Targeting cellular mitophagy as a strategy for human cancers

Frontiers in Cell and Developmental Biology, Год журнала: 2024, Номер 12

Опубликована: Июль 5, 2024

Mitophagy is the cellular process to selectively eliminate dysfunctional mitochondria, governing number and quality of mitochondria. Dysregulation mitophagy may lead accumulation damaged which plays an important role in initiation development tumors. includes ubiquitin-dependent pathways mediated by PINK1/Parkin non-ubiquitin dependent mitochondrial autophagic receptors including NIX, BNIP3, FUNDC1. Cellular widely participates multiple metabolic reprogramming, anti-tumor immunity, ferroptosis, as well interaction between tumor cells tumor-microenvironment. And also regulates proliferation metastasis, stemness, chemoresistance, resistance targeted therapy radiotherapy. In this review, we summarized underlying molecular mechanisms discussed complex diverse contexts tumors, indicating it a promising target mitophagy-related therapy.

Язык: Английский

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Nanomaterials targeting iron homeostasis: a promising strategy for cancer treatment

Frontiers in Bioengineering and Biotechnology, Год журнала: 2025, Номер 13

Опубликована: Март 12, 2025

Iron is essential for vital cellular processes, including DNA synthesis, repair, and proliferation, necessitating enhanced iron uptake intracellular accumulation. Tumor cells, in particular, exhibit a pronounced elevation to sustain their continuous migration invasion. This elevated acquisition facilitated predominantly through the upregulation of transferrin receptors, which are closely associated with tumorigenesis tumor progression. Incorporating into drug delivery systems has been shown enhance cytotoxic effects drug-sensitive cancer offering potential method surpass limitations current therapies. Intracellular exists as ferritin heavy chain (FTH), light (FTL), labile pool (LIP). The innovation nanocarriers incorporating chelating agents attracted considerable interest. chelators such Deferoxamine (DFO), Deferasirox (DFX), Dp44mT have demonstrated significant promise treatment by inducing deficiency within cells. review explores recent advancements nanotechnology aimed at targeting metabolism cells discusses applications strategies.

Язык: Английский

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Galectin-8 drives ERK-dependent mitochondrial fragmentation, perinuclear relocation and mitophagy, with metabolic adaptations for cell proliferation

European Journal of Cell Biology, Год журнала: 2025, Номер unknown, С. 151488 - 151488

Опубликована: Апрель 1, 2025

Mitochondria adapt to the cell proliferative demands induced by growth factors through dynamic changes in morphology, distribution, and metabolic activity. Galectin-8 (Gal-8), a carbohydrate-binding protein that promotes proliferation transactivating EGFR-ERK signaling pathway, is overexpressed several cancers. However, its impact on mitochondrial dynamics during remains unknown. Using MDCK RPTEC kidney epithelial cells, we demonstrate Gal-8 induces fragmentation perinuclear redistribution. Additionally, mitochondria adopt donut-shaped morphologies, live-cell imaging with two Keima-based reporters demonstrates Gal-8-induced mitophagy. ERK inhibition abrogates all these proliferation. Studies established mutant versions of CHO cells reveal response require interactions between N-terminal carbohydrate recognition domain α-2,3-sialylated N-glycans at surface. DRP1, key regulator fission, becomes phosphorylated or an ERK-dependent manner, mediating Bafilomycin A proliferation, suggesting mitophagy serves as adaptation demands. Functional analysis under stimulation shows maintain active electron transport chain, partially uncoupled from ATP synthesis, increased membrane potential, indicative healthy mitochondria. Meanwhile, exhibit extracellular acidification rate lactate production via aerobic glycolysis, hallmark state. Our findings integrate adaptations potential implications for physiology, disease, therapeutic strategies.

Язык: Английский

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Mitochondria-organelle crosstalk in establishing compartmentalized metabolic homeostasis

Molecular Cell, Год журнала: 2025, Номер 85(8), С. 1487 - 1508

Опубликована: Апрель 1, 2025

Язык: Английский

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Gallium Uncouples Iron Metabolism to Enhance Glioblastoma Radiosensitivity

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(18), С. 10047 - 10047

Опубликована: Сен. 18, 2024

Gallium-based therapy has been considered a potentially effective cancer for decades and recently re-emerged as novel therapeutic strategy the management of glioblastoma tumors. Gallium targets iron-dependent phenotype associated with aggressive tumors by mimicking iron in circulation gaining intracellular access through transferrin-receptor-mediated endocytosis. Mechanistically, it is believed that gallium inhibits critical enzymes like ribonucleotide reductase NADH dehydrogenase (electron transport chain complex I) replacing removing ability to transfer electrons protein secondary structure. However, information regarding effects on cellular metabolism limited. As mitochondrial serves central hub metabolic network, goal this study was investigate cells. Here, discovered nitrate can induce depletion, which induction DNA damage. Moreover, generation gallium-resistant cell lines reveals highly unstable characterized impaired colony formation significant decrease content loss uptake transporter, mitoferrin-1. are significantly more sensitive radiation have an repair any sublethal damage survive lethal when left 24 h following radiation. These results support hypothesis disrupt serve potential radiosensitizer.

Язык: Английский

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Unraveling mechanisms of iron acquisition in malaria parasites

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Май 14, 2024

ABSTRACT Plasmodium falciparum malaria parasites invade and multiply inside red blood cells (RBCs), the most iron-rich compartment in humans. Like all cells, P. requires nutritional iron to support essential metabolic pathways, but critical mechanisms of acquisition trafficking during RBC infection have remained obscure. Parasites internalize liberate massive amounts heme large-scale digestion hemoglobin within an acidic food vacuole (FV) lack a oxygenase release porphyrin-bound iron. Although FV is sequestered into inert hemozoin crystals, prior studies indicate that trace escapes biomineralization susceptible non-enzymatic degradation oxidizing environment labile retain homolog divalent metal transporter 1 (DMT1), known mammalian transporter, its role has not been tested. Our phylogenetic DMT1 (PfDMT1) retains conserved molecular features for transport. We localized this protein membrane defined orientation export-competent topology. Conditional knockdown PfDMT1 expression lethal parasites, which display broad cellular defects iron-dependent functions, including impaired apicoplast biogenesis mitochondrial polarization. are selectively rescued from partial by supplementation with exogenous iron, other metals. These results paradigm whereby gatekeeper blood-stage suggest therapeutic targeting may be potent antimalarial strategy.

Язык: Английский

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Comparison of vinculin tension in cellular monolayers and three-dimensional multicellular aggregates

Biomedical Optics Express, Год журнала: 2024, Номер 15(9), С. 5199 - 5199

Опубликована: Авг. 6, 2024

Confocal frequency-domain fluorescence lifetime and Förster resonance energy transfer (FRET) microscopy of Chinese hamster ovary (CHO-K1) cells expressing the vinculin tension sensor (VinTS) is used to compare in three-dimensional (3D) multicellular aggregates 2D cellular monolayers. In both 3D cultures, FRET efficiency VinTS 5-6% lower than that VinTL (p < 0.05), a tail-less control which cannot bind actin or paxillin. The difference between can be mitigated by treatment with Rho-associated kinase inhibitor Y-27632, demonstrating under cultures. However, there an overall decrease compared Expression cultures exhibits puncta consistent adhesions. While paxillin present at sites expression monolayers, it generally absent from aggregates. results suggest experiences modified environment monolayers provide basis for further investigation molecular sensors tissue models.

Язык: Английский

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Identification of a divalent metal transporter required for cellular iron metabolism in malaria parasites

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(45)

Опубликована: Окт. 28, 2024

Plasmodium falciparum malaria parasites invade and multiply inside red blood cells (RBCs), the most iron-rich compartment in humans. Like all cells, P. requires nutritional iron to support essential metabolic pathways, but critical mechanisms of acquisition trafficking during RBC infection have remained obscure. Parasites internalize liberate massive amounts heme large-scale digestion hemoglobin within an acidic food vacuole (FV) lack a oxygenase release porphyrin-bound iron. Although FV is sequestered into inert hemozoin crystals, prior studies indicate that trace escapes biomineralization susceptible nonenzymatic degradation oxidizing environment labile retain homolog divalent metal transporter 1 (DMT1), known mammalian transporter, its role has not been tested. Our phylogenetic DMT1 (PfDMT1) retains conserved molecular features for transport. We localized this protein membrane defined orientation export-competent topology. Conditional knockdown PfDMT1 expression lethal parasites, which display broad cellular defects iron-dependent functions, including impaired apicoplast biogenesis mitochondrial polarization. are selectively rescued from partial by supplementation with exogenous iron, other metals. These results paradigm whereby gatekeeper blood-stage suggest therapeutic targeting may be potent antimalarial strategy.

Язык: Английский

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Iron Metabolism in Aminolevulinic Acid-Photodynamic Therapy with Iron Chelators from the Thiosemicarbazone Group

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(19), С. 10468 - 10468

Опубликована: Сен. 28, 2024

Iron plays a crucial role in various metabolic processes. However, the impact of 5-aminolevulinic acid (ALA) combination with iron chelators on metabolism and efficacy ALA-photodynamic therapy (PDT) remain inadequately understood. This study aimed to examine effect thiosemicarbazone derivatives during ALA treatment specific genes related metabolism, particular emphasis mitochondrial genes. In our study, we observed differences depending cell line studied. For HCT116 MCF-7 lines, most cases, decrease expression selected targets correlated increase protoporphyrin IX (PPIX) concentration photodynamic effect, aligning existing literature data. The Hs683 showed different gene pattern, previously not described literature. this collected an extensive analysis variation occurring after application novel presented versatile effective compounds great potential for use ALA-PDT.

Язык: Английский

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Modeling intratumor heterogeneity in breast cancer

Biofabrication, Год журнала: 2024, Номер 17(1), С. 012009 - 012009

Опубликована: Дек. 6, 2024

Reduced therapy response in breast cancer has been correlated with heterogeneity biomarker composition, expression level, and spatial distribution of cells within a patient tumor. Thus, there is need for models to replicate cell-cell, cell-stromal, cell-microenvironment interactions during progression. Traditional two-dimensional (2D) cell culture are convenient but cannot adequately represent tumor microenvironment histological organization,in vivo3D spatial/cellular context, physiological relevance. Recently, three-dimensional (3D)in vitrotumor have shown provide an improved platform incorporating compositional better mimic the biological characteristics tumors assess drug response. Advances 3D bioprinting allowed creation more complex physiologic representation while controlling reproducibility accuracy. This review aims summarize advantages challenges current 3Din vitromodels evaluating cancer, particular emphasis on bioprinting, addresses several key issues future model development as well their application other cancers.

Язык: Английский

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