestrates both ferritinophagy and mitophagy for ferroptosis. Following the treatment of ferroptosis stimuli such as RSL3, a commonly used ferroptosis inducer, there exists a biphasic change of protein O -GlcNAcylation to modulate ferroptosis. Pharmacological or genetic inhibition of O -GlcNAcylation promoted ferritinophagy, resulting in the accumulation of labile iron towards mitochondria. Inhibition of O -GlcNAcylation resulted in mitochondria fragmentation and enhanced mitophagy, providing an additional source of labile iron and rendering the cell more sensitive to ferroptosis. Mechanistically, we found that de- O -GlcNAcylation of the ferritin heavy chain at S179 promoted its interaction with NCOA4, the ferritinophagy receptor, thereby accumulating labile iron for ferroptosis. Our findings reveal a previously uncharacterized link of dynamic O -GlcNAcylation with iron metabolism and decision-making for ferroptosis, thus offering potential therapeutic intervention for fighting disease.