Ryanodine receptor mediated calcium release contributes to ferroptosis induced in primary hippocampal neurons by GPX4 inhibition
Ferroptosis, a newly described form of regulated cell death, is characterized by the iron-dependent accumulation of lipid peroxides, glutathione depletion, mitochondrial alterations, and enhanced lipoxygenase activity. Inhibition of glutathione peroxidase 4 (GPX4), a key intracellular antioxidant re...
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| Main Authors: | , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
13 March 2023
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| In: |
Antioxidants
Year: 2023, Volume: 12, Issue: 3, Pages: 1-18 |
| ISSN: | 2076-3921 |
| DOI: | 10.3390/antiox12030705 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.3390/antiox12030705 Verlag, lizenzpflichtig, Volltext: https://www.mdpi.com/2076-3921/12/3/705 
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| Author Notes: | Silvia Gleitze, Omar A. Ramírez, Ignacio Vega-Vásquez, Jing Yan, Pedro Lobos, Hilmar Bading, Marco T. Núñez, Andrea Paula-Lima and Cecilia Hidalgo |
| Summary: | Ferroptosis, a newly described form of regulated cell death, is characterized by the iron-dependent accumulation of lipid peroxides, glutathione depletion, mitochondrial alterations, and enhanced lipoxygenase activity. Inhibition of glutathione peroxidase 4 (GPX4), a key intracellular antioxidant regulator, promotes ferroptosis in different cell types. Scant information is available on GPX4-induced ferroptosis in hippocampal neurons. Moreover, the role of calcium (Ca2+) signaling in ferroptosis remains elusive. Here, we report that RSL3, a selective inhibitor of GPX4, caused dendritic damage, lipid peroxidation, and induced cell death in rat primary hippocampal neurons. Previous incubation with the ferroptosis inhibitors deferoxamine or ferrostatin-1 reduced these effects. Likewise, preincubation with micromolar concentrations of ryanodine, which prevent Ca2+ release mediated by Ryanodine Receptor (RyR) channels, partially protected against RSL3-induced cell death. Incubation with RSL3 for 24 h suppressed the cytoplasmic Ca2+ concentration increase induced by the RyR agonist caffeine or by the SERCA inhibitor thapsigargin and reduced hippocampal RyR2 protein content. The present results add to the current understanding of ferroptosis-induced neuronal cell death in the hippocampus and provide new information both on the role of RyR-mediated Ca2+ signals on this process and on the effects of GPX4 inhibition on endoplasmic reticulum calcium content. |
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| Item Description: | Gesehen am 24.11.2023 |
| Physical Description: | Online Resource |
| ISSN: | 2076-3921 |
| DOI: | 10.3390/antiox12030705 |