A study has shown that senescent cells were highly resistant to ferroptosis due to iron accumulation . A specific ferroptosis inhibitor, ferrostatin-1 (Fer-1), has been used to evaluate the role of ferroptosis in Ilya V. Kelmanson, Arina G. Shokhina and 25 more Open Access December 31, 2021. Abstract. By using RNAi screening coupled with subsequent genetic analysis, they were able to identify multiple autophagy-related genes as positive regulators of ferroptosis. Mitochondrial Ferritin Deficiency Promotes Osteoblastic Ferroptosis Via Mitophagy in Type 2 Diabetic Osteoporosis. Ferroptosis is a cell death process driven by damage to cell membranes and linked to numerous human diseases. Targeting ferroptosis synergistically sensitizes apoptotic sonodynamic anti-tumor nanotherapy. Ferroptosis was originally coined as a term for the unique form of cell death initated by the small molecules erastin and RAS-selective lethal 3 (RSL3) [ 3] and is now defined as a form of cell death that involves accumulation of lipid peroxides and that is suppressed by iron chelators and lipophilic antioxidants [ 2 ]. Although mitochondrial dysfunction and ER stress are related to ferroptosis in some cases (Dixon et al., 2014, Gao et al., 2019, Lee et al., 2018, Zhu et al., 2017), the functional role of mitophagy, reticulophagy, or the associated autophagy receptor in ferroptosis remains poorly understood. Overexpression of Parkin, a protein involved in Parkinsons disease and mitophagy, was shown to induce the mitophagy and inhibit cysteine deprivation-induced ferroptosis but not GPX4 inhibition-induced ferroptosis in human fibrosarcoma HT-1080 cells . Ferroptosis is a newly coined non-apoptotic programmed cell death process that was discovered via a chemical screen. A novel role of KEAP1/PGAM5 complex: ROS sensor for inducing mitophagy. For example, low doses of erastin (ferroptosis inducer) enhance the anti-cancer activity of cytarabine or doxorubicin in AML cells . 1 INTRODUCTION. Ferroptosis is a newly described form of caspase-independent RCD characterized by cellular accumulation of reactive oxygen species (ROS) driven through iron-dependent lipid peroxidation (), which is induced by erastin and Ras synthetic lethality molecule 3 (RSL3).Because the cell membrane is damaged directly by lethal lipid peroxidation and subsequent lipid ROS production, ferroptosis shows Bnip3- and Nix-mediated mitophagy; Programmed cell death, incl. Rise of cGMP by partial phosphodiesterase-3A degradation enhances cardioprotection during hypoxia Hao Zheng, Li Jiang and 3 more Open Access December 31, 2021. We found ferroptosis in T2DOP rats bone. This turnover is known as mitophagy. Ferroptosis is remarkably distinct from necroptosis and other forms of regulated cell death at biochemical and morphological levels. Lysosomal degradative pathways, incl. The incidence of type 2 diabetic osteoporosis (T2DOP), which seriously threatens elderly people's health, is rapidly increasing in recent years. Ablation prevents mitophagy, Ferroptosis, others?) The removal of damaged mitochondria through autophagy, a process called mitophagy, is thus critical for maintaining proper cellular functions. Chemical inhibitors of ferroptosis and necroptosis protected against hemoglobin- and hemin-induced toxicity. Ferroptosis inducer erastin sensitizes NSCLC cells to celastrol through activation of the ROSmitochondrial fissionmitophagy axis. Among the three major autophagic pathways, chaperone-mediated autophagy (CMA) is primarily characterized by its selective nature of protein degradation, which is mediated by heat shock cognate 71 kDa protein (HSC70: also known as Olaparib is an autophagy and mitophagy activator. The incidence of type 2 diabetic osteoporosis (T2DOP), which seriously threatens elderly peoples health, is Introduction. A recent study documented that Nrf2 may play a mediator role in doxorubicin-induced ferroptosis, an iron-dependent form of regulated cell death that occurs through the lethal accumulation of lipid peroxides, in cardiomyocytes via upregulating heme oxygenase-1 (Ho-1) . Simvastatin induces ferroptosis, mitophagy, autophagy and apoptosis. Zhou L DC, Ding L. et al. Deferiprone, an iron chelator, increases the expression of mitochondrial ferritin (FTMT) Ferroptosis is a necrotic form of regulated cell death that was associated with lipid peroxidation and free iron-mediated Fenton reactions. Although mitochondrial dysfunction and ER stress are related to ferroptosis in some cases (Dixon et al., 2014; Gao et al., 2019; Lee et al., 2018; Zhu et al., 2017), the functional role of mitophagy, reticulophagy, or the associated autophagy receptor in ferroptosis remains poorly understood. Overexpression of PDSS2 suppressed the ferroptosis of HCAECs induced by ox-LDL via activating Nrf2 pathways . Y-27632 dihydrochloride 129830-38-2 is an inhibitor of glutathione peroxidase 4 (GPX4) (ferroptosis activator), reduces the expression of GPX4 protein, and induces ferroptotic death of head and neck cancer cell. Levels of multiple intracellular nutrients (iron, selenium, vitamin E and coenzyme Q 10) are intimately related to the cellular antioxidant system and participate in It is also a challenge to define the threshold or checkpoints associated with pro-survival and pro-death autophagy Scopus (22) Google Scholar. HT-1080 cells depleted of mitochondria (+CCCP) and treated with the ferroptosis inducer IKE showed an increase in oxidative events relative to mitochondria- However, many mechanisms of resistance 2020;16:1413-35 61. Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells By Farhan Basit, Lisanne M.P.E. Autophagy. Mitochondrial Ferritin Deficiency Promotes Osteoblastic Ferroptosis Via Mitophagy in Type 2 Diabetic Osteoporosis. For example,failure to remove dysfunctional mitochondria by mitophagy leads to high ROS. Ferroptosis is a new form of programmed cell death characterized by iron-dependent increase in ROS . BAY 87-2243 is a potent and selective hypoxia-inducible factor-1 (HIF-1) inhibitor. Therefore, ferroptosis connected with lipid peroxidation and iron storage may play a crucial role in the progression of atherosclerosis. However, the majority of PC is often resistant to chemotherapies (Deplanque and Demartines, 2017; Seufferlein and Ettrich, 2019). Ferroptosis is a new form of regulated cell death that mainly depends on iron accumulation and lipid peroxidation. using the ferroptosis inducers erastin and cystine starvation . In this study, we provide data to support the hypothesis that Magnaporthe MoAtg24 is directly involved in mitophagy in a manner similar to the yeast Atg32 function. In vivo dynamics of acidosis and oxidative stress in the acute phase of an ischemic stroke in a rodent model. 120 In PRKN-expressing HT1080 cells, the depletion of mitochondria by mitophagy fails to The deubiquitylase USP30 is an actionable target considered for treatment of conditions associated with defects in the PINK1-PRKN pathway leading to mitophagy. The current Ferroptosis, a novel type of programmed cell death, is involved in inflammation and oxidation of various human diseases, including diabetic kidney disease. Ferroptosis is an iron-dependent programmed cell death pathway caused by the failure of glutathione-dependent antioxidant defense and unregulated lipid peroxidation . Ferroptosis is a regulated form of necrotic cell death caused by the accumulation of lipid peroxides. Activation of mitophagy leads to decline in Mfn2 and loss of mitochondrial mass in Fuchs endothelial corneal dystrophy The Harvard community has made this article openly available. apoptosis, ferroptosis, necroptosis; Inflammation; Ubiquitin and E3 ligases; Role of mitochondria and mitophagy in cell death and innate immunity; Cell biology; Cancer, Neurodegeneration, Host 21 Importantly, specific inhibitors of ferroptosis have been shown to alleviate organ damage in several clinical models, including a model of heart disease. Ferroptosis is caused by loss of activity of the key enzyme that is tasked with repairing oxidative damage to cell membranesglutathione peroxidase 4 (GPX4). by Farhan Basit, Lisanne Mpe van Oppen, Laura Schckel, Hasse M Bossenbroek, Sjenet E van Emst-de Vries, Johannes Cw Hermeling, Sander Grefte, Charlotte Kopitz, Melanie Heroult, Peter Hgm Willems, Werner Jh Koopman. Nowadays, several cell death pathways have been identified to be involved in ischemic stroke pathophysiology, including apoptosis, necrosis, and auto Ferroptosis is a newly described form of caspase-independent RCD characterized by cellular accumulation of reactive oxygen species (ROS) driven through iron-dependent lipid peroxidation (), which is induced by erastin and Ras synthetic lethality molecule 3 (RSL3).Because the cell membrane is damaged directly by lethal lipid peroxidation and subsequent lipid ROS A Focus on Necroptosis and Ferroptosis Shunsuke Minagawa1, Masahiro Yoshida1, Jun Araya1, Hiromichi Hara1, Hirotaka Imai2, and Kazuyoshi Kuwano1 Parkin is known as a pivotal regulator of mitophagy Glutathione peroxidase 4 (GPx4): GPx4 Ferroptosis is an iron-dependent non-apoptotic cell death (Dixon et al., 2012) caused by the imbalance between oxidative stress and antioxidant systems, and has complex molecular mechanisms and biochemical cascades (Chen et al., 2020). 04137 Mitophagy - animal K08339 ATG5; autophagy-related protein 5 09143 Cell growth and death 04216 Ferroptosis K08339 ATG5; autophagy-related protein 5 09150 Organismal Systems 09151 Immune system 04621 NOD-like receptor signaling pathway K08339 ATG5; autophagy-related protein 5 04622 RIG-I-like receptor signaling pathway Ferroptosis is caused by loss of activity of the key enzyme that is tasked with repairing oxidative damage to cell membranesglutathione peroxidase 4 (GPX4). (b) Mitophagy, the degradation of impaired mitochondria via the gathering of PINK1 and PRKN as well as the transport of cargo receptors, produces killing ROS to advance ferroptosis. Ferroptosis is initiated upon redox imbalance and driven by excessive phospholipid peroxidation. Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells. Ferroptosis is a oxidative damage-dependent form of regulated cell death that has become an emerging target for disease prevention and treatment. In HT1080 cells (fibrosarcoma) treated with carbonyl cyanide 3-chlorophenyl hydrazine (CCCP), Parkin-mediated mitophagy inhibits cysteine-deprivation-induced ferroptosis [139]. describes types of selective autophagy and discuss the regulatory mechanisms and signaling pathways of autophagy-dependent ferroptosis. The role of mitophagy in ferroptosis has received very little attention thus far, limited mainly to in vitro studies using cancer cells. HT-1080 cells depleted of mitochondria (+CCCP) and treated with the ferroptosis inducer IKE showed an increase in oxidative events relative to mitochondria- Objectives. Stroke is one of the major causes of death and disability worldwide (Haley et al., 2019), and includes two main subtypes: ischemic stroke and hemorrhagic stroke. Curative resection is the first to consider for early-stage patients, but 5-year survival is only up to 25% (Kamisawa et al., 2016, Deplanque and Demartines, 2017). Mitophagy Ferroptosis Pyroptosis Apoptosis Necrosis Cell death Erythroblast maturation NIX/BNLP3L Rheb BNIP3 FUNDC1 Mcl-1 Hypoxia, inammation and immunodeciency AMBRA1 Necroptosis Reinforce Inhibition Figure 1: Mechanism of mitophagy in dierent physiological and pathological contexts and mitophagy regulating cell death pathway. Ferroptosis is a newly identified type of iron-dependent programmed cell death that was first reported by Dixon et al in 2012. This overexpression also inhibited the BAY-induced ROS increase and lipid peroxidation. The morphological characteristics of ferroptosis mainly * Department of Biochemistry (286), Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Centre (Radboudumc), PO Box 9101, 6500 HB Nijmegen, The Netherlands. This overexpression also inhibited the BAY-induced ROS increase and lipid peroxidation. Defects in mitophagy have been linked to altered mitochondrial metabolism, production of excess reactive oxygen species and ferroptosis, heightened inflammasome activation, altered cell fate decisions, and senescence, among other cellular consequences. Therefore, new therapeutic measurements for PC are u This turnover is known as mitophagy. Iron loss induces mitochondrial ferritin via hypoxia inducible factor 1-specific protein 1 axis, and triggers mitophagy for the damaged mitochondria. The metabolism of cysteine, polyunsaturated fatty acids (PUFAs) and iron are all closely correlated with ferroptosis initiation. Numerous specific ferroptosis inhibitors have been used to examine the mechanisms of ferroptosis, including Ferrostatin-1 and Liproxstatin-1 (Wu and Chen, 2015; Zilka et al., 2017). Recent Articles. mitochondrial metabolism for crucifixion of ferroptosis,6 reduction of mitochondria via Parkinmediated mitophagy in vitro or suppression of OXPHOS rescued cells from ferroptosis elicited by cystine deprivation or erastin.11 Thereby, due to oxidative stress and induction of ferroptosis causes mitochondrial DNA (mtDNA)depleted 0 cells Ferrostatin-1 was more effective than the other drugs in diminishing mitochondrial depolarization and bax/bcl-2 ratio (Figure A). 1a-e). Interestingly, activators and inhibitors of ferroptosis had been identified before the concept of ferroptosis was introduced. Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells | Cell Death & Disease. Then we found increased ferroptosis in osteoblasts after activating mitophagy by carbonyl cyanide-m-chlorophenyl-hydrazine (CCCP, a mitophagy agonist). Here, we show that dual-specificity phosphatase 1 (DUSP1), a phosphatase playing multiple roles in stress-signaling pathways, is a new repressor of ferroptosis in human pancreatic cancer cells. First, our study indicates that the role of mitochondria in ferroptosis is context dependent: blockage of mitochondrial function potently inhibits CDI ferroptosis; however, upon elimination or pharmacological inhibition of GPX4, the very downstream component of the ferroptosis pathway responsible for lipid ROS clearance, cells can commit This has implications for AML therapy. Its regulatory mechanisms include iron metabolism, fatty acid metabolism, mitochondrial respiration, and antioxidative Ferroptosis is an iron-dependent form of necrotic cell death that is driven by the lethal accumulation of lipid peroxidation products and reactive oxygen species (ROS). Ferroptosis is an RCD mode that is distinct from necroptosis. Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells. Inefficient or excessive mitophagy may contribute to neurodegeneration. 2of18 TANGetal. 2021;39:101212 62. Mitophagy is implicated in HMOX1-mediated ferroptosis through increased ER stress. Compared with healthy control, Ferroptosis inducer erastin sensitizes NSCLC cells to celastrol through activation of the ROSmitochondrial fissionmitophagy axis Ming Liu , Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life A deeper understanding of the process and function of autophagy-dependent cell death is critical for creating innovative therapeutic strategies for oxidative stress-related diseases. Ferroptosis is a newly coined non-apoptotic programmed cell death process that was discovered via a chemical screen. We discovered that PE-binding protein-1 (PEBP1) is pivotal for dynamic interactions between the ferroptotic cell death program and prosurvival autophagy in asthmatic/Type 2 stimulated airway epithelial cells and that concurrent activation of autophagy protects cells from ferroptotic death and mitochondrial DNA Increasing evidence has shown that the accumulation of damaged mitochondria is a characteristic of aging and aging-related diseases, such as metabolic disorder, cancer, and neurodegenerative disease. GPX4 normally removes the dangerous products of iron-dependent lipid peroxidation, Lipid peroxidation in mitochondria-depleted cells. MAP1LC3B2, ATG8G. and cell death, including ferroptosis, a necrosis-like cell death that results from redox stress. BAY 87-2243 inhibits mitochondrial complex I activity, thus triggering a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis.BAY 87 celastrol through activation of the ROSmitochondrial. 1 As a new type of programmed cell death, ferroptosis is different from apoptosis, autophagy, necrosis, pyrolysis and other forms of cell death in terms of morphology and biochemistry. Ferroptosis inhibitor up-regulated GPX4 levels of the lungs in RILF. Cells of the Neurovascular Unit. For autophagy induction, cells grown to mid-log phase in YPD were incubated at 30C in starvation medium (SD-N; 0.17% yeast nitrogen base without amino acids and ammonium sulfate, 2% dextrose). Ferroptosis Research Tools Ferroptosis is an iron-dependent cell death that is triggered when oxidized polyunsaturated fatty acids (PUFAs) in lipid membranes are not repaired or protected by glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1), or tetrahydrobiopterin activity. ssionmitophagy axis. Intriguingly, mitochondrial glutaminase (GLS), GLS2, instead of cytosolic GLS1, has been shown to be required for 1 INTRODUCTION. Glutamine is a key amino acid in the central nervous system (CNS), playing an important role in the glutamate/GABA-Glutamine cycle (GGC). In this review, we summarize the processes of autophagy and ferroptosis and discuss their crosstalk 16 The features and mechanisms of ferroptosis are different from those of typical cell death processes such as apoptosis and autophagy. Ferroptosis is a cell death pathway characterized by iron-dependent accumulation of reactive oxygen species (ROS) within the cell. All cell death inhibitors could decrease cardiac mitophagy, apoptosis and ferroptosis in iron overloaded rats. Nat Biotechnol, 2021, 10.1038/s41587-021-00860-4 Theranostics, 2021, 11(4):1609-1625 Theranostics, 2021, 11(13):6560-6572 Statin-Related Inhibition of Dehydroepiandrosterone Sulfate (DHEAS) Uptake by SLCO2B1 in Prostate Cancer (PC) Cells. Mitophagy is a key mechanism in organellar quality control and is responsible for the removal of damaged or unwanted mitochondria (Liu et al., 2014). For most patients with advanced PC, chemotherapy, such as gemcitabine and oxaliplatin, is the mainstay of treatment. Downregulated FtMt increased osteoblastic ferroptosis, decreased osteogenic function, and induced mitophagy. sulting in amplification of mitochondrial damage when mitophagy is inactivated (Figure 2). Autophagy is a highly conserved mechanism of delivering cytoplasmic components for lysosomal degradation. It has been reported that iron deficiency had been implicated in the pathogenesis of intervertebral disc degeneration (IVDD) by Many classic ferroptosis activators are inhibitors of endogenous antioxidant systems, especially the system xc-glutathione peroxidase 4 BAY-induced cell death was also reduced by the ferroptosis inhibitor ferrostatin-1 and overexpression of the ferroptosis-inhibiting protein glutathione peroxidase 4 (GPX4). Cancer stem cells (CSCs) are a distinct subpopulation of tumor cells with stem cell-like features. HY-10583. Mitochondrial Ferritin Deficiency Promotes Osteoblastic Ferroptosis Via Mitophagy in Type 2 Diabetic Osteoporosis Abstract. Smooth muscle cells - control localized blood flow. It is morphologically, biochemically, and genetically distinct from other known cell death, such as apoptosis, necrosis, and pyroptosis. In yeast, the mitochondrial outer membrane receptor Atg32 is essential for mitophagy (Kanki et al. We provide a detailed cell biological characterization of a benzosulphonamide molecule, compound 39, that has previously been reported to inhibit USP30 in an in vitro enzymatic assay. ferroptosis by iron chelators ciclopirox olamine (CPX) and deferoxamine (DFO) with and without mitophagy. Recent studies have identified metabolic and genetic contributors to ferroptosis. Activate neutrophils as they traverse the blood-brain barrier The present study explored the role of high-mobility group box-1 (HMGB1) on the regulation of ferroptosis in mesangial cells in response to high glucose. Akbar Zeb, Vinay Choubey and 10 more Open Access December 31, 2021. , PINK1/Parkin as core organizers of mitochondrial quality control Mutations in PINK1 or PRKN (Parkin) cause selective loss of SNpc DA neurons. ), and one of the major functions of glutaminolysis is to fuel the mitochondrial tricarboxylic acid (TCA) cycle. Definition. Ischemic stroke results from a lack of blood supply to the brain, and accounts for approximately 85% of all cases of stroke. Gene name. Van Oppen, Laura Schckel, Hasse M. Bossenbroek, Sjenet E. Van Emst-de Vries, Johannes C.W. 1 The general initiation mechanisms of ferroptosis have partially been elucidated with the research going further. Our work identifies regulatory mechanisms between ferroptosis and autophagy. The metabolism of cysteine, polyunsaturated fatty acids (PUFAs) and iron are all closely correlated with Lipid peroxidation in mitochondria-depleted cells. Chronic T1D Induces Ferroptosis via Activating Nrf2 in Cardiomyocytes. Able to initiate and sustain tumor growth and mostly resistant to anti-cancer therapies, they are thought responsible for tumor recurrence and metastasis. The combination of siramesine, a lysosome disruptor, and lapatinib, a dual tyrosine kinase inhibitor, has been shown to synergistically induce cell death in breast cancer cells mediated by ferroptosis. autophagy and endolysosomal signaling; Autophagy receptors, incl. The role of other ferroptosis-related selective autophagy (such as lipophagy and mitophagy) has not been determined in the regulation of ferroptosis in PDAC cells. pernicious (release damage associated molecular patterns) Box 2. GPX4 normally removes the dangerous products of iron-dependent lipid peroxidation, protecting cell membranes from Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells. 1 The general initiation mechanisms of ferroptosis have partially been elucidated with the research going further. First, our study indicates that the role of mitochondria in ferroptosis is context dependent: blockage of mitochondrial function potently inhibits CDI ferroptosis; however, upon elimination or pharmacological inhibition of GPX4, the very downstream component of the ferroptosis pathway responsible for lipid ROS clearance, cells can commit ferroptosis independently of mitochondria Previously, we demonstrated that autophagy proteins promote lung epitheli . Ferroptosis promotes atherosclerosis through lipid peroxidation-induced endothelial dysfunction . Mitophagy is the selective degradation of mitochondria by autophagy. Inefficient or excessive mitophagy may contribute to neurodegeneration. Furthermore, we It can be induced by inhibiting glutathione peroxidase 4 (GPX4), the key enzyme for lipid peroxides reduction from phospholipid membranes. Ferroptosis is a recently identified iron-dependent form of programmed cell death that requires the accumulation of intracellular lipid ROS. 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