scholarly journals Ferroptosis contributes to developmental cell death in rice blast

2019 ◽  
Author(s):  
Qing Shen ◽  
Meiling Liang ◽  
Fan Yang ◽  
Yi Zhen Deng ◽  
Naweed I. Naqvi
Keyword(s):  
Cell Death ◽  
Rice Blast ◽  
Iron Homeostasis ◽  
Apoptotic Cell ◽  
Lipid Peroxides ◽  
Rice Cultivar ◽  
Regulatory Function ◽  
Death Process ◽  
Blast Fungus ◽  
Developmental Cell Death

AbstractWe identified that ferroptosis, an iron-dependent non-apoptotic cell death process, occurs in the rice blast fungus Magnaporthe oryzae, and plays a key role in infection-related development therein. Ferroptosis in the blast fungus was confirmed based on the four basic criteria. We confirmed the dependence of ferroptosis on ferric ions, and optimized C11-BODIPY581/591 as a key sensor for subcellular detection and quantification of lipid peroxides that mediate ferroptotic cell death during the pathogenic growth phase of M. oryzae. In addition, we uncovered an important regulatory function for reduced glutathione and the NADPH oxidases in generating/modulating the superoxide moieties for ferroptotic cell death in Magnaporthe. Ferroptosis was found to be necessary for the specific developmental cell death in conidia during appressorium maturation in rice blast. Such ferroptotic cell death initiated first in the terminal cell and progressed sequentially to the entire conidium. Chelation of iron or chemical inhibition of ferroptosis caused conidial cells to remain viable and led to strong defects in host invasion by M. oryzae. Precocious induction of ferroptosis in a blast-susceptible rice cultivar led to resistance against M. oryzae invasion. Interestingly, ferroptosis and autophagy were found to play inter-reliant or codependent roles in contributing to such precise cell death in M. oryzae conidia during pathogenic differentiation. Our study provides significant molecular insights into understanding the role of developmental cell death and iron homeostasis in infection-associated morphogenesis and in fungus-plant interaction in the blast pathosystem.

scholarly journals Nucleotide Biosynthesis Links Glutathione Metabolism to Ferroptosis Sensitivity

2021 ◽  
Author(s):  
Amy Tarangelo ◽  
Joon Tae Kim ◽  
Jonathan Z Long ◽  
Scott J Dixon
Keyword(s):  
Cell Death ◽  
De Novo ◽  
Apoptotic Cell ◽  
Lipid Peroxides ◽  
Nucleotide Metabolism ◽  
Apoptotic Cell Death ◽  
Death Process ◽  
Glutathione Metabolism ◽  
Dependent Manner ◽  
Nucleotide Synthesis

Nucleotide synthesis is a metabolically demanding process essential for cell division. Several anti-cancer drugs that inhibit nucleotide metabolism induce apoptosis. How inhibition of nucleotide metabolism impacts non-apoptotic cell death is less clear. Here, we report that inhibition of nucleotide metabolism by the p53 pathway is sufficient to suppress the non-apoptotic cell death process of ferroptosis. Mechanistically, stabilization of wild-type p53 and induction of the p53 target gene CDKN1A (p21) leads to decreased expression of the ribonucleotide reductase (RNR) subunits RRM1 and RRM2. RNR is the rate-limiting enzyme of de novo nucleotide synthesis that reduces ribonucleotides to deoxyribonucleotides in a glutathione-dependent manner. Direct inhibition of RNR conserves glutathione which can then be used to limit the accumulation of toxic lipid peroxides, preventing the onset of ferroptosis. These results support a mechanism linking p53-dependent regulation of nucleotide metabolism to non-apoptotic cell death.

scholarly journals HSF-1 activates the ubiquitin proteasome system to promote non-apoptotic developmental cell death in C. elegans

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Maxime J Kinet ◽  
Jennifer A Malin ◽  
Mary C Abraham ◽  
Elyse S Blum ◽  
Melanie R Silverman ◽  
...  
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Ubiquitin Proteasome System ◽  
Mitogen Activated Protein Kinase ◽  
Death Process ◽  
Heat Shock Factor 1 ◽  
Vertebrate Development ◽  
C Elegans ◽  
Ubiquitin Proteasome ◽  
Developmental Cell Death

Apoptosis is a prominent metazoan cell death form. Yet, mutations in apoptosis regulators cause only minor defects in vertebrate development, suggesting that another developmental cell death mechanism exists. While some non-apoptotic programs have been molecularly characterized, none appear to control developmental cell culling. Linker-cell-type death (LCD) is a morphologically conserved non-apoptotic cell death process operating in Caenorhabditis elegans and vertebrate development, and is therefore a compelling candidate process complementing apoptosis. However, the details of LCD execution are not known. Here we delineate a molecular-genetic pathway governing LCD in C. elegans. Redundant activities of antagonistic Wnt signals, a temporal control pathway, and mitogen-activated protein kinase kinase signaling control heat shock factor 1 (HSF-1), a conserved stress-activated transcription factor. Rather than protecting cells, HSF-1 promotes their demise by activating components of the ubiquitin proteasome system, including the E2 ligase LET-70/UBE2D2 functioning with E3 components CUL-3, RBX-1, BTBD-2, and SIAH-1. Our studies uncover design similarities between LCD and developmental apoptosis, and provide testable predictions for analyzing LCD in vertebrates.

scholarly journals APR-246 induces early cell death by ferroptosis in acute myeloid leukemia.

Haematologica ◽  
2021 ◽  
Author(s):  
Rudy Birsen ◽  
Clement Larrue ◽  
Justine Decroocq ◽  
Natacha Johnson ◽  
Nathan Guiraud ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Ex Vivo ◽  
Lipid Peroxides ◽  
Death Process ◽  
Glutathione Biosynthesis ◽  
Acute Myeloid

APR-246 is a promising new therapeutic agent that targets p53 mutated proteins in myelodysplastic syndromes and in acute myeloid leukemia. APR-246 reactivates the transcriptional activity of p53 mutants by facilitating their binding to DNA target sites. Recent studies in solid cancers have found that APR-246 can also induce p53-independent cell death. In this study, we demonstrate that AML cell death occurring early after APR-246 exposure is suppressed by iron chelators, lipophilic antioxidants and inhibitors of lipid peroxidation, and correlates with the accumulation of markers of lipid peroxidation, thus fulfilling the definition of ferroptosis, a recently described cell death process. The capacity of AML cells to detoxify lipid peroxides by increasing their cystine uptake to maintain major antioxidant molecule glutathione biosynthesis after exposure to APR-246 may be a key determinant of sensitivity to this compound. The association of APR-246 with induction of ferroptosis (either by pharmacological compounds, or genetic inactivation of SLC7A11 or GPX4) had a synergistic effect on the promotion of cell death, both in vivo and ex vivo.

scholarly journals Mitochondria: Regulators of Cell Death and Survival

2002 ◽  
Vol 2 ◽  
pp. 1569-1578 ◽  
Author(s):  
David J. Granville ◽  
Roberta A. Gottlieb
Keyword(s):  
Cell Death ◽  
Conformational Changes ◽  
Protein Interactions ◽  
Apoptotic Cell ◽  
Critical Role ◽  
Death Process ◽  
Protein Protein Interactions ◽  
Ionic Changes ◽  
A Cell ◽  
Cyt C

The past 5 years has seen an intense surge in research devoted toward understanding the critical role of mitochondria in the regulation of cell death. Apoptosis can be initiated by a wide array of stimuli, inducing multiple signaling pathways that, for the most part, converge at the mitochondrion. Although classically considered the powerhouses of the cell, it is now understood that mitochondria are also “gatekeepers” that ultimately determine the fate of the cell. The mitochondrial decision as to whether a cell lives or dies is complex, involving protein-protein interactions, ionic changes, reactive oxygen species, and other mechanisms that require further elucidation. Once the death process is initiated, mitochondria undergo conformational changes, resulting in the release of cytochrome c (cyt c), caspases, endonucleases, and other factors leading to the onset and execution of apoptosis. The present review attempts to outline the complex milieu of events regulating the mitochondrial commitment to and processes involved in the implementation of the executioner phase of apoptotic cell death.

RelB silencing to reverse tamoxifen resistance by regulating GPx4 and ferroptosis in breast cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e12513-e12513
Author(s):  
Zhi Xu ◽  
Jinhai Tang
Keyword(s):  
Breast Cancer ◽  
Lipid Peroxidation ◽  
Cell Death ◽  
Cell Lines ◽  
Apoptotic Cell ◽  
Morphological Changes ◽  
Death Process ◽  
Enhancer Element ◽  
High Level

e12513 Background: Tamoxifen(Tam), as an essential therapeutic treatment of estrogen receptor(ER)-positive breast cancer(BCa), has been available for the past three decades. However, the induction of Tam resistance during therapy has indicated a significant challenge with regards to this agent. Tam could increase oxidative stress and induce cell death by regulating reactive oxygen species(ROS). Ferroptosis, a cell death process driven by the accumulation of iron-dependent lipid peroxides, has been induced by inactivation/depletion of glutathione peroxidases(GPxs). Our previous studies found that the expression level of RelB gene, a member of NF-κB family, is negatively correlated with ER targeted by Tam in BCa. Methods: The RelB level of BCa tumor tissues and the corresponding cell lines were examined by immunoblotting and western blot. The effects of Tam on cell viability were determined using colony survival and MTT assay. The ROS and oxygen consumption rates(OCR) were measured using specific ROS detection probes and a Seahorse XF96 Analyzer, respectively. The lipid peroxidation level of cells was analyzed by immunofluorescence assay. The morphological changes of mitochondria were observed by transmission electron microscope. RelB binding to the NF-κB intronic enhancer region of the human GPx4 gene was determined using a ChIP assay. Accordingly, the effect of RelB on BCa Tam resistance was further validated using BCa mice xenograft models. Results: RelB was uniquely expressed at the high level in Tam resistance BCa tissues and cell lines. Down-regulation of RelB based on a CRISPR/Cas9 system remarkably sensitized resistance BCa cells to Tam. Treatment with SN52, a RelB inhibitor, illuminated the role of RelB in Tam-treated BCa cells. The high level of ROS and declination of mitochondrial respiration which induced by Tam were inhibited in resistance cells. Tam enhanced lipid peroxidation with concomitant non-apoptotic cell death, which are negatively regulated by GPx4 activity. In addition to GPx4 knockdown, deferoxamine was able to rescue Tam-induced cell death in BCa cells, verifying that Tam induces cell death partially through ferroptosis. Importantly, RelB upregulates GPx4 expression through binding to an NF-κB enhancer element located at the 5’-flanking region. Consistently, in vivo functional validation confirmed that RelB inhibition not only impairs tumor growth, but also inhibits Tam resistance in nude mice. Conclusions: RelB could inhibit ferroptosis which induced by hydroxyl radicals accumulation through upregulating GPx4 in BCa.

scholarly journals Ferroptosis contributes to developmental cell death in rice blast

2020 ◽  
Vol 227 (6) ◽  
pp. 1831-1846 ◽  
Author(s):  
Qing Shen ◽  
Meiling Liang ◽  
Fan Yang ◽  
Yi Zhen Deng ◽  
Naweed I. Naqvi
Keyword(s):  
Cell Death ◽  
Rice Blast ◽  
Developmental Cell Death
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