Cell Discovery (May 2022)

Dynamic O-GlcNAcylation coordinates ferritinophagy and mitophagy to activate ferroptosis

  • Fan Yu,
  • Qianping Zhang,
  • Hanyu Liu,
  • Jinming Liu,
  • Song Yang,
  • Xiaofan Luo,
  • Wei Liu,
  • Hao Zheng,
  • Qiqi Liu,
  • Yunxi Cui,
  • Guo Chen,
  • Yanjun Li,
  • Xinglu Huang,
  • Xiyun Yan,
  • Jun Zhou,
  • Quan Chen

DOI
https://doi.org/10.1038/s41421-022-00390-6
Journal volume & issue
Vol. 8, no. 1
pp. 1 – 17

Abstract

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Abstract 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.