The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease

Nature Reviews Cardiology, Год журнала: 2022, Номер 20(1), С. 7 - 23

Опубликована: Июль 4, 2022

Язык: Английский

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Mechanisms controlling cellular and systemic iron homeostasis

Nature Reviews Molecular Cell Biology, Год журнала: 2023, Номер 25(2), С. 133 - 155

Опубликована: Окт. 2, 2023

Язык: Английский

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Fin56-induced ferroptosis is supported by autophagy-mediated GPX4 degradation and functions synergistically with mTOR inhibition to kill bladder cancer cells

Cell Death and Disease, Год журнала: 2021, Номер 12(11)

Опубликована: Окт. 29, 2021

Abstract Ferroptosis is a form of regulated cell death that emerges to be relevant for therapy-resistant and dedifferentiating cancers. Although several lines evidence suggest ferroptosis type autophagy-dependent death, the underlying molecular mechanisms remain unclear. Fin56, 3 inducer, triggers by promoting glutathione peroxidase 4 (GPX4) protein degradation via not fully understood pathway. Here, we determined Fin56 induces autophagy in bladder cancer cells Fin56-triggered mechanistically depends on autophagic machinery. Furthermore, found inhibition at different stages attenuates Fin56-induced oxidative stress GPX4 degradation. Moreover, investigated effects combination with Torin 2, potent mTOR inhibitor used activate autophagy, viability. We synergizes 2 cytotoxicity against cells. Collectively, our findings only support concept but imply combined application inducers inhibitors promising approach improve therapeutic options treatment cancer.

Язык: Английский

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GOT1 inhibition promotes pancreatic cancer cell death by ferroptosis

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Авг. 11, 2021

Abstract Cancer metabolism is rewired to support cell survival in response intrinsic and environmental stressors. Identification of strategies target these adaptions an area active research. We previously described a cytosolic aspartate aminotransaminase (GOT1)-driven pathway pancreatic cancer used maintain redox balance. Here, we sought identify metabolic dependencies following GOT1 inhibition exploit this feature provide additional insight into regulation metabolism. Using pharmacological methods, cysteine, glutathione, lipid antioxidant function as vulnerabilities withdrawal. demonstrate that targeting any pathways triggers ferroptosis, oxidative, iron-dependent form death, knockdown cells. Mechanistically, reveal represses mitochondrial promotes catabolic state. Consequently, find enhances labile iron availability through autophagy, which potentiates the activity ferroptotic stimuli. Overall, our study identifies biochemical connection between GOT1, regulation, ferroptosis.

Язык: Английский

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Ferroptosis in cancer: From molecular mechanisms to therapeutic strategies

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Март 8, 2024

Ferroptosis is a non-apoptotic form of regulated cell death characterized by the lethal accumulation iron-dependent membrane-localized lipid peroxides. It acts as an innate tumor suppressor mechanism and participates in biological processes tumors. Intriguingly, mesenchymal dedifferentiated cancer cells, which are usually resistant to apoptosis traditional therapies, exquisitely vulnerable ferroptosis, further underscoring its potential treatment approach for cancers, especially refractory cancers. However, impact ferroptosis on extends beyond direct cytotoxic effect cells. induction not only inhibits but also promotes development due negative anticancer immunity. Thus, comprehensive understanding role crucial successful translation therapy from laboratory clinical applications. In this review, we provide overview recent advancements cancer, covering molecular mechanisms, functions, regulatory pathways, interactions with microenvironment. We summarize applications immunotherapy, radiotherapy, systemic therapy, well inhibition various conditions. finally discuss markers, current challenges future directions cancer.

Язык: Английский

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Molecular Mechanisms of Iron and Heme Metabolism

Annual Review of Nutrition, Год журнала: 2022, Номер 42(1), С. 311 - 335

Опубликована: Май 4, 2022

An abundant metal in the human body, iron is essential for key biological pathways including oxygen transport, DNA metabolism, and mitochondrial function. Most bound to heme but it can also be incorporated into iron-sulfur clusters or bind directly proteins. Iron's capacity cycle between Fe2+ Fe3+ contributes its utility renders toxic excess. Heme an iron-containing tetrapyrrole diverse functions gas transport sensing, oxidative xenobiotic detoxification. Like iron, yet As such, both homeostasis are tightly regulated. Here we discuss molecular physiologic aspects of metabolism. We focus on dietary absorption; cellular import; utilization; export, recycling, elimination, emphasizing studies published recent years. end with a discussion current challenges needs field biology.

Язык: Английский

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Lysosome dysfunction as a cause of neurodegenerative diseases: Lessons from frontotemporal dementia and amyotrophic lateral sclerosis

Neurobiology of Disease, Год журнала: 2021, Номер 154, С. 105360 - 105360

Опубликована: Апрель 1, 2021

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal neurodegenerative disorders that thought to exist on a clinical pathological spectrum. FTD ALS linked by shared genetic causes (e.g. C9orf72 hexanucleotide repeat expansions) neuropathology, such as inclusions of ubiquitinated, misfolded proteins TAR DNA-binding protein 43; TDP-43) in the CNS. Furthermore, some genes cause or when mutated encode localize lysosome modulate endosome-lysosome function, including lysosomal fusion, cargo trafficking, acidification, autophagy, TFEB activity. In this review, we summarize evidence dysfunction, caused mutations C9orf72, GRN, MAPT, TMEM106B) toxic-gain function aggregation TDP-43 tau), is an important pathogenic disease mechanism ALS. Further studies into normal many these required will help uncover mechanisms dysfunction Mutations polymorphisms for also occur other age-dependent diseases, Alzheimer's APOE, PSEN1, APP) Parkinson's GBA, LRRK2, ATP13A2) disease. A more complete understanding common unique features across spectrum neurodegeneration guide development therapies devastating diseases.

Язык: Английский

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NPC1-mTORC1 Signaling Couples Cholesterol Sensing to Organelle Homeostasis and Is a Targetable Pathway in Niemann-Pick Type C

Developmental Cell, Год журнала: 2020, Номер 56(3), С. 260 - 276.e7

Опубликована: Дек. 12, 2020

Язык: Английский

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Iron Metabolism and Immune Regulation

Frontiers in Immunology, Год журнала: 2022, Номер 13

Опубликована: Март 23, 2022

Iron is a critical element for living cells in terrestrial life. Although iron metabolism strictly controlled the body, disturbance of homeostasis under certain type condition leads to innate and adaptive immune response. In immunity, regulates macrophage polarizations, neutrophils recruitment, NK activity. had an effect on activation differentiation Th1, Th2, Th17 CTL, antibody response B cells. this review, we focused regulation listed specific role polarization, T-cell activation, B-cells addition, correlations between several diseases such as cancer aging degenerative some therapeutic strategies targeting those are also discussed.

Язык: Английский

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The emerging roles of vacuolar-type ATPase-dependent Lysosomal acidification in neurodegenerative diseases

Translational Neurodegeneration, Год журнала: 2020, Номер 9(1)

Опубликована: Май 11, 2020

Abstract Background Lysosomes digest extracellular material from the endocytic pathway and intracellular autophagic pathway. This process is performed by resident hydrolytic enzymes activated highly acidic pH within lysosomal lumen. Lysosome gradients are mainly maintained vacuolar (H + ) ATPase (or V-ATPase), which pumps protons into lumen consuming ATP. Dysfunction of V-ATPase affects acidification, disrupts clearance substrates leads to many disorders, including neurodegenerative diseases. Main body As a large multi-subunit complex, composed an integral membrane V0 domain involved in proton translocation peripheral V1 catalyzing ATP hydrolysis. The canonical functions rely on its H -pumping ability multiple vesicle organelles regulate traffic, protein processing degradation, synaptic loading, coupled transport. other non-canonical effects that not readily attributable proton-pumping activity include fusion, sensing, amino-acid-induced activation mTORC1, scaffolding for protein-protein interaction. In response various stimuli, complex can reversibly dissociate domains thus close ATP-dependent Dysregulation dysfunction have been linked human diseases, disorders such as Alzheimer disease, Parkinson’s amyotrophic lateral sclerosis well storage disorders. Conclusion universal pump plays important role lysosome acidification all types cells. Since contributes pathogenesis further understanding mechanisms will reveal molecular details disease help assess or molecules related regulation therapeutic targets.

Язык: Английский

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