1. Academic Validation
  2. Dynamic O-GlcNAcylation coordinates ferritinophagy and mitophagy to activate ferroptosis

Dynamic O-GlcNAcylation coordinates ferritinophagy and mitophagy to activate ferroptosis

  • Cell Discov. 2022 May 3;8(1):40. doi: 10.1038/s41421-022-00390-6.
Fan Yu  # 1 Qianping Zhang  # 1 Hanyu Liu 1 Jinming Liu 1 Song Yang 1 Xiaofan Luo 1 Wei Liu 1 Hao Zheng 1 Qiqi Liu 1 Yunxi Cui 1 Guo Chen 1 Yanjun Li 1 Xinglu Huang 1 Xiyun Yan 2 Jun Zhou 3 Quan Chen 4
Affiliations

Affiliations

  • 1 The State Key Laboratory of Medicinal Chemical Biology and Frontier of Science Center for Cell Response, College of Life Sciences, Nankai University, Tianjin, China.
  • 2 Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  • 3 The State Key Laboratory of Medicinal Chemical Biology and Frontier of Science Center for Cell Response, College of Life Sciences, Nankai University, Tianjin, China. Junzhou@nankai.edu.cn.
  • 4 The State Key Laboratory of Medicinal Chemical Biology and Frontier of Science Center for Cell Response, College of Life Sciences, Nankai University, Tianjin, China. chenq@nankai.edu.cn.
  • # Contributed equally.
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.

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