scholarly journals Lipid peroxidation and the subsequent cell death transmitting from ferroptotic cells to neighboring cells

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Hironari Nishizawa ◽  
Mitsuyo Matsumoto ◽  
Guan Chen ◽  
Yusho Ishii ◽  
Keisuke Tada ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Lipid Peroxide ◽  
Nih3t3 Cells ◽  
Regulated Cell Death ◽  
Primary Mouse ◽  
Ischemic Diseases ◽  
A Chain ◽  
Dying Cells

AbstractFerroptosis is a regulated cell death due to the iron-dependent accumulation of lipid peroxide. Ferroptosis is known to constitute the pathology of ischemic diseases, neurodegenerative diseases, and steatohepatitis and also works as a suppressing mechanism against cancer. However, how ferroptotic cells affect surrounding cells remains elusive. We herein report the transfer phenomenon of lipid peroxidation and cell death from ferroptotic cells to nearby cells that are not exposed to ferroptotic inducers (FINs). While primary mouse embryonic fibroblasts (MEFs) and NIH3T3 cells contained senescence-associated β-galactosidase (SA-β-gal)-positive cells, they were decreased upon induction of ferroptosis with FINs. The SA-β-gal decrease was inhibited by ferroptotic inhibitors and knockdown of Atg7, pointing to the involvement of lipid peroxidation and activated autophagosome formation during ferroptosis. A transfer of cell culture medium of cells treated with FINs, type 1 or 2, caused the reduction in SA-β-gal-positive cells in recipient cells that had not been exposed to FINs. Real-time imaging of Kusabira Orange-marked reporter MEFs cocultured with ferroptotic cells showed the generation of lipid peroxide and deaths of the reporter cells. These results indicate that lipid peroxidation and its aftereffects propagate from ferroptotic cells to surrounding cells, even when the surrounding cells are not exposed to FINs. Ferroptotic cells are not merely dying cells but also work as signal transmitters inducing a chain of further ferroptosis.

scholarly journals Molecular Mechanisms of Ferroptosis and Its Roles in Hematologic Malignancies

2021 ◽  
Vol 11 ◽  
Author(s):  
Yan Zhao ◽  
Zineng Huang ◽  
Hongling Peng
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Hematological Malignancies ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Lipid Peroxide ◽  
Kidney Injury ◽  
Hematologic Malignancies ◽  
Regulated Cell Death ◽  
Normal Metabolism

Cell death is essential for the normal metabolism of human organisms. Ferroptosis is a unique regulated cell death (RCD) mode characterized by excess accumulation of iron-dependent lipid peroxide and reactive oxygen species (ROS) compared with other well-known programmed cell death modes. It has been currently recognized that ferroptosis plays a rather important role in the occurrence, development, and treatment of traumatic brain injury, stroke, acute kidney injury, liver damage, ischemia–reperfusion injury, tumor, etc. Of note, ferroptosis may be explained by the expression of various molecules and signaling components, among which iron, lipid, and amino acid metabolism are the key regulatory mechanisms of ferroptosis. Meanwhile, tumor cells of hematological malignancies, such as leukemia, lymphoma, and multiple myeloma (MM), are identified to be sensitive to ferroptosis. Targeting potential regulatory factors in the ferroptosis pathway may promote or inhibit the disease progression of these malignancies. In this review, a systematic summary was conducted on the key molecular mechanisms of ferroptosis and the current potential relationships of ferroptosis with leukemia, lymphoma, and MM. It is expected to provide novel potential therapeutic approaches and targets for hematological malignancies.

scholarly journals STING1 Promotes Ferroptosis Through MFN1/2-Dependent Mitochondrial Fusion

2021 ◽  
Vol 9 ◽  
Author(s):  
Changfeng Li ◽  
Jiao Liu ◽  
Wen Hou ◽  
Rui Kang ◽  
Daolin Tang
Keyword(s):  
Pancreatic Cancer ◽  
Lipid Peroxidation ◽  
Cell Death ◽  
Mitochondrial Fusion ◽  
Antioxidant Defenses ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancer Cells ◽  
Regulated Cell Death ◽  
Potential Strategy

Ferroptosis is a type of iron-dependent regulated cell death caused by the disruption that occurs when oxidative stress and antioxidant defenses interact, and then driven by lipid peroxidation and subsequent plasma membrane ruptures. The regulation of ferroptosis involves many factors, including the crosstalk between subcellular organelles, such as mitochondria, endoplasmic reticulum (ER), lysosomes, lipid droplets, and peroxisomes. Here, we show that the ER protein STING1 (also known as STING or TMEM173) promotes ferroptosis in human pancreatic cancer cell lines by increasing MFN1/2-dependent mitochondrial fusion, but not mitophagy-mediated mitochondrial removal. The classic ferroptosis inducer erastin, but not sulfasalazine, induces the accumulation of STING1 in the mitochondria, where it binds to MFN1/2 to trigger mitochondrial fusion, leading to subsequent reactive oxygen species production and lipid peroxidation. Consequently, in vitro or xenograft mouse models show that the genetic depletion of STING1 or MFN1/2 (but not the mitophagy regulator PINK1 or PRKN) reduces the sensitivity of pancreatic cancer cells to ferroptosis. These findings not only establish a new mitochondrial fusion-dependent cell death mechanism, but also indicate a potential strategy for enhancing ferroptosis-based therapy.

scholarly journals The adaptive role of cell death in yeast communities stressed with macrolide antifungals

2021 ◽  
Author(s):  
Nataliia Kireeva ◽  
Sviatoslav S Sokolov ◽  
Ekaterina A Smirnova ◽  
Kseniia V Galkina ◽  
Fedor F Severin ◽  
...  
Keyword(s):  
Cell Death ◽  
Extreme Case ◽  
Yeast Cells ◽  
Alarm Signal ◽  
Community Resistance ◽  
Naturally Occurring ◽  
Regulated Cell Death ◽  
Yeast Community ◽  
Dying Cells

Microorganisms cooperate with each other to protect themselves from environmental stressors. An extreme case of such cooperation is regulated cell death for the benefit of other cells. Dying cells can provide surviving cells with nutrients or induce their stress-response by transmitting an alarm signal; however, the role of dead cells in microbial communities is unclear. Here we searched for types of stressors the protection from which can be achieved by death of a subpopulation of cells. Thus, we compared the survival of Saccharomyces cerevisiae cells upon exposure to various stressors in the presence of additionally supplemented living versus dead cells. We found that dead cells contribute to yeast community resistance against macrolide antifungals (e.g. amphotericin B [AmB] and filipin) to a greater extent than living cells. Dead yeast cells absorbed more macrolide filipin than control cells because they exposed intracellular sterol-rich membranes. We also showed that, upon the addition of lethal concentrations of AmB, supplementation with AmB-sensitive cells but not with AmB-resistant cells enabled the survival of wild-type cells. Together, our data suggests that cell-to-cell heterogeneity in sensitivity to AmB can be an adaptive mechanism helping yeast communities to resist macrolides, which are naturally occurring antifungal agents.

scholarly journals Posttranslational Modifications in Ferroptosis

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Xiang Wei ◽  
Xin Yi ◽  
Xue-Hai Zhu ◽  
Ding-Sheng Jiang
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Posttranslational Modifications ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Degenerative Diseases ◽  
Regulated Cell Death ◽  
Parkinson’S Diseases ◽  
Apoptosis Inducing Factor ◽  
Long Chain

Ferroptosis was first coined in 2012 to describe the form of regulated cell death (RCD) characterized by iron-dependent lipid peroxidation. To date, ferroptosis has been implicated in many diseases, such as carcinogenesis, degenerative diseases (e.g., Huntington’s, Alzheimer’s, and Parkinson’s diseases), ischemia-reperfusion injury, and cardiovascular diseases. Previous studies have identified numerous targets involved in ferroptosis; for example, acyl-CoA synthetase long-chain family member 4 (ACSL4) and p53 induce while glutathione peroxidase 4 (GPX4) and apoptosis-inducing factor mitochondria-associated 2 (AIFM2, also known as FSP1) inhibit ferroptosis. At least three major pathways (the glutathione-GPX4, FSP1-coenzyme Q10 (CoQ10), and GTP cyclohydrolase-1- (GCH1-) tetrahydrobiopterin (BH4) pathways) have been identified to participate in ferroptosis regulation. Recent advances have also highlighted the crucial roles of posttranslational modifications (PTMs) of proteins in ferroptosis. Here, we summarize the recently discovered knowledge regarding the mechanisms underlying ferroptosis, particularly the roles of PTMs in ferroptosis regulation.

scholarly journals Foxos Suppress Lipid Peroxidation to Promote AML Progression and Chemotherapy Resistance

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1861-1861
Author(s):  
Turan Aghayev ◽  
Chun Zhou ◽  
Alyssa Klein ◽  
Esteban Martinez ◽  
Claudia Scholl ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Chemotherapy Resistance ◽  
Lipid Peroxide ◽  
Lipid Peroxides ◽  
Intracellular Lipid ◽  
Redox Biology ◽  
Intracellular Ros ◽  
Intracellular Redox

Abstract Over 30% of acute myeloid leukemia (AML) patients do not respond to first-line chemotherapy, and a significant portion of patients that do initially respond subsequently relapse with resistant disease. These unsatisfactory outcomes indicate that AML cells either rapidly evolve or inherently possess mechanisms for evading standard chemotherapeutic approaches. Several studies have suggested that AML cells utilize pathways that regulate intracellular redox biology to promote chemotherapy resistance; however, the precise pathways governing resistance and redox biology in AML have yet to be fully determined. We recently discovered that the FOXO family of transcription factors, which have been traditionally considered tumor suppressor genes, actually support AML cell survival and the differentiation blockade. Specifically, we observed that the expression of FOXO1 and FOXO3 are significantly increased in approximately 40% of primary human AML samples (p<0.0001) and that short hairpin RNA (shRNA)-mediated inhibition of FOXO3 caused human AML cells to acquire characteristics of myeloid differentiation such as increased CD11b expression, cytoplasmic volume, size and granularity. Moreover, we also found that compound ablation of the FoxO family members FoxO1, FoxO3 and FoxO4 significantly extends disease latency and improves survival (p=0.0009) in a murine model of AML driven by the leukemogenic allele MLL-AF9. Previous studies have shown that, in variety of cell types, FOXOs influence the intracellular redox environment by suppressing the production of reactive oxygen species (ROS). Therefore, to determine the molecular role of FOXOs in AML, we initially focused on the impact of FOXO inhibition on AML cell redox biology. Using fluorogenic probes that detect either total intracellular ROS content (CellRox) or superoxide production (MitoSox), we found that shRNA-mediated inhibition of FOXO3 did not affect total levels of intracellular ROS or superoxides. However, using a lipid peroxidation sensor (BODIPY¨ 581/591 C11), we did observe that two distinct FOXO3-targeting shRNAs increased both homeostatic and stress-induced levels of lipid peroxides in AML cells (shFOXO3-1, p=0.0004; shFOXO3-2, p=0.0023). Consistent with this, we also found that AML cells treated with a chemical inhibitor of FOXOs (AS1842856) display increased steady-state levels of intracellular lipid peroxides (p=0.0076) as well as increased signs of differentiation (CD11b and morphological changes) and death (Annexin V staining). To elucidate the importance of lipid peroxidation in AML, we evaluated how two chemical anti-oxidants, N-acetyl-L-cysteine (NAC) and butylated hydroxyanisole (BHA), impact the anti-leukemia effects and increased lipid peroxidation mediated by FOXO inhibition. From these analyses, we have observed that BHA treatment suppresses lipid peroxide production and partly blocks AML cell death induced by shRNA-mediated FOXO3 inhibition (shFOXO3-1, p=0.0001; shFOXO3-2, p<0.0001). Interestingly, NAC treatment, which does protect healthy hematopoietic stem and progenitor cells from FOXO inhibition, is unable to reverse the anti-leukemia effects or lipid peroxidation induced by FOXO inhibition, suggesting that FOXOs may differentially regulate redox biology between normal and malignant hematopoietic progenitors. Both basic and clinical studies have shown that anthracyclines such as daunorubicin (DNR) induce lipid peroxidation; however, the role of lipid peroxidation in chemotherapy effectiveness is largely unknown. We have discovered that co-treatment of AML cells with DNR and BHA (but not NAC) completely blocks the cytotoxic effects of DNR (p<0.0001), suggesting that suppression of lipid peroxides could promote chemotherapy resistance. Consistent with this idea, we have observed that shRNA-mediated inhibition of FOXO3 enhance DNR-mediated AML cell death (p<0.0001), whereas enforced expression of FOXO3 protects human AML cells from DNR cytotoxicity (p=0.003). Collectively, these results suggest that FOXOs are critical mediators of AML progression and chemotherapy resistance by directly regulating intracellular lipid peroxide levels. Disclosures No relevant conflicts of interest to declare.

scholarly journals Ferroptosis: The Silver Lining of Cancer Therapy

2021 ◽  
Vol 9 ◽  
Author(s):  
Zhengming Tang ◽  
Zhijie Huang ◽  
Yisheng Huang ◽  
Yuanxin Chen ◽  
Mingshu Huang ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Cancer Therapy ◽  
Cancer Cells ◽  
Future Perspectives ◽  
Major Focus ◽  
Therapeutic Modalities ◽  
Regulated Cell Death ◽  
Physiological Properties ◽  
Silver Lining

Regulatory cell death has been a major focus area of cancer therapy research to improve conventional clinical cancer treatment (e.g. chemotherapy and radiotherapy). Ferroptosis, a novel form of regulated cell death mediated by iron-dependent lipid peroxidation, has been receiving increasing attention since its discovery in 2012. Owing to the highly iron-dependent physiological properties of cancer cells, targeting ferroptosis is a promising approach in cancer therapy. In this review, we summarised the characteristics of ferroptotic cells, associated mechanisms of ferroptosis occurrence and regulation and application of the ferroptotic pathway in cancer therapy, including the use of ferroptosis in combination with other therapeutic modalities. In addition, we presented the challenges of using ferroptosis in cancer therapy and future perspectives that may provide a basis for further research.

scholarly journals Flipping the dogma – phosphatidylserine in non-apoptotic cell death

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Inbar Shlomovitz ◽  
Mary Speir ◽  
Motti Gerlic
Keyword(s):  
Cell Death ◽  
Inflammatory Cell ◽  
Unique Feature ◽  
Apoptotic Cell ◽  
Apoptotic Cells ◽  
Complete Understanding ◽  
Cell Death Pathways ◽  
Regulated Cell Death ◽  
Dying Cells ◽  
Outer Plasma Membrane

Abstract The exposure of phosphatidylserine (PS) on the outer plasma membrane has long been considered a unique feature of apoptotic cells. Together with other “eat me” signals, it enables the recognition and phagocytosis of dying cells (efferocytosis), helping to explain the immunologically-silent nature of apoptosis. Recently, however, PS exposure has also been reported in non-apoptotic forms of regulated inflammatory cell death, such as necroptosis, challenging previous dogma. In this review, we outline the evidence for PS exposure in non-apoptotic cells and extracellular vesicles (EVs), and discuss possible mechanisms based on our knowledge of apoptotic-PS exposure. In addition, we examine the outcomes of non-apoptotic PS exposure, including the reversibility of cell death, efferocytosis, and consequent inflammation. By examining PS biology, we challenge the established approach of distinguishing apoptosis from other cell death pathways by AnnexinV staining of PS externalization. Finally, we re-evaluate how PS exposure is thought to define apoptosis as an immunologically silent process distinct from other non-apoptotic and inflammatory cell death pathways. Ultimately, we suggest that a complete understanding of how regulated cell death processes affect the immune system is far from being fully elucidated. Graphical abstract

Ferroptosis Is Regulated by Mitochondria in Neurodegenerative Diseases

2020 ◽  
Vol 20 (1) ◽  
pp. 20-34 ◽  
Author(s):  
Juepu Zhou ◽  
Yao Jin ◽  
Yuhong Lei ◽  
Tianyi Liu ◽  
Zheng Wan ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Nervous System ◽  
Neurodegenerative Diseases ◽  
Iron Homeostasis ◽  
Cell Metabolism ◽  
Lipid Peroxide ◽  
Mitochondrial Damage ◽  
Mitochondrial Activity ◽  
Dependent Form

Background: Neurodegenerative diseases are characterized by a gradual decline in motor and/or cognitive function caused by the selective degeneration and loss of neurons in the central nervous system, but their pathological mechanism is still unclear. Previous research has revealed that many forms of cell death, such as apoptosis and necrosis, occur in neurodegenerative diseases. Research in recent years has noticed that there is a new type of cell death in neurodegenerative diseases: ferroptosis. An increasing body of literature provides evidence for an involvement of ferroptosis in neurodegenerative diseases. Summary: In this article, we review a new form of cell death in neurodegenerative diseases: ferroptosis. Ferroptosis is defined as an iron-dependent form of regulated cell death, which occurs through the lethal accumulation of lipid-based reactive oxygen species when glutathione-dependent lipid peroxide repair systems are compromised. Several salient and established features of neurodegenerative diseases (including lipid peroxidation and iron dyshomeostasis) are consistent with ferroptosis, which means that ferroptosis may be involved in the progression of neurodegenerative diseases. In addition, as the center of energy metabolism in cells, mitochondria are also closely related to the regulation of iron homeostasis in the nervous system. At the same time, neurodegenerative diseases are often accompanied by degeneration of mitochondrial activity. Mitochondrial damage has been found to be involved in lipid peroxidation and iron dyshomeostasis in neurodegenerative diseases. Key Messages: Based on the summary of the related mechanisms of ferroptosis, we conclude that mitochondrial damage may affect neurodegenerative diseases by regulating many aspects of ferroptosis, including cell metabolism, iron dyshomeostasis, and lipid peroxidation.

scholarly journals Characterization of ferroptosis in kidney tubular cell death under diabetic conditions

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Seonghun Kim ◽  
Shin-Wook Kang ◽  
Jeongho Joo ◽  
Seung Hyeok Han ◽  
Huiyoon Shin ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Diabetic Nephropathy ◽  
Transforming Growth Factor ◽  
Lipid Peroxide ◽  
Tubular Cell ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Glutathione Concentration ◽  
Tgf Β1

AbstractKidney tubular cell death induced by transforming growth factor-β1 (TGF-β1) is known to contribute to diabetic nephropathy, a major complication of diabetes. Caspase-3-dependent apoptosis and caspase-1-dependent pyroptosis are also involved in tubular cell death under diabetic conditions. Recently, ferroptosis, an atypical form of iron-dependent cell death, was reported to cause kidney disease, including acute kidney injury. Ferroptosis is primed by lipid peroxide accumulation through the cystine/glutamate antiporter system Xc− (xCT) and glutathione peroxidase 4 (GPX4)-dependent mechanisms. The aim of this study was to evaluate the role of ferroptosis in diabetes-induced tubular injury. TGF-β1-stimulated proximal tubular epithelial cells and diabetic mice models were used for in vitro and in vivo experiments, respectively. xCT and GPX4 expression, cell viability, glutathione concentration, and lipid peroxidation were quantified to indicate ferroptosis. The effect of ferroptosis inhibition was also assessed. In kidney biopsy samples from diabetic patients, xCT and GPX4 mRNA expression was decreased compared to nondiabetic samples. In TGF-β1-stimulated tubular cells, intracellular glutathione concentration was reduced and lipid peroxidation was enhanced, both of which are related to ferroptosis-related cell death. Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, alleviated TGF-β1-induced ferroptosis. In diabetic mice, kidney mRNA and protein expressions of xCT and GPX4 were reduced compared to control. Kidney glutathione concentration was decreased, while lipid peroxidation was increased in these mice, and these changes were alleviated by Fer-1 treatment. Ferroptosis is involved in kidney tubular cell death under diabetic conditions. Ferroptosis inhibition could be a therapeutic option for diabetic nephropathy.

Theoretical insights into the mechanism of ferroptosis suppression via inactivation of a lipid peroxide radical by liproxstatin-1

2017 ◽  
Vol 19 (20) ◽  
pp. 13153-13159 ◽  
Author(s):  
Xiehuang Sheng ◽  
Chao Shan ◽  
Jianbiao Liu ◽  
Jintong Yang ◽  
Bin Sun ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Apoptotic Cell ◽  
Lipid Peroxide ◽  
Membrane Lipid ◽  
Peroxide Radical ◽  
Membrane Lipid Peroxidation ◽  
Pathological Conditions ◽  
Dependent Form ◽  
The Brain

Ferroptosis is a recently discovered iron-dependent form of non-apoptotic cell death caused by the accumulation of membrane lipid peroxidation products, which is involved in various pathological conditions of the brain, kidneys, liver and heart.

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