Ferroptosis-Induced Endoplasmic Reticulum Stress: Cross-talk between Ferroptosis and Apoptosis

Lee, Young‐Sun; Lee, Dae-Hee; Choudry, Haroon A.; Bartlett, David L.

doi:10.1158/1541-7786.mcr-18-0055

Cited by 276 publications

(169 citation statements)

References 47 publications

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“…Along with the evidence that miR-132/212 was consistently downregulated in AD [24], it is reasonable to speculate that miR-212 may act like a bridge between TBI and neurodegenerative diseases. Moreover, there is a consensus that crosstalk widely exists between ferroptosis and other forms of regulated cell death [53,[63][64][65][66], and emerging evidence indicates that miR-212 may prevent neuron death by inhibiting other target genes, like Sirt2 [67] or participating in other pathways, like autophagy [65,66] or apoptosis [63]. Further studies are urgently required to identify whether miR-212-5p is involved in any other pathologic process of TBI.…”

Section: Discussionmentioning

confidence: 99%

miR-212-5p attenuates ferroptotic neuronal death after traumatic brain injury by targeting Ptgs2

et al. 2019

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Ferroptosis, a newly discovered form of iron-dependent regulated cell death, has been implicated in traumatic brain injury (TBI). MiR-212-5p has previously been reported to be downregulated in extracellular vesicles following TBI. To investigate whether miR-212-5p is involved in the ferroptotic neuronal death in TBI mice, we first examined the accumulation of malondialdehyde (MDA) and ferrous ion, and the expression of ferroptosis-related molecules at 6 h, 12 h, 24 h, 48 h and 72 h following controlled cortical impact (CCI) in mice. There was a significant upregulation in the expression of Gpx4 and Acsl4 at 6 h, Slc7a11 from 12 h to 72 h, and Nox2 and Sat1 from 6 h to 72 h post injury. Similarly, an upregulation in the expression of Gpx4 at 6 h, Nox2 from 6 h to 72 h, xCT from 12 h to 72 h, and Sat1 at 72 h after CCI was observed at the protein level. Interestingly, MDA and ferrous ion were increased whereas miR-212-5p was decreased in the CCI group compared to the sham group. Furthermore, we found that overexpression of miR-212-5p attenuated ferroptosis while downregulation of miR-212-5p promoted ferroptotic cell death partially by targeting prostaglandin-endoperoxide synthase-2 (Ptgs2) in HT-22 and Neuro-2a cell lines. In addition, administration of miR-212-5p in CCI mice significantly improved learning and spatial memory. Collectively, these findings indicate that miR-212-5p may protect against ferroptotic neuronal death in CCI mice partially by targeting Ptgs2.

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Section: Discussionmentioning

confidence: 99%

miR-212-5p attenuates ferroptotic neuronal death after traumatic brain injury by targeting Ptgs2

et al. 2019

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“…Activating transcription factor 4 (ATF4) is an essential mediator of endoplasmic reticulum (ER) stress (Bi et al, 2005). Besides ER stress damages, diverse microenvironmental stimuli, including exposure to ferroptosis inducers, can also induce its elevation (Lee, Lee, Choudry, Bartlett, & Lee, 2018). ATF4 has recently been demonstrated to act as a negative regulator in ferroptosis (Chen, Fan et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA‐214‐3p enhances erastin‐induced ferroptosis by targeting ATF4 in hepatoma cells

Bai

Liang

Zhu

et al. 2020

Journal Cellular Physiology

102

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Primary liver cancer is the second most frequent cause of cancer‐related deaths. Ferroptosis, a recognized form of regulated cell death, recently gains attention. MicroRNA‐214‐3p (miR‐214) plays a regulatory role in hepatocarcinogenesis. However, the role of miR‐214 in cellular ferroptosis is unclear. This study aimed at elucidating whether miR‐214 could regulate ferroptosis of liver cancer. In vitro, HepG2 and Hep3B cancer cells were treated with erastin, a ferroptosis inducer, and then erastin was demonstrated to suppress the cell viability. Moreover, pre‐miR‐214 overexpression caused that HepG2 and Hep3B cells were more susceptible to erastin, whereas anti‐miR‐214 sponge showed the opposite effect. Additionally, pre‐miR‐214 overexpression increased the malondialdehyde and reactive oxygen species levels, upregulated Fe2+ concentration, and decreased glutathione levels in cancer cells exposed to erastin. Further, erastin enhanced the activation of transcription factor 4 (ATF4) in HepG2 and Hep3B cells, and pre‐miR‐214 overexpression inhibited ATF4 expression. The luciferase reporter data validated ATF4 as a direct target of miR‐214. Cancer cells transfected with ATF4 overexpression plasmid rendered lower susceptible to miR‐214‐induced ferroptotic death. In vivo, erastin significantly reduced the size and weight of xenografted tumors, and miR‐214 elevated the ferroptosis‐promoting effects of erastin and decreased ATF4 expression. In summary, our study demonstrates that the ferroptosis‐promoting effects of miR‐214 in hepatoma cells are attributed at least to its inhibitory effects on ATF4, which may provide a new target for therapy of hepatoma regarding ferroptosis.

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“…Ferroptosis is considered distinct from other forms of cell death such as necrosis and apoptosis. Nevertheless, several studies have reported a cross-talk between ferroptosis and apoptosis, especially related to ER-stress 49,50 . Thus, to investigate the alteration of ferroptosis by iron overload, we assessed ferroptotic markers, such as the levels of GPX activity and lipid peroxidation, in hippocampal tissues from HFe-fed WT and Prx5 −/− mice with or without NAC.…”

Section: Discussionmentioning

confidence: 99%

Peroxiredoxin 5 deficiency exacerbates iron overload-induced neuronal death via ER-mediated mitochondrial fission in mouse hippocampus

et al. 2020

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Iron is an essential element for cellular functions, including those of neuronal cells. However, an imbalance of iron homeostasis, such as iron overload, has been observed in several neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Iron overload causes neuronal toxicity through mitochondrial fission, dysregulation of Ca 2+ , ER-stress, and ROS production. Nevertheless, the precise mechanisms between iron-induced oxidative stress and iron toxicity related to mitochondria and endoplasmic reticulum (ER) in vivo are not fully understood. Here, we demonstrate the role of peroxiredoxin 5 (Prx5) in iron overload-induced neurotoxicity using Prx5-deficient mice. Iron concentrations and ROS levels in mice fed a high iron diet were significantly higher in Prx5 −/− mice than wildtype (WT) mice. Prx5 deficiency also exacerbated ER-stress and ER-mediated mitochondrial fission via Ca 2+ /calcineurin-mediated dephosphorylation of Drp1 at Serine 637. Moreover, immunoreactive levels of cleaved caspase3 in the CA3 region of the hippocampus were higher in iron-loaded Prx5 −/− mice than WT mice. Furthermore, treatment with N-acetylcysteine, a reactive oxygen species (ROS) scavenger, attenuated iron overload-induced hippocampal damage by inhibiting ROS production, ER-stress, and mitochondrial fission in iron-loaded Prx5 −/− mice. Therefore, we suggest that iron overload-induced oxidative stress and ER-mediated mitochondrial fission may be essential for understanding ironmediated neuronal cell death in the hippocampus and that Prx5 may be useful as a novel therapeutic target in the treatment of iron overload-mediated diseases and neurodegenerative diseases.

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Ferroptosis-Induced Endoplasmic Reticulum Stress: Cross-talk between Ferroptosis and Apoptosis

Cited by 276 publications

References 47 publications

miR-212-5p attenuates ferroptotic neuronal death after traumatic brain injury by targeting Ptgs2

miR-212-5p attenuates ferroptotic neuronal death after traumatic brain injury by targeting Ptgs2

MicroRNA‐214‐3p enhances erastin‐induced ferroptosis by targeting ATF4 in hepatoma cells

Peroxiredoxin 5 deficiency exacerbates iron overload-induced neuronal death via ER-mediated mitochondrial fission in mouse hippocampus

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