regulated cell death
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2022 ◽  
Vol 8 (1) ◽  
pp. 78
Joana Terra-Matos ◽  
Marta Oliveira Teixeira ◽  
Cátia Santos-Pereira ◽  
Henrique Noronha ◽  
Lucília Domingues ◽  

Yeast-based bioethanol production from lignocellulosic hydrolysates (LH) is an attractive and sustainable alternative for biofuel production. However, the presence of acetic acid (AA) in LH is still a major problem. Indeed, above certain concentrations, AA inhibits yeast fermentation and triggers a regulated cell death (RCD) process mediated by the mitochondria and vacuole. Understanding the mechanisms involved in AA-induced RCD (AA-RCD) may thus help select robust fermentative yeast strains, providing novel insights to improve lignocellulosic ethanol (LE) production. Herein, we hypothesized that zinc vacuolar transporters are involved in vacuole-mediated AA-RCD, since zinc enhances ethanol production and zinc-dependent catalase and superoxide dismutase protect from AA-RCD. In this work, zinc limitation sensitized wild-type cells to AA-RCD, while zinc supplementation resulted in a small protective effect. Cells lacking the vacuolar zinc transporter Zrt3 were highly resistant to AA-RCD, exhibiting reduced vacuolar dysfunction. Moreover, zrt3Δ cells displayed higher ethanol productivity than their wild-type counterparts, both when cultivated in rich medium with AA (0.29 g L−1 h−1 versus 0.11 g L−1 h−1) and in an LH (0.73 g L−1 h−1 versus 0.55 g L−1 h−1). Overall, the deletion of ZRT3 emerges as a promising strategy to increase strain robustness in LE industrial production.

Lin Lin ◽  
Mu-Xin Zhang ◽  
Lei Zhang ◽  
Dan Zhang ◽  
Chao Li ◽  

Atherosclerosis is a chronic inflammatory disorder characterized by the gradual buildup of plaques within the vessel wall of middle-sized and large arteries. The occurrence and development of atherosclerosis and the rupture of plaques are related to the injury of vascular cells, including endothelial cells, smooth muscle cells, and macrophages. Autophagy is a subcellular process that plays an important role in the degradation of proteins and damaged organelles, and the autophagy disorder of vascular cells is closely related to atherosclerosis. Pyroptosis is a proinflammatory form of regulated cell death, while ferroptosis is a form of regulated nonapoptotic cell death involving overwhelming iron-dependent lipid peroxidation. Both of them exhibit distinct features from apoptosis, necrosis, and autophagy in morphology, biochemistry, and genetics. However, a growing body of evidence suggests that pyroptosis and ferroptosis interact with autophagy and participate in the development of cancers, degenerative brain diseases and cardiovascular diseases. This review updated the current understanding of autophagy, pyroptosis, and ferroptosis, finding potential links and their effects on atherogenesis and plaque stability, thus providing ways to develop new pharmacological strategies to address atherosclerosis and stabilize vulnerable, ruptured plaques.

2022 ◽  
Ning Liu ◽  
Zong Miao ◽  
Wei Tian ◽  
Zhongyuan Bao ◽  
Guangchi Sun ◽  

Abstract Background: Ferroptosis is a newly identified form of regulated cell death (RCD) characterized by the iron-dependent lipid reactive oxygen species (ROS) accumulation, but its exact mechanism in gliomas remains elusive. Acyl–coenzyme A (CoA) synthetase long-chain family member 4 (Acsl4), a pivotal enzyme in the regulation of lipid biosynthesis, has been found to benefit the initiation of ferroptosis, but its role in gliomas likewise needs clarification. Erastin, widely investigated as an inducer of ferroptosis, was recently found to regulate lipid peroxidation by regulating Acsl4 other than glutathione peroxidase 4 (GPX4) in ferroptosis. Methods: Relationship between Hsp90, Drp1 and Acsl4 was determined by Co-immunoprecipitation/ Mass spectrometry and western blot assay. The impact of Hsp90 and Drp1 on Acsl4-dependent ferroptosis was examined by lipid peroxidation indicators in patient-derived PL1 and PG7 cells. The morphological changes of mitochondria are observed by confocal-fluorescence microscopy and transmission electron microscope. Therapeutic efficacy of Erastin-induced ferroptosis in vivo was examined in xenograft mouse models.Results: In this study, we demonstrated that heat shock protein 90 (Hsp90) and dynamin-related protein 1 (Drp1) actively regulated Acsl4 expression in erastin-induced ferroptosis in gliomas. Hsp90 overexpression and calcineurin (CN)–mediated Drp1 dephosphorylation at serine 637 (Ser637) promoted ferroptosis by altering mitochondrial morphology and increasing Acsl4-mediated lipid peroxidation. Importantly, the Hsp90–Acsl4 pathway mediated Acsl4-dependent ferroptosis, amplifying the anticancer activity of erastin in vitro and in vivo. Conclusions: Our study not only uncovered an important role of Hsp90–Drp1–Acsl4 pathway in erastin-induced ferroptosis but also reveals an efficient mechanism of Acsl4 as a potential therapeutic target to ferroptosis-mediated glioma therapy.

2022 ◽  
Vol 5 (1) ◽  
Cliff J. Luke ◽  
Stephanie Markovina ◽  
Misty Good ◽  
Ira E. Wight ◽  
Brian J. Thomas ◽  

AbstractLysosomal membrane permeabilization (LMP) and cathepsin release typifies lysosome-dependent cell death (LDCD). However, LMP occurs in most regulated cell death programs suggesting LDCD is not an independent cell death pathway, but is conscripted to facilitate the final cellular demise by other cell death routines. Previously, we demonstrated that Caenorhabditis elegans (C. elegans) null for a cysteine protease inhibitor, srp-6, undergo a specific LDCD pathway characterized by LMP and cathepsin-dependent cytoplasmic proteolysis. We designated this cell death routine, lysoptosis, to distinguish it from other pathways employing LMP. In this study, mouse and human epithelial cells lacking srp-6 homologues, mSerpinb3a and SERPINB3, respectively, demonstrated a lysoptosis phenotype distinct from other cell death pathways. Like in C. elegans, this pathway depended on LMP and released cathepsins, predominantly cathepsin L. These studies suggested that lysoptosis is an evolutionarily-conserved eukaryotic LDCD that predominates in the absence of neutralizing endogenous inhibitors.

2022 ◽  
Benedikt Kolbrink ◽  
Theresa Riebeling ◽  
Nikolas K. Teiwes ◽  
Claudia Steinem ◽  
Hubert Kalbacher ◽  

Murine cytomegalovirus protein M45 contains a RIP homotypic interaction motif (RHIM) that is sufficient to confer protection of infected cells against necroptotic cell death. Mechanistically, the N-terminal region of M45 drives rapid self-assembly into homo-oligomeric amyloid fibrils, and interacts with the endogenous RHIM domains of receptor-interacting protein kinases (RIPK) 1, RIPK3, Z-DNA binding protein 1, and TIR domain-containing adaptor-inducing interferon-β. Remarkably, all four mammalian proteins harbouring such a RHIM domain are key components of inflammatory signalling and regulated cell death processes. Immunogenic cell death by regulated necrosis causes extensive tissue damage in a wide range of diseases, including ischemia reperfusion injury, myocardial infarction, sepsis, stroke and organ transplantation. To harness the cell death suppression properties of M45 protein in a therapeutically usable manner, we developed a synthetic peptide encompassing only the RHIM domain of M45. To trigger delivery of RHIM into target cells, we fused the transactivator protein transduction domain of human immunodeficiency virus 1 to the N-terminus of the peptide. The fused peptide could efficiently penetrate eukaryotic cells, but unexpectedly it killed all tested cancer cell lines and primary cells irrespective of species without further stimulus through a necrosis-like cell death. Typical inhibitors of different forms of regulated cell death cannot impede this process, which appears to involve a direct disruption of biomembranes. Nevertheless, our finding has potential clinical relevance; reliable induction of a necrotic form of cell death distinct from all known forms of regulated cell death may offer a novel therapeutic approach to combat resistant tumour cells.

2022 ◽  
Vol 29 ◽  
Nadia Zaffaroni ◽  
Giovanni Luca Beretta

Abstract: Lipid peroxidation-driven iron-dependent ferroptosis is a regulated cell death mechanism implicated in numerous disease, such as neurological diseases, kidney injury, ischemia, and tumors, including prostate cancer. The cellular mechanisms of ferrosptosis are strongly associated with iron, reactive oxygen species and aminoacid metabolic pathways. Several compounds, namely ferroptosis inducers, impact on these pathways and trigger ferroptosis by i) inhibiting Xc– transporter system, ii) impairing GPX4 functions and iii) oxidizing iron and polyunsaturated phospholipids. Preclinical studies showed that in combination with conventional anticancer drugs, ferroptosis inducers are effective in prostate cancer and in combating the progression towards the castration resistant disease. This review overviews the mechanisms implicated in ferroptosis and discusses the findings achieved in prostate cancer.

2022 ◽  
Vol 22 (1) ◽  
Qing Nie ◽  
Yue Hu ◽  
Xiao Yu ◽  
Xiao Li ◽  
Xuedong Fang

AbstractAt present, more than one cell death pathways have been found, one of which is ferroptosis. Ferroptosis was discovered in 2012 and described as an iron-dependent and lipid peroxidation-driven regulated cell death pathway. In the past few years, ferroptosis has been shown to induce tumor cell death, providing new ideas for tumor treatment. In this article, we summarize the latest advances in ferroptosis-induced tumor therapy at the intersection of tumor biology, molecular biology, redox biology, and materials chemistry. First, we state the characteristics of ferroptosis in cells, then introduce the key molecular mechanism of ferroptosis, and describes the relationship between ferroptosis and oxidative stress signaling pathways. Finally, we focused on several types of ferroptosis inducers discovered by scholars, and the application of ferroptosis in systemic chemotherapy, radiotherapy, immunotherapy and nanomedicine, in the hope that ferroptosis can exert its potential in the treatment of tumors.

Wei Dai ◽  
Yu Tian ◽  
Deqiang Luo ◽  
Qian Xie ◽  
Fen Liu ◽  

IntroductionSepsis is a leading cause of mortality in intensive care units worldwide. Ferroptosis, a form of regulated cell-death–related iron, has been proven to be altered during sepsis, including increased iron transport and uptake into cells and decreased iron export. A better understanding of the role of ferroptosis in sepsis should expedite the identification of biomarkers for prognostic evaluation and therapeutic interventions.Material and methodsWe used the mRNA expression profiles of sepsis patients from Gene Expression Omnibus (GEO) to analyze the expression level of ferroptosis-related genes and construct molecular subtypes.ResultsTwo distinct ferroptosis patterns were determined, and the overall survival of the two clusters was highly significantly different. Gene comparison analysis was performed on these two groups, and there were a total of 106 differentially expressed genes(DEGs). Pathway enrichment analysis of these genes showed that ferroptosis and immune-related pathways were enriched, suggesting that immune pathways might be critically involved in sepsis. To systematically predict the prognosis of sepsis, we constructed a nomogram model, the calibration plot nomogram showed excellent concordance for the 7-, 14-, and 28-days predicted and actual overall survival probabilities. Finally, the results of bioinformatics analysis were validated in animal and cell modelsConclusionsIn this study, we construct a ferroptosis-related nomogram that can be used for prognostic prediction in sepsis. In addition, we revealed the ferroptosis played a non-negligible role in immune cell infiltration and guiding more effective immunotherapy strategies.

2022 ◽  
Vol 13 (1) ◽  
Shuping Zhang ◽  
Wei Xin ◽  
Gregory J. Anderson ◽  
Ruibin Li ◽  
Ling Gao ◽  

AbstractIron is vital for many physiological functions, including energy production, and dysregulated iron homeostasis underlies a number of pathologies. Ferroptosis is a recently recognized form of regulated cell death that is characterized by iron dependency and lipid peroxidation, and this process has been reported to be involved in multiple diseases. The mechanisms underlying ferroptosis are complex, and involve both well-described pathways (including the iron-induced Fenton reaction, impaired antioxidant capacity, and mitochondrial dysfunction) and novel interactions linked to cellular energy production. In this review, we examine the contribution of iron to diverse metabolic activities and their relationship to ferroptosis. There is an emphasis on the role of iron in driving energy production and its link to ferroptosis under both physiological and pathological conditions. In conclusion, excess reactive oxygen species production driven by disordered iron metabolism, which induces Fenton reaction and/or impairs mitochondrial function and energy metabolism, is a key inducer of ferroptosis.

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