ROS induced lipid peroxidation and their role in ferroptosis

Frontiers in Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 11

Published: Aug. 1, 2023

Reactive oxygen species (ROS) play a crucial part in the process of cell death, including apoptosis, autophagy, and ferroptosis. ROS involves oxidation lipids generate 4-hydroxynonenal other compounds associated with it. Ferroptosis may be facilitated by lipid peroxidation phospholipid bilayers. In order to offer novel ideas directions for investigation disorders connected these processes, we evaluate function which ultimately leads ferroptosis as well proposed crosstalk mechanisms between types programmed death.

Language: Английский

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Polysulfur-based bulking of dynamin-related protein 1 prevents ischemic sulfide catabolism and heart failure in mice

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 2, 2025

Abstract The presence of redox-active molecules containing catenated sulfur atoms (supersulfides) in living organisms has led to a review the concepts redox biology and its translational strategy. Glutathione (GSH) is body’s primary detoxifier antioxidant, oxidized form (GSSG) been considered as marker oxidative status. However, we report that GSSG, but not reduced GSH, prevents ischemic supersulfide catabolism-associated heart failure male mice by electrophilic modification dynamin-related protein (Drp1). In healthy exercised hearts, redox-sensitive Cys644 Drp1 highly S-glutathionylated. Nearly 40% normally polysulfidated, which preferential target for GSSG-mediated S-glutathionylation. S-glutathionylation resistant depolysulfidation-dependent mitochondrial hyperfission myocardial dysfunction caused hypoxic stress. MD simulation structure site-directed mutagenetic analysis reveal functional interaction between critical phosphorylation site Ser637, through Glu640. Bulky at via polysulfidation or reduces activity disrupting Ser637-Glu640-Cys644 interaction. Disruption nullifies cardioprotective effect GSSG against after infarction. Our findings suggest therapeutic potential supersulfide-based Cys bulking on disease.

Language: Английский

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Analysis and characterization of sulfane sulfur

Analytical Biochemistry, Journal Year: 2024, Volume and Issue: 687, P. 115458 - 115458

Published: Jan. 4, 2024

Language: Английский

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Sulfur metabolism as a new therapeutic target of heart failure

Journal of Pharmacological Sciences, Journal Year: 2024, Volume and Issue: 155(3), P. 75 - 83

Published: April 23, 2024

Sulfur-based redox signaling has long attracted attention as critical mechanisms underlying the development of cardiac diseases and resultant heart failure. Especially, post-translational modifications cysteine (Cys) thiols in proteins mediate oxidative stress-dependent remodeling including myocardial hypertrophy, senescence, interstitial fibrosis. However, we recently revealed existence Cys persulfides polysulfides cells tissues, which show higher activities than substantially contribute to energy metabolism. We have established simple evaluation methods that can detect inorganic abundantly expressed normal hearts are dramatically catabolized by exposure ischemic/hypoxic environmental electrophilic stress, causes vulnerability mechanical load. Accumulation hydrogen sulfide, a nucleophilic catabolite persulfides/polysulfides, may lead reductive stress ischemic hearts, perturbation polysulfide catabolism improve chronic failure after infarction mice. This review focuses on (patho)physiological role sulfur metabolism proposes during great potential new therapeutic strategy for treatment

Language: Английский

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Arylsulfonothioates: Thiol-Activated Donors of Hydropersulfides which are Excreted to Maintain Cellular Redox Homeostasis or Retained to Counter Oxidative Stress

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: 147(9), P. 7765 - 7776

Published: Feb. 18, 2025

Despite their biological significance, the study of hydropersulfides (RSSH) is often limited due to inherent instability. Here, we introduce arylsulfonothioates as thiol-activated RSSH donors and provide insight into cellular reactive sulfur species homeostasis. These precursors persulfidate physiologically relevant thiols (RSH) form corresponding RSSH. Real-time monitoring hydrogen sulfide (H2S) generation via membrane inlet mass spectrometry (MIMS) was employed follow production, revealing that electron-donating aryl substituents marginally slow release rates, whereas electron-withdrawing slightly accelerate release. Furthermore, with strong offer superior protection against doxorubicin (DOX)-induced cardiotoxicity. Experiments using H9c2 cardiomyocytes affirmed cell-permeability ability increase intracellular levels protein persulfidation levels. Notably, observe excretion extracellular medium. Further investigations revealed involvement cystine/glutamate antiporter SLC7A11, cotreatment its inhibitor, sulfasalazine, significantly reduce cells exhibit tolerance arylsulfonothioate 1g an 4-cyano group at 1 mM; however, inhibition cystine results in a minor decrease cell viability. Under oxidative stress conditions induced by DOX or peroxide (H2O2), diminishes confers cytoprotection H2O2-mediated toxicity. Our findings show adaptive responses levels, demonstrating under elevated maintain redox homeostasis retention protective response during stress.

Language: Английский

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Supersulfide prevents cigarette smoke extract-induced mitochondria hyperfission and cardiomyocyte early senescence by inhibiting Drp1-filamin complex formation

Journal of Pharmacological Sciences, Journal Year: 2023, Volume and Issue: 154(2), P. 127 - 135

Published: Dec. 27, 2023

Smoking is one of the most serious risk factors for cardiovascular diseases. Although cigarette mainstream and sidestream smoke are significant contributors to increased mortality morbidity, underlying mechanism still unclear. Here, we report that exposure rat neonatal cardiomyocytes extract (CSE) induces mitochondrial hyperfission-mediated myocardial senescence. CSE leads fission reactive oxygen species (ROS) production through complex formation between factor Drp1 actin-binding protein, filamin A. Pharmacological perturbation interaction A by cilnidipine gene knockdown or inhibited CSE-induced hyperfission ROS as well We previously reported activity controlled supersulfide-induced Cys644 polysulfidation. The redox-sensitive was critical CSE-mediated with administration supersulfide donor, Na2S3 also improved senescence induced CSE. Our results suggest important role Drp1-filamin on smoke-mediated cardiac contribution fission-associated

Language: Английский

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Cystathionine γ-Lyase Self-Inactivates by Polysulfidation during Cystine Metabolism

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(12), P. 9982 - 9982

Published: June 10, 2023

Cystathionine γ-lyase (CSE) is an enzyme responsible for the biosynthesis of cysteine from cystathionine in final step transsulfuration pathway. It also has β-lyase activity toward cystine, generating persulfide (Cys-SSH). The chemical reactivity Cys-SSH thought to be involved catalytic particular proteins via protein polysulfidation, formation -S-(S)n-H on their reactive residues. Cys136/171 residues CSE have been proposed redox-sensitive Herein, we investigated whether polysulfidation occurs at during cystine metabolism. Transfection wild-type into COS-7 cells resulted increased intracellular production, which was significantly when Cys136Val or Cys136/171Val mutants were transfected, instead enzyme. A biotin-polyethylene glycol-conjugated maleimide capture assay revealed that Cys136 In vitro incubation with CSE-enzymatically synthesized inhibition production. contrast, mutant CSEs (Cys136Val and Cys136/171Val) proved resistant inhibition. Cys-SSH-producing higher than Meanwhile, cysteine-producing this equivalent assumed could auto-inactivated Thus, residue may integral feature metabolism, functions down-regulate synthesis by

Language: Английский

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Increased intracellular persulfide levels attenuate HlyU-mediated hemolysin transcriptional activation in Vibrio cholerae

Journal of Biological Chemistry, Journal Year: 2023, Volume and Issue: 299(9), P. 105147 - 105147

Published: Aug. 10, 2023

The vertebrate host's immune system and resident commensal bacteria deploy a range of highly reactive small molecules that provide barrier against infections by microbial pathogens. Gut pathogens, such as Vibrio cholerae, sense respond to these stressors modulating the expression exotoxins are crucial for colonization. Here, we employ mass spectrometry-based profiling, metabolomics, assays, biophysical approaches show transcriptional activation hemolysin gene hlyA in V. cholerae is regulated intracellular forms sulfur with sulfur-sulfur bonds, termed species (RSS). We first present comprehensive sequence similarity network analysis arsenic repressor superfamily regulators, where RSS hydrogen peroxide sensors segregate into distinct clusters sequences. HlyU, activator belongs RSS-sensing cluster readily reacts organic persulfides, showing no reactivity or DNA dissociation following treatment glutathione disulfide peroxide. Surprisingly, cell cultures, both sulfide downregulate HlyU-dependent hlyA. However, metabolite profiling shows raise endogenous inorganic levels similar extent, accounting this crosstalk, confirming attenuates HlyU-mediated specific response RSS. These findings new evidence gut pathogens may harness an evolutionary adaptation allows them overcome inflammatory exotoxins.

Language: Английский

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Extracellularly secreted cysteine derived from cystine regulates oxidative and electrophilic stress in HepG2 cells

Free Radical Research, Journal Year: 2024, Volume and Issue: 58(5), P. 323 - 332

Published: May 3, 2024

While cysteine (CysSH) is known to be exported into the extracellular space, its biological significance not well understood. The present study examined movement of CysSH using stable isotope-labeled cystine (CysSSCys), which transported cells and reduced CysSH. Exposure HepG2 100 µM CysSSCys resulted in 70 labeled cell medium 1 h after exposure. When was collected incubated with either hydrogen peroxide (H2O2) or atmospheric electrophiles, such as 1,2-naphthoquinone, 1,4-naphthoquinone 1,4-benzoquinone, almost completely consumed. In contrast, levels were unaltered during exposure H2O2 for up 2 h, suggesting redox cycling CysSSCys/CysSH system. Experiments without changing containing from revealed that oxidative electrophilic modifications cellular proteins, caused by significantly repressed medium. We also participation enzymes and/or antioxidants intracellular reduction These results provide new findings derived plays a role regulation stress.

Language: Английский

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Supersulfide catabolism participates in maladaptive remodeling of cardiac cells

Journal of Pharmacological Sciences, Journal Year: 2024, Volume and Issue: 155(4), P. 121 - 130

Published: May 21, 2024

The atrophic myocardium resulting from mechanical unloading and nutritional deprivation is considered crucial as maladaptive remodeling directly associated with heart failure, well interstitial fibrosis. Conversely, myocardial hypertrophy hemodynamic loading perceived compensatory stress adaptation. We previously reported the abundant presence of highly redox-active polysulfide molecules, termed supersulfide, two or more sulfur atoms catenated in normal hearts, supersulfide catabolism pathologic hearts after infarction correlated worsened prognosis failure. However, impact on remains unclear. Here, we investigated involvement metabolism cardiomyocyte remodeling, using a model adenosine 5'-triphosphate (ATP) receptor-stimulated atrophy endothelin-1 neonatal rat cardiomyocytes. Results revealed contrasting changes intracellular its catabolite, hydrogen sulfide (H

Language: Английский

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