Mitophagy in cardiovascular diseases: molecular mechanisms, pathogenesis, and treatment

Trends in Molecular Medicine, Journal Year: 2022, Volume and Issue: 28(10), P. 836 - 849

Published: July 22, 2022

Language: Английский

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Aspirin promotes RSL3-induced ferroptosis by suppressing mTOR/SREBP-1/SCD1-mediated lipogenesis in PIK3CA-mutant colorectal cancer

Redox Biology, Journal Year: 2022, Volume and Issue: 55, P. 102426 - 102426

Published: Aug. 4, 2022

Ferroptosis, a new form of regulated cell death triggered by the iron-dependent peroxidation phospholipids, is associated with cellular metabolism, redox homeostasis, and various signaling pathways related to cancer. Aspirin widely used non-steroidal anti-inflammatory drug (NSAID) has been reported show therapeutic benefit in cancers harboring oncogenic PIK3CA, which encodes catalytic p110α subunit phosphoinositide 3-kinase (PI3K). In this study, we found that aspirin sensitized cancer cells activation PIK3CA ferroptosis induction. Mechanistically, inhibited protein kinase B (AKT)/mammalian target rapamycin (mTOR) signaling, suppressed downstream sterol regulatory element-binding 1 (SREBP-1) expression, attenuated stearoyl-CoA desaturase-1 (SCD1)-mediated lipogenesis monounsaturated fatty acids, thus promoting RSL3-induced colorectal (CRC) cells. Moreover, genetic ablation SREBP-1 or SCD1 conferred greater sensitivity Conversely, ectopic expression restored resistance CRC abolished effect on cytotoxicity. Additionally, synergistic effects RSL3 were confirmed xenograft mouse model. The combined use resulted significant tumor suppression. Our work demonstrated enhanced cytotoxic PIK3CA-mutant cancers, combination inducer displayed promising treatment.

Language: Английский

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The crosstalk between ferroptosis and mitochondrial dynamic regulatory networks

International Journal of Biological Sciences, Journal Year: 2023, Volume and Issue: 19(9), P. 2756 - 2771

Published: Jan. 1, 2023

Ferroptosis is an iron-driven cell death modality characterized by iron accumulation and excessive lipid peroxidation.Ferroptosis closely related to mitochondrial function, as indicated studies showing that dysfunction damage promote oxidative stress, which in turn induces ferroptosis.Mitochondria play crucial roles cellular homeostasis, abnormalities their morphology function are associated with the development of many diseases.Mitochondria highly dynamic organelles, stability maintained through a series regulatory pathways.Mitochondrial homeostasis dynamically regulated, mainly via key processes such fission, fusion mitophagy; however, prone dysregulation.Mitochondrial fission mitophagy intimately ferroptosis.Therefore, investigations into regulation during ferroptosis important provide better understanding disease.In this paper, we systematically summarized changes ferroptosis, in-depth mechanism underlying corresponding reference for treatment diseases.

Language: Английский

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FUNDC1 protects against doxorubicin-induced cardiomyocyte PANoptosis through stabilizing mtDNA via interaction with TUFM

Cell Death and Disease, Journal Year: 2022, Volume and Issue: 13(12)

Published: Dec. 5, 2022

Abstract Doxorubicin (DOX) is an effective anthracycline chemotherapeutic anticancer drug with its life-threatening cardiotoxicity severely limiting clinical application. Mitochondrial damage-induced cardiomyocyte death considered essential cue for DOX cardiotoxicity. FUN14 domain containing 1 (FUNDC1) a mitochondrial membrane protein participating in the regulation of integrity multiple diseases although role cardiomyopathy remains elusive. Here, we examined whether PANoptosis, novel type programmed cell closely associated damage, was involved DOX-induced heart injury, and FUNDC1-mediated if any. FUNDC1 downregulated tissues patients dilated (DCM) DOX-challenged mice. deficiency aggravated cardiac dysfunction, PANoptosis. Further examination revealed that countered cytoplasmic release DNA (mtDNA) activation PANoptosome through interaction Tu translation elongation factor (TUFM), key translational expression repair DNA, via 96–133 amino acid domain. TUFM intervention reversed FUNDC1-elicited protection against mtDNA cytosolic Our findings shed light toward beneficial thus offering therapeutic promises

Language: Английский

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PANoptosis: Mechanisms, biology, and role in disease

Immunological Reviews, Journal Year: 2023, Volume and Issue: 321(1), P. 246 - 262

Published: Oct. 12, 2023

Summary Cell death can be executed through distinct subroutines. PANoptosis is a unique inflammatory cell modality involving the interactions between pyroptosis, apoptosis, and necroptosis, which mediated by multifaceted PANoptosome complexes assembled via integrating components from other modalities. There growing interest in process function of PANoptosis. Accumulating evidence suggests that occurs under diverse stimuli, for example, viral or bacterial infection, cytokine storm, cancer. Given impact across disease spectrum, this review briefly describes relationships highlights key molecules formation activation, outlines roles diseases together with potential therapeutic targeting. We also discuss important concepts pressing issues future research. Improved understanding its mechanisms crucial identifying novel targets strategies.

Language: Английский

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STAT3 signaling promotes cardiac injury by upregulating NCOA4-mediated ferritinophagy and ferroptosis in high-fat-diet fed mice

Free Radical Biology and Medicine, Journal Year: 2023, Volume and Issue: 201, P. 111 - 125

Published: March 20, 2023

High-fat diet (HFD) intake provokes obesity and cardiac anomalies. Recent studies have found that ferroptosis plays a role in HFD-induced injury, but the underlying mechanism is largely unclear. Ferritinophagy an important part of regulated by nuclear receptor coactivator 4 (NCOA4). However, relationship between ferritinophagy damage has not been explored. In this study, we oleic acid/palmitic acid (OA/PA) increased level ferroptotic events including iron ROS accumulation, upregulation PTGS2 mRNA protein levels, reduced SOD GSH significant mitochondrial H9C2 cells, which could be reversed inhibitor ferrostatin-1 (Fer-1). Intriguingly, autophagy 3-methyladenine mitigated OA/PA-induced ferritin downregulation, overload ferroptosis. OA/PA NCOA4. Knockdown NCOA4 SiRNA partly reduction ferritin, lipid peroxidation, subsequently alleviated cell death, indicating NCOA4-mediated was required for Furthermore, demonstrated IL-6/STAT3 signaling. Inhibition or knockdown STAT3 effectively levels to protect cells from ferritinophagy-mediated ferroptosis, whereas overexpression plasmid appeared increase expression contribute classical events. Consistently, phosphorylated upregulation, activation, induction also occurred HFD-fed mice were responsible injury. addition, evidence piperlongumine, natural compound, cardiomyocytes both vitro vivo. Based on these findings, concluded one critical mechanisms contributing The STAT3/NCOA4/FTH1 axis might novel therapeutic target treatment

Language: Английский

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EGCG attenuated acute myocardial infarction by inhibiting ferroptosis via miR-450b-5p/ACSL4 axis

Phytomedicine, Journal Year: 2023, Volume and Issue: 119, P. 154999 - 154999

Published: July 28, 2023

Epigallocatechin gallate (EGCG) has multiple biological effects such as anti-tumor drug resistance, antioxidation and anti-inflammatory properties. Ferroptosis is the main driving factor of ischemic heart injury, thus inhibiting ferroptosis may prove to be an effective treatment strategy for cardiovascular diseases. However, role EGCG on in myocardium underlying mechanisms remain uncertain.This study was aimed investigate potential myocardial ischemic-induced both vitro vivo.Cardiomyocyte hypoxia model mouse acute infarction (AMI) were established vivo. MiR-450b-5p ACSL4 silencing or overexpression plasmids transfected, with without pretreatment. Cell viability determined by CCK-8 assay. Hematoxylin eosin (HE) staining transmission electron microscopy (TEM) used evaluate morphologic alterations. TTC observe area, echocardiography adopted appraise function. Using flow cytometry, presence reactive oxygen species (ROS) assessed. The content cardiac troponin I (cTn I), glutathione (GSH), malondialdehyde (MDA), divalent iron ions (Fe2+) superoxide dismutase (SOD) detected using reagent kits. A luciferase activity assay performed assess binding ability miR-450b-5p ACSL4. Expressions related genes proteins measured RT-qPCR western blotting respectively.EGCG attenuated AMI-induced improved ischemia which associated reducing deposition cTn I, inhibition lipid peroxidation, decreasing TFR1 ACSL4, upregulating SLC7A11, FTH1 GPX4. Meanwhile, pretreatment increased expression myocardium. Further researches discovered that knockdown partially compromised EGCG-generated protective effect HL-1 cells, while combination mimic could strengthen potency dual-luciferase test demonstrated Furthermore, synergistically cardioprotective EGCG. More significantly, regulated ferroptosis-related via miR-450b-5p/ACSL4 axis.In summary, present evidently attenuates injury targeting ferroptosis. Our work revealed axis AMI first time. Further, it also elucidated molecular greatly depend axis, suggesting act a novel anti-ferroptosis agent exert therapeutic AMI.

Language: Английский

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Cardiovascular disease: Mitochondrial dynamics and mitophagy crosstalk mechanisms with novel programmed cell death and macrophage polarisation

Pharmacological Research, Journal Year: 2024, Volume and Issue: 206, P. 107258 - 107258

Published: June 21, 2024

Several cardiovascular illnesses are associated with aberrant activation of cellular pyroptosis, ferroptosis, necroptosis, cuproptosis, disulfidptosis and macrophage polarisation as hallmarks contributing to vascular damage abnormal cardiac function. Meanwhile, these three novel forms dysfunction closely related mitochondrial homeostasis. Mitochondria the main organelles that supply energy maintain Mitochondrial stability is maintained through a series regulatory pathways, such fission, fusion mitophagy. Studies have shown (e.g., impaired dynamics mitophagy) promotes ROS production, leading oxidative stress, which induces M1 phenotypic polarisation. Therefore, an in-depth knowledge dynamic regulation mitochondria during necessary understand disease development. This paper systematically summarises impact changes in mitophagy on regulating dysfunctions promote understanding pathogenesis diseases provide corresponding theoretical references for treating diseases.

Language: Английский

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Inhibition of METTL3 ameliorates doxorubicin-induced cardiotoxicity through suppression of TFRC-mediated ferroptosis

Redox Biology, Journal Year: 2024, Volume and Issue: 72, P. 103157 - 103157

Published: April 12, 2024

Doxorubicin (DOX) is a chemotherapeutic drug, while its clinical use greatly limited by the life-threatening cardiotoxicity. N6-methyladenosine (m6A) RNA modification participates in varieties of cellular processes. Nonetheless, it remains elusive whether m6A and methyltransferase METTL3 are involved progression DOX-induced cardiotoxicity (DIC). Mice were administrated with DOX (accumulative dosage 20 mg/kg) repeatedly to establish chronic DIC model. Cardiomyocyte-specific conditional knockout mice employed evaluate effects altered on DIC. The cardiomyocyte ferroptosis also examined response stimulation. led increased levels expression cardiomyocytes c-Jun-dependent manner. METTL3-knockout exhibited improved cardiac function, remodeling injury following insult. Besides, inhibition alleviated iron accumulation cardiomyocytes, whereas overexpression exerted opposite effects. Mechanistically, promoted TFRC mRNA, critical gene governing uptake, enhanced stability through recognition reader protein, IGF2BP2. Moreover, pharmacological administration highly selective inhibitor STM2457 effectively ameliorated mice. plays cardinal role etiology regulating metabolism modification. Inhibition might be potential therapeutic avenue for

Language: Английский

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α-Ketoglutarate improves cardiac insufficiency through NAD+-SIRT1 signaling-mediated mitophagy and ferroptosis in pressure overload-induced mice

Molecular Medicine, Journal Year: 2024, Volume and Issue: 30(1)

Published: Jan. 22, 2024

Abstract Background In heart failure (HF), mitochondrial dysfunction and metabolic remodeling lead to a reduction in energy productivity aggravate cardiomyocyte injury. Supplementation with α-ketoglutarate (AKG) alleviated myocardial hypertrophy fibrosis mice HF improved cardiac insufficiency. However, the protective mechanism of AKG remains unclear. We verified hypothesis that improves function by upregulating NAD + levels activating silent information regulator 2 homolog 1 (SIRT1) cardiomyocytes. Methods vivo, 2% was added drinking water undergoing transverse aortic constriction (TAC) surgery. Echocardiography biopsy were performed evaluate pathological changes. Myocardial metabolomics analyzed liquid chromatography‒mass spectrometry (LC‒MS/MS) at 8 weeks after vitro, expression SIRT1 or PINK1 proteins inhibited selective inhibitors siRNA cardiomyocytes stimulated angiotensin II (AngII) AKG. detected using an test kit. Mitophagy ferroptosis evaluated Western blotting, qPCR, JC-1 staining lipid peroxidation analysis. Results supplementation TAC surgery could alleviate improve mice. Metabolites malate-aspartate shuttle (MAS) increased, but TCA cycle fatty acid metabolism pathway be myocardium supplementation. Decreased protein observed AngII-treated After treatment, these changes reversed, increased mitophagy, ferroptosis, damage observed. When inhibitor siRNA, effect suppressed. Conclusion can hypertrophy, chronic insufficiency caused pressure overload. By increasing level , SIRT-PINK1 SIRT1-GPX4 signaling pathways are activated promote mitophagy inhibit cardiomyocytes, which ultimately alleviates damage.

Language: Английский

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