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
  • 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. [email protected].
  • 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. [email protected].
  • # Contributed equally.
PMID: 35504898 DOI: 10.1038/s41421-022-00390-6
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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