Labile iron, ROS, and cell death are prominently induced by haemin, but not by non-transferrin-bound iron

AbstractSodium iodate (SI) is a widely used oxidant for generating retinal degeneration models by inducing the death of retinal pigment epithelium (RPE) cells. However, the mechanism of RPE cell death induced by SI remains unclear. In this study, we investigated the necrotic features of cultured human retinal pigment epithelium (ARPE-19) cells treated with SI and found that apoptosis or necroptosis was not the major death pathway. Instead, the death process was accompanied by significant elevation of intracellular labile iron level, ROS, and lipid peroxides which recapitulated the key features of ferroptosis. Ferroptosis inhibitors deferoxamine mesylate (DFO) and ferrostatin-1(Fer-1) partially prevented SI-induced cell death. Further studies revealed that SI treatment did not alter GPX4 (glutathione peroxidase 4) expression, but led to the depletion of reduced thiol groups, mainly intracellular GSH (reduced glutathione) and cysteine. The study on iron trafficking demonstrated that iron influx was not altered by SI treatment but iron efflux increased, indicating that the increase in labile iron was likely due to the release of sequestered iron. This hypothesis was verified by showing that SI directly promoted the release of labile iron from a cell-free lysate. We propose that SI depletes GSH, increases ROS, releases labile iron, and boosts lipid damage, which in turn results in ferroptosis in ARPE-19 cells.

Download Full-text

Susceptibility of Skin Cells to UVA-induced Necrotic Cell Death Reflects the Intracellular Level of Labile Iron

Journal of Investigative Dermatology ◽

10.1111/j.0022-202x.2004.23419.x ◽

2004 ◽

Vol 123 (4) ◽

pp. 771-780 ◽

Cited By ~ 36

Author(s):

Julia Li Zhong ◽

Anthie Yiakouvaki ◽

Patricia Holley ◽

Rex M. Tyrrell ◽

Charareh Pourzand

Keyword(s):

Cell Death ◽

Necrotic Cell Death ◽

Intracellular Level ◽

Necrotic Cell ◽

Skin Cells ◽

Labile Iron

Download Full-text

Downregulation of ferritin heavy chain increases labile iron pool, oxidative stress and cell death in cardiomyocytes

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2008.09.714 ◽

2009 ◽

Vol 46 (1) ◽

pp. 59-66 ◽

Cited By ~ 29

Author(s):

Shigemiki Omiya ◽

Shungo Hikoso ◽

Yukiko Imanishi ◽

Atsuhiro Saito ◽

Osamu Yamaguchi ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Heavy Chain ◽

Labile Iron Pool ◽

Ferritin Heavy Chain ◽

Labile Iron ◽

Iron Pool

Download Full-text

GOT1 inhibition promotes pancreatic cancer cell death by ferroptosis

Nature Communications ◽

10.1038/s41467-021-24859-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Daniel M. Kremer ◽

Barbara S. Nelson ◽

Lin Lin ◽

Emily L. Yarosz ◽

Christopher J. Halbrook ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Death ◽

Cancer Metabolism ◽

Redox Balance ◽

Cancer Cell Death ◽

Antioxidant Function ◽

Dependent Form ◽

Catabolic State ◽

Labile Iron ◽

Active Research

AbstractCancer metabolism is rewired to support cell survival in response to intrinsic and environmental stressors. Identification of strategies to target these adaptions is an area of active research. We previously described a cytosolic aspartate aminotransaminase (GOT1)-driven pathway in pancreatic cancer used to maintain redox balance. Here, we sought to identify metabolic dependencies following GOT1 inhibition to exploit this feature of pancreatic cancer and to provide additional insight into regulation of redox metabolism. Using pharmacological methods, we identify cysteine, glutathione, and lipid antioxidant function as metabolic vulnerabilities following GOT1 withdrawal. We demonstrate that targeting any of these pathways triggers ferroptosis, an oxidative, iron-dependent form of cell death, in GOT1 knockdown cells. Mechanistically, we reveal that GOT1 inhibition represses mitochondrial metabolism and promotes a catabolic state. Consequently, we find that this enhances labile iron availability through autophagy, which potentiates the activity of ferroptotic stimuli. Overall, our study identifies a biochemical connection between GOT1, iron regulation, and ferroptosis.

Download Full-text

Transcriptional Repression of Ferritin Light Chain Increases Ferroptosis Sensitivity in Lung Adenocarcinoma

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.719187 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yikun Wang ◽

Shiyu Qiu ◽

Hong Wang ◽

Jiangtao Cui ◽

Xiaoting Tian ◽

...

Keyword(s):

Lipid Peroxidation ◽

Cell Death ◽

Lung Adenocarcinoma ◽

Light Chain ◽

Transcriptional Repression ◽

Target Genes ◽

Intracellular Iron ◽

Factors Affecting ◽

Normal Tissues ◽

Labile Iron

Ferroptosis is an iron- and lipid peroxidation-dependent form of regulated cell death. The release of labile iron is one of the important factors affecting sensitivity to ferroptosis. Yes-associated protein (YAP) controls intracellular iron levels by affecting the transcription of ferritin heavy chain (FTH) and transferrin receptor (TFRC). However, whether YAP regulates iron metabolism through other target genes remains unknown. Here, we observed that the system Xc– inhibitor erastin inhibited the binding of the WW domain and PSY motif between YAP and transcription factor CP2 (TFCP2), and then suppressed the transcription of ferritin light chain (FTL) simultaneously mediated by YAP, TFCP2 and forkhead box A1 (FOXA1). Furthermore, inhibition of FTL expression abrogated ferroptosis-resistance in cells with sustained YAP expression. Unlike FTH, which exhibited first an increase and then a decrease in transcription, FTL transcription continued to decline after the addition of erastin, and a decrease in lysine acetyltransferase 5 (KAT5)-dependent acetylation of FTL was also observed. In lung adenocarcinoma (LUAD) tissues, lipid peroxidation and labile iron decreased, while YAP, TFCP2 and FTL increased compared to their adjacent normal tissues, and the lipid peroxidation marker 4-hydroxynonenal (4-HNE) was negatively correlated with the level of FTL or the degree of LUAD malignancy, but LUAD tissues with lower levels of 4-HNE showed a higher sensitivity to ferroptosis. In conclusion, the findings from this study indicated that the suppression of FTL transcription through the inhibition of the YAP-TFCP2-KAT5 complex could be another mechanism for elevating ferroptosis sensitivity and inducing cell death, and ferroptotic therapy is more likely to achieve better results in LUAD patients with a lower degree of lipid peroxidation.

Download Full-text

Downregulation of ferritin heavy chain increases labile iron pool, oxidative stress and cell death in cardimyocytes

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2008.09.659 ◽

2008 ◽

Vol 45 (4) ◽

pp. S21

Author(s):

Shigemiki Omiya ◽

Shungo Hikoso ◽

Kinya Otsu

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Heavy Chain ◽

Labile Iron Pool ◽

Ferritin Heavy Chain ◽

Labile Iron ◽

Iron Pool

Download Full-text

MYCN mediates TFRC-dependent ferroptosis and reveals vulnerabilities in neuroblastoma

Cell Death and Disease ◽

10.1038/s41419-021-03790-w ◽

2021 ◽

Vol 12 (6) ◽

Author(s):

Yuxiong Lu ◽

Qing Yang ◽

Yubin Su ◽

Yin Ji ◽

Guobang Li ◽

...

Keyword(s):

Cell Death ◽

Iron Uptake ◽

Lipid Peroxide ◽

Labile Iron Pool ◽

Cellular Iron ◽

Transferrin Receptor 1 ◽

Labile Iron ◽

Iron Pool ◽

Selective Sensitivity ◽

The Relationship

AbstractMYCN amplification is tightly associated with the poor prognosis of pediatric neuroblastoma (NB). The regulation of NB cell death by MYCN represents an important aspect, as it directly contributes to tumor progression and therapeutic resistance. However, the relationship between MYCN and cell death remains elusive. Ferroptosis is a newly identified cell death mode featured by lipid peroxide accumulation that can be attenuated by GPX4, yet whether and how MYCN regulates ferroptosis are not fully understood. Here, we report that MYCN-amplified NB cells are sensitive to GPX4-targeting ferroptosis inducers. Mechanically, MYCN expression reprograms the cellular iron metabolism by upregulating the expression of TFRC, which encodes transferrin receptor 1 as a key iron transporter on the cell membrane. Further, the increased iron uptake promotes the accumulation of labile iron pool, leading to enhanced lipid peroxide production. Consistently, TFRC overexpression in NB cells also induces selective sensitivity to GPX4 inhibition and ferroptosis. Moreover, we found that MYCN fails to alter the general lipid metabolism and the amount of cystine imported by System Xc(−) for glutathione synthesis, both of which contribute to ferroptosis in alternative contexts. In conclusion, NB cells harboring MYCN amplification are prone to undergo ferroptosis conferred by TFRC upregulation, suggesting that GPX4-targeting ferroptosis inducers or TFRC agonists can be potential strategies in treating MYCN-amplified NB.

Download Full-text