Mitophagy coordinates the mitochondrial unfolded protein response to attenuate inflammation-mediated myocardial injury

Redox Biology, Год журнала: 2021, Номер 45, С. 102049 - 102049

Опубликована: Июнь 17, 2021

Mitochondrial dysfunction is a fundamental challenge in septic cardiomyopathy. Mitophagy and the mitochondrial unfolded protein response (UPRmt) are predominant stress-responsive protective mechanisms involved repairing damaged mitochondria. Although homeostasis requires coordinated actions of mitophagy UPRmt, their molecular basis interactive poorly understood sepsis-induced myocardial injury. Our investigations showed that lipopolysaccharide (LPS)-induced sepsis contributed to cardiac damage. both UPRmt were slightly activated by LPS cardiomyocytes, endogenous activation failed prevent sepsis-mediated However, administration urolithin A, an inducer mitophagy, obviously reduced depression normalizing function. Interestingly, this beneficial action was undetectable cardiomyocyte-specific FUNDC1 knockout (FUNDC1CKO) mice. Notably, supplementation with had no impact on whereas genetic ablation significantly upregulated expression genes related LPS-treated hearts. In contrast, enhancement through oligomycin injury dysfunction; cardioprotective effect imperceptible FUNDC1CKO Lastly, once inhibited, mitophagy-mediated protection mitochondria cardiomyocytes partly blunted. Taken together, it plausible stress they work together sustain performance Endogenous downstream signal played compensatory role maintaining case inhibition. negative inhibition compromised partial mitophagy. This study shows how modulates attenuate inflammation-related suggests potential application targeting treatment stress.

Язык: Английский

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ALOX15-launched PUFA-phospholipids peroxidation increases the susceptibility of ferroptosis in ischemia-induced myocardial damage

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Авг. 15, 2022

Abstract Myocardial ischemia/reperfusion (I/R) injury is a classic type of cardiovascular disease characterized by to cardiomyocytes leading various forms cell death. It believed that irreversible myocardial damage resulted from I/R occurs due oxidative stress evoked during the reperfusion phase. Here we demonstrate ischemia triggers specific redox reaction polyunsaturated fatty acids (PUFA)-phospholipids in cells, which acts as priming signaling initiates outbreak robust Using animal and vitro models, crucial lipid species were identified be oxidized PUFAs enriched phosphatidylethanolamines. multi-omics, arachidonic acid 15-lipoxygenase-1 (ALOX15) was primary mediator ischemia-provoked phospholipid peroxidation, further confirmed using chemogenetic approaches. Collectively, our results reveal ALOX15 induction phase “burning point” ignite oxidization into ferroptotic signals. This finding characterizes novel molecular mechanism for offers potential therapeutic target early intervention injury.

Язык: Английский

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Empagliflozin attenuates cardiac microvascular ischemia/reperfusion through activating the AMPKα1/ULK1/FUNDC1/mitophagy pathway

Redox Biology, Год журнала: 2022, Номер 52, С. 102288 - 102288

Опубликована: Март 18, 2022

Mitophagy preserves microvascular structure and function during myocardial ischemia/reperfusion (I/R) injury. Empagliflozin, an anti-diabetes drug, may also protect mitochondria. We explored whether empagliflozin could reduce cardiac I/R injury by enhancing mitophagy. In mice, induced luminal stenosis, microvessel wall damage, erythrocyte accumulation perfusion defects in the microcirculation. Additionally, triggered endothelial hyperpermeability neutrophil infiltration, which upregulated adhesive factors endothelin-1 but downregulated vascular cadherin nitric oxide synthase heart tissue. vitro, impaired barrier integrity of cells (CMECs), while preserved CMEC homeostasis thus maintained function. activated mitochondrial fission, oxidative stress apoptotic signaling CMECs, whereas normalized fission fusion, neutralized supraphysiologic reactive oxygen species concentrations suppressed apoptosis. Empagliflozin exerted these protective effects activating FUNDC1-dependent mitophagy through AMPKα1/ULK1 pathway. Both vitro vivo, genetic ablation AMPKα1 or FUNDC1 abolished beneficial on microvasculature CMECs. Taken together, preservation activation AMPKα1/ULK1/FUNDC1/mitophagy pathway is working mechanism attenuating

Язык: Английский

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Mitochondrial quality control mechanisms as molecular targets in diabetic heart

Metabolism, Год журнала: 2022, Номер 137, С. 155313 - 155313

Опубликована: Сен. 17, 2022

Язык: Английский

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Role of mitochondrial metabolic disorder and immune infiltration in diabetic cardiomyopathy: new insights from bioinformatics analysis

Journal of Translational Medicine, Год журнала: 2023, Номер 21(1)

Опубликована: Фев. 1, 2023

Diabetic cardiomyopathy (DCM) is one of the common cardiovascular complications diabetes and a leading cause death in diabetic patients. Mitochondrial metabolism immune-inflammation are key for DCM pathogenesis, but their crosstalk remains an open issue. This study explored separate roles mitochondrial immune microenvironment with bioinformatics.DCM chip data (GSE4745, GSE5606, GSE6880) were obtained from NCBI GEO, while gene downloaded MitoCarta3.0 database. Differentially expressed genes (DEGs) screened by GEO2R processed GSEA, GO KEGG pathway analyses. Mitochondria-related DEGs (MitoDEGs) obtained. A PPI network was constructed, hub MitoDEGs closely linked to or heart failure identified CytoHubba, MCODE CTD scores. Transcription factors target miRNAs predicted Cytoscape miRWalk database, respectively, regulatory established. The infiltration pattern analyzed ImmuCellAI, relationship between abundance investigated using Spearman method. rat model established validate expression cardiac function.MitoDEGs significantly enriched pathways involved metabolism, immunoregulation, collagen synthesis. Nine Immune analysis revealed increased B cells decreased DCs DCM. demonstrated that positively associated pro-inflammatory cells, negatively anti-inflammatory cells. In animal experiment, 4 (Pdk4, Hmgcs2, Decr1, Ivd) showed trend consistent bioinformatics result. Additionally, up-regulation Pdk4, Decr1 down-regulation Ivd distinctly reduced function.This unraveled interaction DCM, providing new insights into research on potential pathogenesis exploration novel targets medical interventions.

Язык: Английский

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Myocardial ischemia-reperfusion injury; Molecular mechanisms and prevention

Microvascular Research, Год журнала: 2023, Номер 149, С. 104565 - 104565

Опубликована: Июнь 10, 2023

Язык: Английский

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The traditional Chinese medicines treat chronic heart failure and their main bioactive constituents and mechanisms

Acta Pharmaceutica Sinica B, Год журнала: 2023, Номер 13(5), С. 1919 - 1955

Опубликована: Фев. 11, 2023

Chronic heart failure (CHF) is a severe public health problem with increasing morbidity and mortality, any treatment targeting single session insufficient to tackle this. CHF characterized by reduced cardiac output resulting from neurohumoral dysregulation remodeling, which might be related oxidative stress, inflammation, endoplasmic reticulum apoptosis, autophagy, mitochondrial function, angiogenesis. These molecular mechanisms interact each other through crosstalk. Historically, Chinese medicinal herbs have been widely applied in the of CHF, therapeutic effects their ingredients scientifically confirmed over past decades. Traditional medicine (TCM) multiple components can confront different pathogenesis targets. This review analyzes commonly used TCM patent drugs decoctions that are applicable stages based on clinical trials. Diverse bioactive found treat via mechanisms. comprehensively covers key works underlying TCM, herbal synergistic constituent compatibility treating providing additional ideas address this threat.

Язык: Английский

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Intravenous Transplantation of an Ischemic-specific Peptide-TPP-mitochondrial Compound Alleviates Myocardial Ischemic Reperfusion Injury

ACS Nano, Год журнала: 2023, Номер 17(2), С. 896 - 909

Опубликована: Янв. 10, 2023

It is known that mitochondrial dysfunction a critical factor involved in myocardial ischemia–reperfusion injury. Mitochondrial transplantation has been suggested as an effective therapeutic strategy to protect against However, its clinical translation remains limited because it requires the local injection of mitochondria into myocardium. Here, polypeptide, CSTSMLKAC (PEP), bound triphenylphosphonium cations (TPP+) effectively binds form PEP–TPP–mitochondrial compound. Further investigation this compound revealed ischemia-sensing properties PEP promote translocation ischemic Additionally, targeting peptide, PEP, readily dissociates from compound, allowing for transplanted be efficiently internalized by cardiomyocytes or transferred endothelial cells. promotes cardiomyocyte energetics and mechanical contraction, subsequently reducing cellular apoptosis, macrophage infiltration, pro-inflammatory response, all which lead attenuation Thus, study provides promising evidence intravenous myocardium ameliorates

Язык: Английский

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Involvement of mitochondrial dynamics and mitophagy in diabetic endothelial dysfunction and cardiac microvascular injury

Archives of Toxicology, Год журнала: 2023, Номер 97(12), С. 3023 - 3035

Опубликована: Сен. 14, 2023

Язык: Английский

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Morinda officinalis oligosaccharides mitigate depression-like behaviors in hypertension rats by regulating Mfn2-mediated mitophagy

Journal of Neuroinflammation, Год журнала: 2023, Номер 20(1)

Опубликована: Фев. 10, 2023

Patients with hypertension have a risk of depression. Morinda officinalis oligosaccharides (MOOs) anti-depressant properties. In this study, we aimed to determine whether MOOs can improve the symptoms depression in individuals hypertension.Dahl salt-sensitive rats fed high-salt diet were stimulated by chronic unpredictable mild stress mimic Primary astrocytes and neurons isolated from these rats. Astrocytes underwent LPS stimulation simulate inflammatory during administrated at 0.1 mg/g/day vivo 1.25, 2.5, 5 mg/mL vitro. Mitophagy was inhibited using mM 3-methyladenine (3-MA). Astrocyte-mediated neurotoxicity detected co-culturing neurons.MOOs decreased systolic pressure, diastolic mean arterial thereby improving depression-like behavior, including behavioral despair, lack enthusiasm, loss pleasure Furthermore, inflammation, astrocytic dysfunction, mitochondrial damage brain. Then, promoted autophagosome lysosome enriched mitochondria LPS-stimulated astrocytes. suppressed release tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1β undergoing stimulation. Importantly, rescued impaired co-cultured The effects on reversed 3-MA. Finally, upregulated LPS-downregulated Mfn2 expression inhibition partly Intriguingly, suppression activated PI3K/Akt/mTOR pathway treatment.Astrocytes develop neuroinflammation response activate pathway-mediated mitophagy, removing astrocytes.1. anti-hypertensive anti-depressive 2. inhibit inflammation injury 3. induce mitophagy activation damage. 4. upregulate 5. activates resist

Язык: Английский

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