Iron Metabolism: An Under Investigated Driver of Renal Pathology in Lupus Nephritis.
Wlazlo Ewa,Mehrad Borna,Morel Laurence,Scindia Yogesh
Frontiers in medicine
Nephritis is a common manifestation of systemic lupus erythematosus, a condition associated with inflammation and iron imbalance. Renal tubules are the work horse of the nephron. They contain a large number of mitochondria that require iron for oxidative phosphorylation, and a tight control of intracellular iron prevents excessive generation of reactive oxygen species. Iron supply to the kidney is dependent on systemic iron availability, which is regulated by the hepcidin-ferroportin axis. Most of the filtered plasma iron is reabsorbed in proximal tubules, a process that is controlled in part by iron regulatory proteins. This review summarizes tubulointerstitial injury in lupus nephritis and current understanding of how renal tubular cells regulate intracellular iron levels, highlighting the role of iron imbalance in the proximal tubules as a driver of tubulointerstitial injury in lupus nephritis. We propose a model based on the dynamic ability of iron to catalyze reactive oxygen species, which can lead to an accumulation of lipid hydroperoxides in proximal tubular epithelial cells. These iron-catalyzed oxidative species can also accentuate protein and autoantibody-induced inflammatory transcription factors leading to matrix, cytokine/chemokine production and immune cell infiltration. This could potentially explain the interplay between increased glomerular permeability and the ensuing tubular injury, tubulointerstitial inflammation and progression to renal failure in LN, and open new avenues of research to develop novel therapies targeting iron metabolism.
10.3389/fmed.2021.643686
Iron Homeostasis in Healthy Kidney and its Role in Acute Kidney Injury.
Scindia PhD Yogesh,Leeds Md Joseph,Swaminathan Md Sundararaman
Seminars in nephrology
Iron is required for key aspects of cellular physiology including mitochondrial function and DNA synthesis and repair. However, free iron is an aberration because of its ability to donate electrons, reduce oxygen, and generate reactive oxygen species. Iron-mediated cell injury or ferroptosis is a central player in the pathogenesis of acute kidney injury. There are several homeostatic proteins and pathways that maintain critical balance in iron homeostasis to allow iron's biologic functions yet avoid ferroptosis. Hepcidin serves as the master regulator of iron homeostasis through its ability to regulate ferroportin-mediated iron export and intracellular H-ferritin levels. Hepcidin is a protective molecule in acute kidney injury. Drugs targeting hepcidin, H-ferritin, and ferroptosis pathways hold great promise to prevent or treat kidney injury. In this review we discuss iron homeostasis under physiological and pathologic conditions and highlight its importance in acute kidney injury.
10.1016/j.semnephrol.2018.10.006
Iron Homeostasis Pathways as Therapeutic Targets in Acute Kidney Injury.
Swaminathan Sundararaman
Nephron
BACKGROUND:Iron is critical for fundamental biologic functions such as cell division and mitochondrial electron transport. However, by the virtue of its ability to donate electrons, iron is probably the most effective oxidant in biologic systems. SUMMARY:To avoid damage from iron-mediated oxidative injury or ferroptosis, multiple defense mechanisms exist including iron binding proteins and robust glutathione-dependent intracellular pathways. Hepcidin, through its ability to sequester iron within macrophages and induce H-ferritin, serves as an endogenous protective molecule against ferroptosis. Key Messages: Recent studies have demonstrated the protective role of hepcidin in both ischemic reperfusion injury and heme-mediated models of acute kidney injury (AKI). Ferroptosis-inhibiting drugs and hepcidin offer exciting novel prospects to treat AKI.
10.1159/000490808
An Overview of Pathways of Regulated Necrosis in Acute Kidney Injury.
Kers Jesper,Leemans Jaklien C,Linkermann Andreas
Seminars in nephrology
Necrosis is the predominant form of regulated cell death in acute kidney injury (AKI) and represents results in the formation of casts that appear in the urine sedimentation, referred to as muddy brown casts, which are part of the diagnosis of AKI. Pathologists referred to this typical feature as acute tubular necrosis. We are only beginning to understand the dynamics and the molecular pathways that underlie such typical necrotic morphology. In this review, we provide an overview of candidate pathways and summarize the emerging evidence for the relative contribution of these pathways of regulated necrosis, such as necroptosis, ferroptosis, mitochondrial permeability transition-mediated regulated necrosis, parthanatos, and pyroptosis. Inhibitors of each of these pathways are available, and clinical trials may be started after the detection of the most promising drug targets, which will be discussed here. With the global burden of AKI in mind, inhibitiors of regulated necrosis represent promising means to prevent this disease.
10.1016/j.semnephrol.2016.03.002
Iron deficiency exacerbates cisplatin- or rhabdomyolysis-induced acute kidney injury through promoting iron-catalyzed oxidative damage.
Free radical biology & medicine
Iron deficiency is the most common micronutrient deficiency worldwide. While iron deficiency is known to suppress embryonic organogenesis, its effect on the adult organ in the context of clinically relevant damage has not been considered. Here we report that iron deficiency is a risk factor for nephrotoxic intrinsic acute kidney injury of the nephron (iAKI). Iron deficiency exacerbated cisplatin-induced iAKI by markedly increasing non-heme catalytic iron and Nox4 protein which together catalyze production of hydroxyl radicals followed by protein and DNA oxidation, apoptosis and ferroptosis. Crosstalk between non-heme catalytic iron/Nox4 and downstream oxidative damage generated a mutual amplification cycle that facilitated rapid progression of cisplatin-induced iAKI. Iron deficiency also exacerbated a second model of iAKI, rhabdomyolysis, via increasing catalytic heme-iron. Heme-iron induced lipid peroxidation and DNA oxidation by interacting with Nox4-independent mechanisms, promoting p53/p21 activity and cellular senescence. Our data suggests that correcting iron deficiency and/or targeting specific catalytic iron species are strategies to mitigate iAKI in a wide range of patients with diverse forms of kidney injury.
10.1016/j.freeradbiomed.2021.07.025
Novel Ferroptosis Inhibitors with Improved Potency and ADME Properties.
Hofmans Sam,Vanden Berghe Tom,Devisscher Lars,Hassannia Behrouz,Lyssens Sophie,Joossens Jurgen,Van Der Veken Pieter,Vandenabeele Peter,Augustyns Koen
Journal of medicinal chemistry
Ferroptosis is a nonapoptotic, iron-catalyzed form of regulated necrosis that is critically dependent on glutathione peroxidase 4 (GPX4). It has been shown to contribute to liver and kidney ischemia reperfusion injury in mice. A chemical inhibitor discovered by high-throughput screening displayed inhibition of ferroptosis with nanomolar activity and was dubbed ferrostatin-1 (fer-1). Ferrostatins inhibit oxidative lipid damage, but suffer from inherent stability problems due to the presence of an ester moiety. This limits the application of these molecules in vivo, due to rapid hydrolysis of the ester into the inactive carboxylic acid. Previous studies highlighted the importance of the ethyl ester and suggested steric modifications of the ester for generating improved molecules. In this study, we report the synthesis of novel ferroptosis inhibitors containing amide and sulfonamide moieties with improved stability, single digit nanomolar antiferroptotic activity, and good ADME properties suitable for application in in vivo disease models.
10.1021/acs.jmedchem.5b01641
Heme oxygenase-1 mitigates ferroptosis in renal proximal tubule cells.
Adedoyin Oreoluwa,Boddu Ravindra,Traylor Amie,Lever Jeremie M,Bolisetty Subhashini,George James F,Agarwal Anupam
American journal of physiology. Renal physiology
Ferroptosis is an iron-dependent form of regulated nonapoptotic cell death, which contributes to damage in models of acute kidney injury (AKI). Heme oxygenase-1 (HO-1) is a cytoprotective enzyme induced in response to cellular stress, and is protective against AKI because of its antiapoptotic and anti-inflammatory properties. However, the role of HO-1 in regulating ferroptosis is unclear. The purpose of this study was to elucidate the role of HO-1 in regulating ferroptotic cell death in renal proximal tubule cells (PTCs). Immortalized PTCs obtained from HO-1 and HO-1 mice were treated with erastin or RSL3, ferroptosis inducers, in the presence or absence of antioxidants, an iron source, or an iron chelator. Cells were assessed for changes in morphology and metabolic activity as an indicator of cell viability. Treatment of HO-1 PTCs with erastin resulted in a time- and dose-dependent increase in HO-1 gene expression and protein levels compared with vehicle-treated controls. HO-1 cells showed increased dose-dependent erastin- or RSL3-induced cell death in comparison to HO-1 PTCs. Iron supplementation with ferric ammonium citrate in erastin-treated cells decreased cell viability further in HO-1 PTCs compared with HO-1 cells. Cotreatment with ferrostatin-1 (ferroptosis inhibitor), deferoxamine (iron chelator), or N-acetyl-l-cysteine (glutathione replenisher) significantly increased cell viability and attenuated erastin-induced ferroptosis in both HO-1 and HO-1 PTCs. These results demonstrate an important antiferroptotic role of HO-1 in renal epithelial cells.
10.1152/ajprenal.00044.2017
Correction: Characterization of ferroptosis in kidney tubular cell death under diabetic conditions.
Kim Seonghun,Kang Shin-Wook,Joo Jeongho,Han Seung Hyeok,Shin Huiyoon,Nam Bo Young,Park Jimin,Yoo Tae-Hyun,Kim Gyuri,Lee Pureunchowon,Park Jung Tak
Cell death & disease
10.1038/s41419-021-03667-y
Drugs Repurposed as Antiferroptosis Agents Suppress Organ Damage, Including AKI, by Functioning as Lipid Peroxyl Radical Scavengers.
Mishima Eikan,Sato Emiko,Ito Junya,Yamada Ken-Ichi,Suzuki Chitose,Oikawa Yoshitsugu,Matsuhashi Tetsuro,Kikuchi Koichi,Toyohara Takafumi,Suzuki Takehiro,Ito Sadayoshi,Nakagawa Kiyotaka,Abe Takaaki
Journal of the American Society of Nephrology : JASN
BACKGROUND:Ferroptosis, nonapoptotic cell death mediated by free radical reactions and driven by the oxidative degradation of lipids, is a therapeutic target because of its role in organ damage, including AKI. Ferroptosis-causing radicals that are targeted by ferroptosis suppressors have not been unequivocally identified. Because certain cytochrome P450 substrate drugs can prevent lipid peroxidation obscure mechanisms, we evaluated their antiferroptotic potential and used them to identify ferroptosis-causing radicals. METHODS:Using a cell-based assay, we screened cytochrome P450 substrate compounds to identify drugs with antiferroptotic activity and investigated the underlying mechanism. To evaluate radical-scavenging activity, we used electron paramagnetic resonance-spin trapping methods and a fluorescence probe for lipid radicals, NBD-Pen, that we had developed. We then assessed the therapeutic potency of these drugs in mouse models of cisplatin-induced AKI and LPS/galactosamine-induced liver injury. RESULTS:We identified various US Food and Drug Administration-approved drugs and hormones that have antiferroptotic properties, including rifampicin, promethazine, omeprazole, indole-3-carbinol, carvedilol, propranolol, estradiol, and thyroid hormones. The antiferroptotic drug effects were closely associated with the scavenging of lipid peroxyl radicals but not significantly related to interactions with other radicals. The elevated lipid peroxyl radical levels were associated with ferroptosis onset, and known ferroptosis suppressors, such as ferrostatin-1, also functioned as lipid peroxyl radical scavengers. The drugs exerted antiferroptotic activities in various cell types, including tubules, podocytes, and renal fibroblasts. Moreover, in mice, the drugs ameliorated AKI and liver injury, with suppression of tissue lipid peroxidation and decreased cell death. CONCLUSIONS:Although elevated lipid peroxyl radical levels can trigger ferroptosis onset, some drugs that scavenge lipid peroxyl radicals can help control ferroptosis-related disorders, including AKI.
10.1681/ASN.2019060570
Necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure.
Müller Tammo,Dewitz Christin,Schmitz Jessica,Schröder Anna Sophia,Bräsen Jan Hinrich,Stockwell Brent R,Murphy James M,Kunzendorf Ulrich,Krautwald Stefan
Cellular and molecular life sciences : CMLS
Ferroptosis is a recently recognized caspase-independent form of regulated cell death that is characterized by the accumulation of lethal lipid ROS produced through iron-dependent lipid peroxidation. Considering that regulation of fatty acid metabolism is responsible for the membrane-resident pool of oxidizable fatty acids that undergo lipid peroxidation in ferroptotic processes, we examined the contribution of the key fatty acid metabolism enzyme, acyl-CoA synthetase long-chain family member 4 (ACSL4), in regulating ferroptosis. By using CRISPR/Cas9 technology, we found that knockout of Acsl4 in ferroptosis-sensitive murine and human cells conferred protection from erastin- and RSL3-induced cell death. In the same cell types, deletion of mixed lineage kinase domain-like (Mlkl) blocked susceptibility to necroptosis, as expected. Surprisingly, these studies also revealed ferroptosis and necroptosis are alternative, in that resistance to one pathway sensitized cells to death via the other pathway. These data suggest a mechanism by which one regulated necrosis pathway compensates for another when either ferroptosis or necroptosis is compromised. We verified the synergistic contributions of ferroptosis and necroptosis to tissue damage during acute organ failure in vivo. Interestingly, in the course of pathophysiological acute ischemic kidney injury, ACSL4 was initially upregulated and its expression level correlated with the severity of tissue damage. Together, our findings reveal ACSL4 to be a reliable biomarker of the emerging cell death modality of ferroptosis, which may also serve as a novel therapeutic target in preventing pathological cell death processes.
10.1007/s00018-017-2547-4
Ferroptosis: process and function.
Xie Y,Hou W,Song X,Yu Y,Huang J,Sun X,Kang R,Tang D
Cell death and differentiation
Ferroptosis is a recently recognized form of regulated cell death. It is characterized morphologically by the presence of smaller than normal mitochondria with condensed mitochondrial membrane densities, reduction or vanishing of mitochondria crista, and outer mitochondrial membrane rupture. It can be induced by experimental compounds (e.g., erastin, Ras-selective lethal small molecule 3, and buthionine sulfoximine) or clinical drugs (e.g., sulfasalazine, sorafenib, and artesunate) in cancer cells and certain normal cells (e.g., kidney tubule cells, neurons, fibroblasts, and T cells). Activation of mitochondrial voltage-dependent anion channels and mitogen-activated protein kinases, upregulation of endoplasmic reticulum stress, and inhibition of cystine/glutamate antiporter is involved in the induction of ferroptosis. This process is characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS) derived from iron metabolism and can be pharmacologically inhibited by iron chelators (e.g., deferoxamine and desferrioxamine mesylate) and lipid peroxidation inhibitors (e.g., ferrostatin, liproxstatin, and zileuton). Glutathione peroxidase 4, heat shock protein beta-1, and nuclear factor erythroid 2-related factor 2 function as negative regulators of ferroptosis by limiting ROS production and reducing cellular iron uptake, respectively. In contrast, NADPH oxidase and p53 (especially acetylation-defective mutant p53) act as positive regulators of ferroptosis by promotion of ROS production and inhibition of expression of SLC7A11 (a specific light-chain subunit of the cystine/glutamate antiporter), respectively. Misregulated ferroptosis has been implicated in multiple physiological and pathological processes, including cancer cell death, neurotoxicity, neurodegenerative diseases, acute renal failure, drug-induced hepatotoxicity, hepatic and heart ischemia/reperfusion injury, and T-cell immunity. In this review, we summarize the regulation mechanisms and signaling pathways of ferroptosis and discuss the role of ferroptosis in disease.
10.1038/cdd.2015.158
Ferroptosis in Different Pathological Contexts Seen through the Eyes of Mitochondria.
Otasevic V,Vucetic M,Grigorov I,Martinovic V,Stancic A
Oxidative medicine and cellular longevity
Ferroptosis is a recently described form of regulated cell death characterized by intracellular iron accumulation and severe lipid peroxidation due to an impaired cysteine-glutathione-glutathione peroxidase 4 antioxidant defence axis. One of the hallmarks of ferroptosis is a specific morphological phenotype characterized by extensive ultrastructural changes of mitochondria. Increasing evidence suggests that mitochondria play a significant role in the induction and execution of ferroptosis. The present review summarizes existing knowledge about the mitochondrial impact on ferroptosis in different pathological states, primarily cancer, cardiovascular diseases, and neurodegenerative diseases. Additionally, we highlight pathologies in which the ferroptosis/mitochondria relation remains to be investigated, where the process of ferroptosis has been confirmed (such as liver- and kidney-related pathologies) and those in which ferroptosis has not been studied yet, such as diabetes. We will bring attention to avenues that could be followed in future research, based on the use of mitochondria-targeted approaches as anti- and proferroptotic strategies and directed to the improvement of existing and the development of novel therapeutic strategies.
10.1155/2021/5537330
Regulated necrosis in kidney ischemia-reperfusion injury.
Pefanis Aspasia,Ierino Francesco L,Murphy James M,Cowan Peter J
Kidney international
Ischemia-reperfusion injury (IRI) is the outcome of an inflammatory process that is triggered when an organ undergoes a transient reduction or cessation of blood flow, followed by re-establishment of perfusion. In the clinical setting, IRI contributes to significant acute kidney injury, patient morbidity and mortality, and adverse outcomes in transplantation. Tubular cell death by necrosis and apoptosis is a central feature of renal IRI. Recent research has challenged traditional views of cell death by identifying new pathways in which cells die in a regulated manner but with the morphologic features of necrosis. This regulated necrosis (RN) takes several forms, with necroptosis and ferroptosis being the best described. The precise mechanisms and relationships between the RN pathways in renal IRI are currently the subject of active research. The common endpoint of RN is cell membrane rupture, resulting in the release of cytosolic components with subsequent inflammation and activation of the immune system. We review the evidence and mechanisms of RN in the kidney following renal IRI, and discuss the use of small molecule inhibitors and genetically modified mice to better understand this process and guide potentially novel therapeutic interventions.
10.1016/j.kint.2019.02.009
Ferroptosis: A Novel Therapeutic Target for Ischemia-Reperfusion Injury.
Chen Yunqing,Fan Hongyan,Wang Shijun,Tang Guanmin,Zhai Changlin,Shen Liang
Frontiers in cell and developmental biology
Ischemia-reperfusion (I/R) injury is a major cause of cell death and organ damage in numerous pathologies, including myocardial infarction, stroke, and acute kidney injury. Current treatment methods for I/R injury are limited. Ferroptosis, which is a newly uncovered type of regulated cell death characterized by iron overload and lipid peroxidation accumulation, has been investigated in various diseases. There is increasing evidence of a close association between ferroptosis and I/R injury, with ferroptosis frequently identified as a new therapeutic target for the management of I/R injury. This review summarizes the current status of ferroptosis and discusses its relationship with I/R injury, as well as potential treatment strategies targeting it.
10.3389/fcell.2021.688605
Regulation of Ferroptosis Pathway by Ubiquitination.
Wang Xinbo,Wang Yanjin,Li Zan,Qin Jieling,Wang Ping
Frontiers in cell and developmental biology
Ferroptosis is an iron-dependent form of programmed cell death, which plays crucial roles in tumorigenesis, ischemia-reperfusion injury and various human degenerative diseases. Ferroptosis is characterized by aberrant iron and lipid metabolisms. Mechanistically, excess of catalytic iron is capable of triggering lipid peroxidation followed by Fenton reaction to induce ferroptosis. The induction of ferroptosis can be inhibited by sufficient glutathione (GSH) synthesis via system Xc transporter-mediated cystine uptake. Therefore, induction of ferroptosis by inhibition of cystine uptake or dampening of GSH synthesis has been considered as a novel strategy for cancer therapy, while reversal of ferroptotic effect is able to delay progression of diverse disorders, such as cardiopathy, steatohepatitis, and acute kidney injury. The ubiquitin (Ub)-proteasome pathway (UPP) dominates the majority of intracellular protein degradation by coupling Ub molecules to the lysine residues of protein substrate, which is subsequently recognized by the 26S proteasome for degradation. Ubiquitination is crucially involved in a variety of physiological and pathological processes. Modulation of ubiquitination system has been exhibited to be a potential strategy for cancer treatment. Currently, more and more emerged evidence has demonstrated that ubiquitous modification is involved in ferroptosis and dominates the vulnerability to ferroptosis in multiple types of cancer. In this review, we will summarize the current findings of ferroptosis surrounding the viewpoint of ubiquitination regulation. Furthermore, we also highlight the potential effect of ubiquitination modulation on the perspective of ferroptosis-targeted cancer therapy.
10.3389/fcell.2021.699304
Immunological consequences of kidney cell death.
Sarhan Maysa,von Mässenhausen Anne,Hugo Christian,Oberbauer Rainer,Linkermann Andreas
Cell death & disease
Death of renal cells is central to the pathophysiology of acute tubular necrosis, autoimmunity, necrotizing glomerulonephritis, cystic kidney disease, urosepsis, delayed graft function and transplant rejection. By means of regulated necrosis, immunogenic damage-associated molecular patterns (DAMPs) and highly reactive organelles such as lysosomes, peroxisomes and mitochondria are released from the dying cells, thereby causing an overwhelming immunologic response. The rupture of the plasma membrane exhibits the "point of no return" for the immunogenicity of regulated cell death, explaining why apoptosis, a highly organized cell death subroutine with long-lasting plasma membrane integrity, elicits hardly any immune response. Ferroptosis, an iron-dependent necrotic type cell death, results in the release of DAMPs and large amounts of lipid peroxides. In contrast, anti-inflammatory cytokines are actively released from cells that die by necroptosis, limiting the DAMP-induced immune response to a surrounding microenvironment, whereas at the same time, inflammasome-associated caspases drive maturation of intracellularly expressed interleukin-1β (IL-1β). In a distinct setting, additionally interleukin-18 (IL-18) is expressed during pyroptosis, initiated by gasdermin-mediated plasma membrane rupture. As all of these pathways are druggable, we provide an overview of regulated necrosis in kidney diseases with a focus on immunogenicity and potential therapeutic interventions.
10.1038/s41419-017-0057-9
Targeting Cell Death Pathways for Therapeutic Intervention in Kidney Diseases.
Garg Jay P,Vucic Domagoj
Seminars in nephrology
Precise regulation of cell death and survival is essential for proper maintenance of organismal homeostasis, development, and the immune system. Deregulated cell death can lead to developmental defects, neuropathies, infections, and cancer. Kidney diseases, especially acute pathologies linked to ischemia-reperfusion injury, are among illnesses that profoundly are affected by improper regulation or execution of cell death pathways. Attempts to develop medicines for kidney diseases have been impacted by the complexity of these pathologies given the heterogeneous patient population and diverse etiologies. By analyzing cell death pathways activated in kidney diseases, we attempt to differentiate their importance for these pathologies with a goal of identifying those that have more profound impact and the best therapeutic potential. Although classic apoptosis still might be important, regulated necrosis pathways including necroptosis, ferroptosis, parthanatos, and mitochondrial permeability transition-associated cell death play a significantly role in kidney diseases, especially in acute kidney pathologies. Although targeting receptor-interacting protein 1 kinase appears to be the best therapeutic strategy, combination with inhibitors of other cell death pathways is likely to bring superior benefit and possible cure to patients suffering from kidney diseases.
10.1016/j.semnephrol.2016.03.003
Ferroptosis and necroinflammation, a yet poorly explored link.
Cell death and differentiation
Ferroptosis is a non-apoptotic form of cell death characterized by overwhelming iron-dependent lipid peroxidation, which contributes to a number of pathologies, most notably tissue ischemia/reperfusion injury, neurodegeneration and cancer. Cysteine availability, glutathione biosynthesis, polyunsaturated fatty acid metabolism and modulation of the phospholipidome are the key events of this necrotic cell death pathway. Non-enzymatic and enzymatic lipoxygenase (LOX)-mediated lipid peroxidation of lipid bilayers is efficiently counteracted by the glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis. Preliminary studies suggest that bursting ferroptotic cells release pro-inflammatory damage-associated molecular patterns (DAMPs) that trigger the innate immune system as exemplified by diseased kidney and brain tissues where ferroptosis contributes to organ demise in a predominant manner. The GSH/GPX4 node is known to control the activities of LOX and prostaglandin-endoperoxide synthase (PTGS) via the so-called peroxide tone. Since LOX and PTGS products do have pro- and anti-inflammatory effects, one may speculate that these enzymes contribute to the ferroptotic process on several levels in cell-autonomous and non-autonomous ways. Hence, this review provides the reader with an outline on what is currently known about the link between ferroptosis and necroinflammation and discusses critical events that may alert the innate immune system in early phases when cells become sensitized towards ferroptosis.
10.1038/s41418-018-0173-9
Plasticity of ether lipids promotes ferroptosis susceptibility and evasion.
Zou Yilong,Henry Whitney S,Ricq Emily L,Graham Emily T,Phadnis Vaishnavi V,Maretich Pema,Paradkar Sateja,Boehnke Natalie,Deik Amy A,Reinhardt Ferenc,Eaton John K,Ferguson Bryan,Wang Wenyu,Fairman Joshua,Keys Heather R,Dančík Vlado,Clish Clary B,Clemons Paul A,Hammond Paula T,Boyer Laurie A,Weinberg Robert A,Schreiber Stuart L
Nature
Ferroptosis-an iron-dependent, non-apoptotic cell death process-is involved in various degenerative diseases and represents a targetable susceptibility in certain cancers. The ferroptosis-susceptible cell state can either pre-exist in cells that arise from certain lineages or be acquired during cell-state transitions. However, precisely how susceptibility to ferroptosis is dynamically regulated remains poorly understood. Here we use genome-wide CRISPR-Cas9 suppressor screens to identify the oxidative organelles peroxisomes as critical contributors to ferroptosis sensitivity in human renal and ovarian carcinoma cells. Using lipidomic profiling we show that peroxisomes contribute to ferroptosis by synthesizing polyunsaturated ether phospholipids (PUFA-ePLs), which act as substrates for lipid peroxidation that, in turn, results in the induction of ferroptosis. Carcinoma cells that are initially sensitive to ferroptosis can switch to a ferroptosis-resistant state in vivo in mice, which is associated with extensive downregulation of PUFA-ePLs. We further find that the pro-ferroptotic role of PUFA-ePLs can be extended beyond neoplastic cells to other cell types, including neurons and cardiomyocytes. Together, our work reveals roles for the peroxisome-ether-phospholipid axis in driving susceptibility to and evasion from ferroptosis, highlights PUFA-ePL as a distinct functional lipid class that is dynamically regulated during cell-state transitions, and suggests multiple regulatory nodes for therapeutic interventions in diseases that involve ferroptosis.
10.1038/s41586-020-2732-8
Endoplasmic reticulum stress-mediated autophagy activation is involved in cadmium-induced ferroptosis of renal tubular epithelial cells.
Zhao Caijun,Yu Duo,He Zhaoqi,Bao Lijuan,Feng Lianjun,Chen Luotong,Liu Zhuoyu,Hu Xiaoyu,Zhang Naisheng,Wang Tiejun,Fu Yunhe
Free radical biology & medicine
Acute cadmium (Cd) exposure is a significant risk factor for renal injury and lacks effective treatment strategies. Ferroptosis is a recently identified iron-dependent form of nonapoptotic cell death mediated by membrane damage resulting from lipid peroxidation, and it is implicated in many diseases. However, whether ferroptosis is involved in Cd-induced renal injury and, if so, how it operates. Here, we show that Cd can induce ferroptosis in kidney and renal tubular epithelial cells, as demonstrated by elevation of intracellular iron levels and lipid peroxidation, as well as impaired antioxidant production. Treatment with a ferroptosis inhibitor alleviated Cd-induced cell death. Intriguingly, we established that Cd-induced ferroptosis depended on endoplasmic reticulum (ER) stress, by demonstrating that Cd activated the PERK-eIF2α-ATF4-CHOP pathway and that inhibition of ER stress reduced ferroptosis caused by Cd. We further found that autophagy was required for Cd-induced ferroptosis because the inhibition of autophagy by chloroquine mitigated Cd-induced ferroptosis. Furthermore, we showed that iron dysregulation by ferritinophagy contributed to Cd-induced ferroptosis, by showing that the iron chelator desferrioxamine alleviated Cd-induced cell death and lipid peroxidation. In addition, ER stress is likely activated by MitoROS which trigger autophagy and ferroptosis. Collectively, our results indicate that ferroptosis is involved in Cd-induced renal toxicity and regulated by the MitoROS-ER stress-ferritinophagy axis.
10.1016/j.freeradbiomed.2021.09.008
Iron, ferroptosis, and new insights for prevention in acute kidney injury.
Borawski Bartlomiej,Malyszko Jolanta
Advances in medical sciences
Acute kidney injury (AKI) is a very common condition with high morbidity and mortality, which can be seen in 5-7% of all hospitalized patients and in up to 57% of all intensive care unit admissions. Despite recent advances in clinical care, the prevalence of AKI has been shown to increase with virtually no change in mortality. AKI is a complex syndrome occurring in a variety of clinical settings. Early detection is crucial to prevent irreversible loss of renal function. The pathogenesis of AKI is highly multifactorial and complex, including vasoconstriction, reactive oxygen species formation, cell death, abnormal immune modulators and growth factors. Emerging evidence from both human and animal studies suggests that dysregulation of iron metabolism may play a potentially important role in AKI. Therefore, targeting the iron homeostasis may provide a new therapeutic intervention for AKI. New therapeutic strategies including iron chelation therapy, targeting iron metabolism related proteins and direct inhibitors of ferroptosis are imperative to improve the outcomes of patients. Taking into consideration the complexity of AKI, one intervention may not be enough for therapeutic success. Future preclinical studies in animal disease models followed by well-designed clinical trials should be conducted to extend findings from animal AKI models to humans.
10.1016/j.advms.2020.06.004
Zinc transporter ZIP7 is a novel determinant of ferroptosis.
Chen Po-Han,Wu Jianli,Xu Yitong,Ding Chien-Kuang Cornelia,Mestre Alexander A,Lin Chao-Chieh,Yang Wen-Hsuan,Chi Jen-Tsan
Cell death & disease
Ferroptosis is a newly described form of regulated cell death triggered by oxidative stresses and characterized by extensive lipid peroxidation and membrane damages. The name of ferroptosis indicates that the ferroptotic death process depends on iron, but not other metals, as one of its canonical features. Here, we reported that zinc is also essential for ferroptosis in breast and renal cancer cells. Zinc chelator suppressed ferroptosis, and zinc addition promoted ferroptosis, even during iron chelation. By interrogating zinc-related genes in a genome-wide RNAi screen of ferroptosis, we identified SLC39A7, encoding ZIP7 that controls zinc transport from endoplasmic reticulum (ER) to cytosol, as a novel genetic determinant of ferroptosis. Genetic and chemical inhibition of the ZIP7 protected cells against ferroptosis, and the ferroptosis protection upon ZIP7 knockdown can be abolished by zinc supplementation. We found that the genetic and chemical inhibition of ZIP7 triggered ER stresses, including the induction of the expression of HERPUD1 and ATF3. Importantly, the knockdown of HERPUD1 abolished the ferroptosis protection phenotypes of ZIP7 inhibition. Together, we have uncovered an unexpected role of ZIP7 in ferroptosis by maintaining ER homeostasis. These findings may have therapeutic implications for human diseases involving ferroptosis and zinc dysregulations.
10.1038/s41419-021-03482-5
Ferritins in Kidney Disease.
Seminars in nephrology
Ferritins are evolutionarily conserved proteins that regulate cellular iron metabolism. It is the only intracellular protein that is capable of storing large quantities of iron. Although the ratio of different subunits determines the iron content of each ferritin molecule, the exact mechanism that dictates organization of these subunits still is unclear. In this review, we address renal ferritin expression and its implication in kidney disease. Specifically, we address the role of ferritin subunits in preventing kidney injury and also promoting tolerance against infection-associated kidney injury. We describe functions for ferritin that are independent of its ability to ferroxidize and store iron. We further discuss the implications of ferritin in body fluids, including blood and urine, during inflammation and kidney disease. Although there are several in-depth review articles on ferritin in the context of iron metabolism, we chose to focus on the role of ferritin particularly in kidney health and disease and highlight unanswered questions in the field.
10.1016/j.semnephrol.2020.01.007
Ferroptosis: past, present and future.
Li Jie,Cao Feng,Yin He-Liang,Huang Zi-Jian,Lin Zhi-Tao,Mao Ning,Sun Bei,Wang Gang
Cell death & disease
Ferroptosis is a new type of cell death that was discovered in recent years and is usually accompanied by a large amount of iron accumulation and lipid peroxidation during the cell death process; the occurrence of ferroptosis is iron-dependent. Ferroptosis-inducing factors can directly or indirectly affect glutathione peroxidase through different pathways, resulting in a decrease in antioxidant capacity and accumulation of lipid reactive oxygen species (ROS) in cells, ultimately leading to oxidative cell death. Recent studies have shown that ferroptosis is closely related to the pathophysiological processes of many diseases, such as tumors, nervous system diseases, ischemia-reperfusion injury, kidney injury, and blood diseases. How to intervene in the occurrence and development of related diseases by regulating cell ferroptosis has become a hotspot and focus of etiological research and treatment, but the functional changes and specific molecular mechanisms of ferroptosis still need to be further explored. This paper systematically summarizes the latest progress in ferroptosis research, with a focus on providing references for further understanding of its pathogenesis and for proposing new targets for the treatment of related diseases.
10.1038/s41419-020-2298-2
The emerging role of ferroptosis in intestinal disease.
Xu Shu,He Yao,Lin Lihui,Chen Peng,Chen Minhu,Zhang Shenghong
Cell death & disease
Ferroptosis is a newly recognised type of regulated cell death (RCD) characterised by iron-dependent accumulation of lipid peroxidation. It is significantly distinct from other RCDs at the morphological, biochemical, and genetic levels. Recent reports have implicated ferroptosis in multiple diseases, including neurological disorders, kidney injury, liver diseases, and cancer. Ferroptotic cell death has also been associated with dysfunction of the intestinal epithelium, which contributes to several intestinal diseases. Research on ferroptosis may provide a new understanding of intestinal disease pathogenesis that benefits clinical treatment. In this review, we provide an overview of ferroptosis and its underlying mechanisms, then describe its emerging role in intestinal diseases, including intestinal ischaemia/reperfusion (I/R) injury, inflammatory bowel disease (IBD), and colorectal cancer (CRC).
10.1038/s41419-021-03559-1
Ferroptosis in hepatic ischemia‑reperfusion injury: Regulatory mechanisms and new methods for therapy (Review).
Luo Linfeng,Mo Guoheng,Huang Deqiang
Molecular medicine reports
Ischemia‑reperfusion injury (IRI), also called reoxygenation injury, is the outcome of inflammatory processes and oxidative damage through the induction of oxidative stress. In the clinical setting, IRI contributes to severe hepatic injury, including liver cell death by apoptosis and ferroptosis. Ferroptosis is a novel type of cell death in hepatic IRI that involves small molecules that inhibit glutathione biosynthesis or glutathione peroxidase 4 (GPX4), which is a glutathione‑dependent antioxidant enzyme, causing mitochondrial damage. Currently, ferroptosis has been systematically described in neurological settings, kidney diseases and different types of cancer, while few studies have analysed the presence of ferroptosis and the regulatory mechanism of ferroptosis in hepatic IRI. Exploring the exact role played by ferroptosis in the liver following hepatic IRI in accordance with existing evidence and mechanisms could guide potential therapeutic interventions and provide a novel research avenue.
10.3892/mmr.2021.11864
Ferroptosis and Necroptosis in the Kidney.
Belavgeni Alexia,Meyer Claudia,Stumpf Julian,Hugo Christian,Linkermann Andreas
Cell chemical biology
In the last decade, the role of apoptosis in the pathophysiology of acute kidney injury (AKI) and AKI to chronic kidney disease (CKD) progression has been revisited as our understanding of ferroptosis and necroptosis has emerged. A growing body of evidence, reviewed here, ascribes a central pathophysiological role for ferroptosis and necroptosis to AKI, nephron loss, and acute tubular necrosis. We will introduce concepts to the non-cell-autonomous manner of kidney tubular injury during ferroptosis, a phenomenon that we refer to as a "wave of death." We hypothesize that necroptosis might initiate cell death propagation through ferroptosis. The remaining necrotic debris requires effective removal processes to prevent a secondary inflammatory response, referred to as necroinflammation. Open questions include the differences in the immunogenicity of ferroptosis and necroptosis, and the specificity of necrostatins and ferrostatins to therapeutically target these processes to prevent AKI-to-CKD progression and end-stage renal disease.
10.1016/j.chembiol.2020.03.016
Emerging Role of Ferroptosis in Acute Kidney Injury.
Hu Zhaoxin,Zhang Hao,Yang Shi-Kun,Wu Xueqin,He Dong,Cao Ke,Zhang Wei
Oxidative medicine and cellular longevity
Acute kidney injury (AKI) is a heterogeneous group of critical disease conditions with high incidence and mortality. Vasoconstriction, oxidative stress, apoptosis, and inflammation are generally thought to be the main pathogenic mechanisms of AKI. Ferroptosis is a type of iron-dependent nonapoptotic cell death characterized by membrane lipid peroxide accumulation and polyunsaturated fatty acid consumption, and it plays essential roles in many diseases, including cancers and neurologic diseases. Recent studies have revealed an emerging role of ferroptosis in the pathophysiological processes of AKI. Here, in the present review, we summarized the most recent discoveries on the role of ferroptosis in the pathogenesis of AKI as well as its therapeutic potential in AKI.
10.1155/2019/8010614
Characterization of ferroptosis in kidney tubular cell death under diabetic conditions.
Cell death & disease
Kidney 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 X (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.
10.1038/s41419-021-03452-x
The Cross-Link between Ferroptosis and Kidney Diseases.
Wang Jingyu,Liu Yi,Wang Yaqing,Sun Li
Oxidative medicine and cellular longevity
Acute and chronic kidney injuries result from structural dysfunction and metabolic disorders of the kidney in various etiologies, which significantly affect human survival and social wealth. Nephropathies are often accompanied by various forms of cell death and complex microenvironments. In recent decades, the study of kidney diseases and the traditional forms of cell death have improved. Nontraditional forms of cell death, represented by ferroptosis and necroptosis, have been discovered in the field of kidney diseases, which have reshuffled the role of traditional cell death in nephropathies. Although interactions between ferroptosis and acute kidney injury (AKI) have been continuously explored, studies on ferroptosis and chronic kidney disease (CKD) remain limited. Here, we have reviewed the therapeutic significance of ferroptosis in AKI and anticipated the curative potential of ferroptosis for CKD in the hope of providing insights into ferroptosis and CKD.
10.1155/2021/6654887
Ferroptosis and kidney disease.
Martin-Sanchez Diego,Fontecha-Barriuso Miguel,Martinez-Moreno Julio M,Ramos Adrian M,Sanchez-Niño Maria D,Guerrero-Hue Melania,Moreno Juan A,Ortiz Alberto,Sanz Ana B
Nefrologia
Cell death is a finely regulated process occurring through different pathways. Regulated cell death, either through apoptosis or regulated necrosis offers the possibility of therapeutic intervention. Necroptosis and ferroptosis are among the best studied forms of regulated necrosis in the context of kidney disease. We now review the current evidence supporting a role for ferroptosis in kidney disease and the implications of this knowledge for the design of novel therapeutic strategies. Ferroptosis is defined functionally, as a cell modality characterized by peroxidation of certain lipids, constitutively suppressed by GPX4 and inhibited by iron chelators and lipophilic antioxidants. There is functional evidence of the involvement of ferroptosis in diverse forms of kidneys disease. In a well characterized nephrotoxic acute kidney injury model, ferroptosis caused an initial wave of death, triggering an inflammatory response that in turn promoted necroptotic cell death that perpetuated kidney dysfunction. This suggests that ferroptosis inhibitors may be explored as prophylactic agents in clinical nephrotoxicity or ischemia-reperfusion injury such as during kidney transplantation. Transplantation offers the unique opportunity of using anti-ferroptosis agent ex vivo, thus avoiding bioavailability and in vivo pharmacokinetics and pharmacodynamics issues.
10.1016/j.nefro.2020.03.005
Ferroptosis and kidney diseases.
Tang Shumei,Xiao Xiangcheng
International urology and nephrology
Ferroptosis is a form of iron-dependent, non-apoptotic regulated cell death, which is characterized by the accumulation of lipid hydroperoxides to lethal levels. Ferroptosis recently has been shown to have implications in diverse kidney diseases, such as acute kidney injury, polycystic kidney disease and renal cell carcinoma. This review summarizes current research on ferroptosis, its underlying mechanisms and its role in the progression of different kidney diseases to provide more information regarding treatment and prevention of these destructive diseases.
10.1007/s11255-019-02335-7