Hypoxia inhibits ferritinophagy, increases mitochondrial ferritin, and protects from ferroptosis

Fuhrmann, Dominik C.; Mondorf, A. W.; Beifuß, Josefine; Jung, Michaela; Brüne, Bernhard

doi:10.1016/j.redox.2020.101670

Cited by 232 publications

(171 citation statements)

References 43 publications

Supporting

Mentioning

149

Contrasting

Order By: Relevance

“…However, our experiment with iron co-treatment demonstrated that iron potentiates the effect of RSL3. Recently it was shown that knockdown of FTH and mitochondrial ferritin sensitized human macrophages and fibrosarcoma cells for RSL3-induced ferroptosis, demonstrating that ferritin protects cells also from ferroptotic cell death induced by GPX4 inhibition [53]. Even if it is partially in disagreement with our results where cells with higher ferritin level (NCOA4 KO cell line) are more sensitive for RSL3-induced ferroptosis, it may suggest that the observed effect in our cell clones may be due to the other mechanism unrelated to ferritin level.…”

Section: Discussionmentioning

confidence: 99%

NCOA4-mediated ferritinophagy promotes ferroptosis induced by erastin, but not by RSL3 in HeLa cells

Gryzik

Asperti

Denardo

et al. 2021

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

View full text Add to dashboard Cite

Ferroptosis is a regulated cell death characterized by a lethal accumulation of lipid peroxides due to an increase of intracellular iron and a decrease of antioxidant capacity. The reduction of antioxidant activity is obtained by using chemical agents, such as erastin and RSL3, the first one inhibiting the transmembrane cystine-glutamate antiporter causing a cysteine and glutathione depletion and the second one inactivating directly the glutathione peroxidase 4 (GPX4) respectively. The role of iron and its related proteins in supporting the formation of lipid peroxides, is not completely understood hence to try to shed light on it we generated HeLa clones with altered ferritinophagy, the ferritin degradation process, by knocking-out or overexpressing Nuclear Receptor Coactivator 4 (NCOA4), the ferritin autophagic cargo-receptor. NCOA4 deficiency abolished ferritinophagy increasing ferritin level and making the cells more resistant to erastin, but unexpectedly more sensitive to RSL3. Interestingly, we found that erastin promoted ferritinophagy in HeLa cells expressing NCOA4, increasing the free iron, lipid peroxidation and the sensitivity to ferroptosis. In contrast, RSL3 did not modulate ferritinophagy, while NCOA4 overexpression delayed RSL3-induced cell death suggesting that RSL3 mechanism of action is independent of ferritin degradation process. Therefore, the ferritin-iron release in the execution of ferroptosis seems to depend on the inducing compound, its target and downstream pathway of cell death activation.

show abstract

Section: Discussionmentioning

confidence: 99%

NCOA4-mediated ferritinophagy promotes ferroptosis induced by erastin, but not by RSL3 in HeLa cells

Gryzik

Asperti

Denardo

et al. 2021

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

View full text Add to dashboard Cite

show abstract

“…Several pathways have been implicated in the activation of NCOA4 expression, ferritinophagy, and ferroptosis. JNK pathway has been implicated in hypoxia‐regulated NCOA4 transcription by targeting microRNA 6862‐5p, and phosphoinositide 3‐kinase is also involved in the transcription of NCOA4 in a hypoxic condition, 38 while c‐JUN N‐terminal kinase and p38 activation were involved in cell death of erastin‐treated HL‐60 cells 39 . Cold stress triggers ferroptosis by the ASK1‐p38 MAPK pathway, 40 while our present study indicated that phosphorylation of p38 MAPK promoted NCOA4 expression in P .…”

Section: Discussionmentioning

confidence: 99%

NCOA4‐mediated ferritinophagy promoted inflammatory responses in periodontitis

Guo

Zhao

et al. 2021

J of Periodontal Research

View full text Add to dashboard Cite

Background/Objectives Iron homeostasis plays a crucial role in the combat against pathogen invasion. Ferrous iron can trigger generous production of reactive oxygen species (ROS) by Fenton reaction. Nuclear receptor coactivator 4 (NCOA4), a selective cargo receptor to deliver ferritin to lysosome, may trigger release of ferritin‐bound iron into the cytosol. The aim of the present study was to explore whether NCOA4‐mediated ferritinophagy participated in the pathogenesis of periodontitis, and its role in promoting the periodontal inflammation. Methods Inflamed and healthy periodontal tissues were harvested for immunobiological staining of ferritinophagy‐related genes in the periodontal tissues, while real‐time quantitative PCR (qPCR) was utilized to detect mRNA transcription. Periodontal ligament fibroblasts (PDLFs) were isolated and infected with Porphyromonas gingivalis. The mRNA transcription and protein expression of genes involved in the iron metabolism, including NCOA4, transferrin receptor 1 (TFR1), and ferroportin (SLC40A1) were detected by qPCR and western blot. Levels of labile iron pool and ROS production were detected by flow cytometry and confocal endoscopy. Small interference RNA was utilized to knock down NCOA4. Results Elevated expression of NCOA4, ferritin heavy chain, and light chain were observed in the diseased periodontal tissues. P. gingivalis infection promoted expression of TFR1, NCOA4, and microtubule‐associated protein 1‐light chain 3 B (LC3B), enhanced levels of intracellular labile iron pool and ROS production. NCOA4 knockdown reduced ROS generation in PDLFs in response to P. gingivalis and mitigated production of pro‐inflammatory monocyte chemoattractant protein‐1 and interleukin 6. P. gingivalis triggered activation of c‐Jun N‐terminal kinase (JNK) and p38 mitogen‐activated protein kinase signaling pathway. In addition, inhibitors of JNK, SP600125, and inhibitors of p38, SB203580 blocked NCOA4 transcription. Conclusion NCOA4‐ferritinophagy participated in the progress of periodontitis progression. P. gingvalis‐triggered ferritinophagy aggravated production of ROS and inflammatory responses in PDLFS. These findings suggest iron homeostasis plays an important role in the pathogenesis of periodontitis.

show abstract

“…miR-6862 is a relatively novel miRNA with its functions largely unknown. Fuhrmannet al, demonstrated that miR-6862 silenced nuclear receptor coactivator 4 (NCOA4) to inhibit mitochondrial ferritin (FTMT) formation [ 37 ]. Zhu et al, reported that miR-6862 expression is dysregulated in lung adenocarcinoma.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-6862 inhibition elevates sphingosine kinase 1 and protects neuronal cells from MPP+-induced apoptosis

Chen

et al. 2020

Aging

View full text Add to dashboard Cite

MPP + (1-methyl-4-phenylpyridinium)-induced dopaminergic neuronal cell apoptosis is associated with sphingosine kinase 1 (SphK1) inhibition. We here tested the potential effect of microRNA-6862 (miR-6862), a novel SphK1-targeting miRNA, on MPP + -induced cytotoxicity in neuronal cells. MiR-6862 locates in the cytoplasm of SH-SY5Y neuronal cells. It directly binds to SphK1 mRNA. In SH-SY5Y cells and HCN-2 cells, ectopic overexpression of miR-6862 decreased SphK13’-untranslated region luciferase reporter activity and downregulated its expression. miR-6862 inhibition exerted opposite activity and elevated SphK1 expression. In neuronal cells, MPP + -induced cell death was significantly inhibited through miR-6862 inhibition. Conversely, ectopic overexpression of miR-6862 or CRISPR/Cas9-induced SphK1 knockout augmented MPP + -induced apoptosis in the neuronal cells. Importantly, antagomiR-6862 failed to inhibit MPP + -induced apoptosis in SphK1-knockout SH-SY5Y cells. These results suggest that inhibition of miR-6862 induces SphK1 elevation and protects neuronal cells from MPP + -induced cell death.

show abstract

Hypoxia inhibits ferritinophagy, increases mitochondrial ferritin, and protects from ferroptosis

Cited by 232 publications

References 43 publications

NCOA4-mediated ferritinophagy promotes ferroptosis induced by erastin, but not by RSL3 in HeLa cells

NCOA4-mediated ferritinophagy promotes ferroptosis induced by erastin, but not by RSL3 in HeLa cells

NCOA4‐mediated ferritinophagy promoted inflammatory responses in periodontitis

MicroRNA-6862 inhibition elevates sphingosine kinase 1 and protects neuronal cells from MPP+-induced apoptosis

Contact Info

Product

Resources

About