Dynamic O-GlcNAcylation coordinates ferritinophagy and mitophagy to activate ferroptosis

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.

Small Molecule-Activated O-GlcNAcase for Spatiotemporal Removal of O-GlcNAc in Live Cells

“…Supported by this work and many other studies, triggering OGA activation for reduced O -GlcNAcylation may have potential therapeutic benefits by synergizing with other treatments. For example, reduction of O -GlcNAc through inhibiting OGT was recently reported to promote ferroptosis in U2OS cancer cells . Recent advances in mRNA delivery provide the opportunity to implement this selectively activatable OGA for assisting O -GlcNAc modulation in vivo.…”

“…For example, reduction of O-GlcNAc through inhibiting OGT was recently reported to promote ferroptosis in U2OS cancer cells. 49 Recent advances in mRNA delivery 50 provide the opportunity to implement this selectively activatable OGA for assisting O-GlcNAc modulation in vivo. As findings about the modulation of O-GlcNAc and its spatiotemporal relationship to cellular processes are refined, the connection of O-GlcNAc to biological functions and eventually new therapeutic targets will increase in the future.…”

Meta-Analysis of RNA-Seq Datasets Identifies Novel Players in Glioblastoma

“…Ferroptosis was shown to be regulated by DElncRNA-enriched pathways, protein O-glycosylation as well as glutamine, glutamate and transferrin [ 121 , 122 , 123 , 124 ]. On the other hand, ferroptosis was previously shown to be influenced by DEPCG-enriched pathways, induced by glutathione peroxidase suppression (selenocysteine-containing enzyme) and SMG9 (a component of the NMD machinery) and inhibited by ceruloplasmin and Hedgehog pathway activation [ 125 , 126 , 127 , 128 , 129 , 130 , 131 ].…”

Mitochondrial regulatory mechanisms in spinal cord injury: A narrative review

“…[ 47 ] In addition, resveratrol can enhance MB by activating sirtuin 1 to catalyze the deacetylation of PGC-1α, resulting in improved neurological function. [ 9 , 87 ] Studies have found that the expression of PGC-1α is reduced in rats after spinal cord injury, and lentivirus overexpression (PGC-1a) in neuronal cells effectively reduces neuronal cell death. [ 88 ] This suggests that the modulation of MB by increasing PGC-1α levels can potentially improve functional recovery after SCI.…”