Copper-dependent autophagic degradation of GPX4 drives ferroptosis

Autophagy, Journal Year: 2023, Volume and Issue: 19(7), P. 1982 - 1996

Published: Jan. 9, 2023

Ferroptosis is a type of iron-dependent regulated cell death characterized by unrestricted lipid peroxidation and membrane damage. Although GPX4 (glutathione peroxidase 4) plays master role in blocking ferroptosis eliminating phospholipid hydroperoxides, the regulation remains poorly understood. Here, we report an unexpected for copper promoting ferroptotic death, but not cuproptosis, inducing macroautophagic/autophagic degradation GPX4. Copper chelators reduce sensitivity do inhibit other types such as apoptosis, necroptosis, alkaliptosis. Conversely, exogenous increases ubiquitination formation aggregates directly binding to protein cysteines C107 C148. TAX1BP1 (Tax1 1) then acts autophagic receptor subsequent response stress. Consequently, enhances ferroptosis-mediated tumor suppression mouse model pancreatic cancer tumor, whereas attenuate experimental acute pancreatitis associated with ferroptosis. Taken together, these findings provide new insights into link between metal stress autophagy-dependent death.Abbreviations: CALCOCO2, calcium coiled-coil domain 2; GPX4, glutathione 4; MAP1LC3A/B, microtubule 1 light chain 3 alpha/beta; MPO, myeloperoxidase; NCOA4, nuclear coactivator OPTN, optineurin; PDAC, ductal adenocarcinoma; RIPK1, interacting serine/threonine kinase 1; ROS, reactive oxygen species; SLC40A1, solute carrier family 40 member SQSTM1, sequestosome TAX1BP1, Tax1 TEPA, tetraethylenepentamine; TM, tetrathiomolybdate.

Language: Английский

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Breakdown of an Ironclad Defense System: The Critical Role of NRF2 in Mediating Ferroptosis

Cell chemical biology, Journal Year: 2020, Volume and Issue: 27(4), P. 436 - 447

Published: April 1, 2020

Ferroptosis is a non-apoptotic mode of regulated cell death that iron and lipid peroxidation dependent. As new mechanistic insight into ferroptotic effectors how they are in different disease contexts uncovered, our understanding the physiological pathological relevance this continues to grow. Along these lines, host pharmacological modulators pathway have been identified, targeting proteins involved homeostasis; generation reduction peroxides; or cystine import glutathione metabolism. Also, note, many components ferroptosis cascade target genes transcription factor nuclear erythroid 2-related 2 (NRF2), indicating its critical role mediating response. In review, we discuss vitro, vivo, clinical evidence disease, including brief discussion upstream mediators cascade, NRF2, treat ferroptosis-driven diseases.

Language: Английский

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Autophagy: Regulator of cell death

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(10)

Published: Oct. 4, 2023

Abstract Autophagy is the process by which cells degrade and recycle proteins organelles to maintain intracellular homeostasis. Generally, autophagy plays a protective role in cells, but disruption of mechanisms or excessive autophagic flux usually leads cell death. Despite recent progress study regulation underlying molecular autophagy, numerous questions remain be answered. How does regulate death? What are fine-tuned regulatory autophagy-dependent death (ADCD) autophagy-mediated (AMCD)? In this article, we highlight different roles discuss six main autophagy-related modalities, with focus on metabolic changes caused endoplasmic reticulum-phagy (ER-phagy)-induced mitophagy ferroptosis. Finally, enhancement treatment diseases offer new perspective based use for functional conversions (including conversion that modalities) clinical tumors.

Language: Английский

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Copper metabolism in cell death and autophagy

Autophagy, Journal Year: 2023, Volume and Issue: 19(8), P. 2175 - 2195

Published: April 14, 2023

Copper is an essential trace element in biological systems, maintaining the activity of enzymes and function transcription factors. However, at high concentrations, copper ions show increased toxicity by inducing regulated cell death, such as apoptosis, paraptosis, pyroptosis, ferroptosis, cuproptosis. Furthermore, can trigger macroautophagy/autophagy, a lysosome-dependent degradation pathway that plays dual role regulating survival or death fate cells under various stress conditions. Pathologically, impaired metabolism due to environmental genetic causes implicated variety human diseases, rare Wilson disease common cancers. Therapeutically, copper-based compounds are potential chemotherapeutic agents be used alone combination with other drugs approaches treat cancer. Here, we review progress made understanding metabolic processes their impact on regulation autophagy. This knowledge may help design future clinical tools improve cancer diagnosis treatment.

Language: Английский

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Ferritinophagy is involved in the zinc oxide nanoparticles-induced ferroptosis of vascular endothelial cells

Autophagy, Journal Year: 2021, Volume and Issue: 17(12), P. 4266 - 4285

Published: April 12, 2021

Zinc oxide nanoparticles (ZnONPs) hold great promise for biomedical applications. Previous studies have revealed that ZnONPs exposure can induce toxicity in endothelial cells, but the underlying mechanisms not been fully elucidated. In this study, we report ferroptosis of both HUVECs and EA.hy926 as evidenced by elevation intracellular iron levels, lipid peroxidation cell death a dose- time-dependent manner. addition, reactive oxygen species (ROS) scavenger ferrostatin-1 chelator deferiprone attenuated ZnONPs-induced death. Intriguingly, found is macroautophagy/autophagy-dependent, because inhibition autophagy with pharmacological inhibitor or ATG5 gene knockout profoundly mitigated ferroptosis. We further demonstrated NCOA4 (nuclear receptor coactivator 4)-mediated ferritinophagy (autophagic degradation major storage protein ferritin) was required induced ZnONPs, showing knockdown reduce level peroxidation, subsequently alleviate Furthermore, showed ROS originating from mitochondria (mtROS) probably activated AMPK-ULK1 axis to trigger ferritinophagy. Most importantly, pulmonary caused vascular inflammation mice, supplementation significantly reversed injury exposure. Overall, our study indicates novel mechanism cytotoxicity, NCOA4-mediated ferroptotic

Language: Английский

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