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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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 therapeutic targets in doxorubicin-induced cardiotoxicity

Trends in Pharmacological Sciences, Год журнала: 2022, Номер 44(1), С. 34 - 49

Опубликована: Ноя. 14, 2022

Язык: Английский

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Molecular Mechanisms of Mitochondrial Quality Control in Ischemic Cardiomyopathy

International Journal of Biological Sciences, Год журнала: 2022, Номер 19(2), С. 426 - 448

Опубликована: Дек. 19, 2022

Ischemic cardiomyopathy (ICM) is a special type of coronary heart disease or an advanced stage the disease, which related to pathological mechanism primary dilated cardiomyopathy. mainly occurs in long-term myocardial ischemia, resulting diffuse fibrosis. This turn affects cardiac ejection function, significant impact on systolic and diastolic decrease fraction. The pathogenesis ICM closely disease. Mainly due atherosclerosis caused by stenosis vascular occlusion, causing inflammatory lesions thrombosis. As progresses, it leads ischemia eventually ICM. mechanisms inflammation, hypertrophy, fibrosis remodeling. Mitochondria are organelles with double-membrane structure, so composition mitochondrial outer compartment basically similar that cytoplasm. When ischemia-reperfusion induces large influx calcium into cell, concentration ions also increases. subsequent opening membrane permeability transition pore inner overload homeostasis cardiomyocytes activates pathway apoptosis. Mitochondrial Quality Control (MQC), as important for regulating function cardiomyocytes, morphological structure/function lifespan mitochondria. In this review, we discuss role MQC (including mitophagy, dynamics, biosynthesis) provide evidence targeting

Язык: Английский

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Molecular mechanisms of coronary microvascular endothelial dysfunction in diabetes mellitus: focus on mitochondrial quality surveillance

Angiogenesis, Год журнала: 2022, Номер 25(3), С. 307 - 329

Опубликована: Март 18, 2022

Язык: Английский

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Therapeutic strategies in ischemic cardiomyopathy: Focus on mitochondrial quality surveillance

EBioMedicine, Год журнала: 2022, Номер 84, С. 104260 - 104260

Опубликована: Сен. 19, 2022

Язык: Английский

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New insights into the role of mitochondrial metabolic dysregulation and immune infiltration in septic cardiomyopathy by integrated bioinformatics analysis and experimental validation

Cellular & Molecular Biology Letters, Год журнала: 2024, Номер 29(1)

Опубликована: Янв. 30, 2024

Abstract Background Septic cardiomyopathy (SCM), a common cardiovascular comorbidity of sepsis, has emerged among the leading causes death in patients with sepsis. SCM’s pathogenesis is strongly affected by mitochondrial metabolic dysregulation and immune infiltration disorder. However, specific mechanisms their intricate interactions SCM remain unclear. This study employed bioinformatics analysis drug discovery approaches to identify regulatory molecules, distinct functions, underlying metabolism microenvironment, along potential interventional strategies SCM. Methods GSE79962, GSE171546, GSE167363 datasets were obtained from Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) module identified using Limma Weighted Correlation Network Analysis (WGCNA), followed functional enrichment analysis. Machine learning algorithms, including support vector machine–recursive feature elimination (SVM–RFE), least absolute shrinkage selection operator (LASSO) regression, random forest, used screen mitochondria-related hub for early diagnosis Subsequently, nomogram was developed based on six genes. The immunological landscape evaluated single-sample gene set (ssGSEA). We also explored expression pattern distribution mitochondria/inflammation-related pathways UMAP plots single-cell dataset. Potential drugs Drug Signatures Database (DSigDB). In vivo vitro experiments performed validate pathogenetic mechanism therapeutic efficacy candidate drugs. Results Six DEGs [MitoDEGs; translocase inner membrane domain-containing 1 (TIMMDC1), ribosomal protein S31 (MRPS31), F-box only 7 (FBXO7), phosphatidylglycerophosphate synthase (PGS1), LYR motif containing (LYRM7), chaperone BCS1 (BCS1L)] identified. diagnostic model demonstrated high reliability validity both training validation sets. microenvironment differed between control groups. Spearman correlation revealed that MitoDEGs significantly associated cells. Upregulated showed remarkably naive/memory B cell, CD14 + monocyte, plasma cell subgroup, evidenced plot. varied across subgroups individuals. Metformin predicted be most promising highest combined score. Its restoring function suppressing inflammatory responses been validated. Conclusions presents comprehensive SCM, providing novel direction medical intervention

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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Mitochondrial dysfunction: A fatal blow in depression

Biomedicine & Pharmacotherapy, Год журнала: 2023, Номер 167, С. 115652 - 115652

Опубликована: Окт. 4, 2023

Mitochondria maintain the normal physiological function of nerve cells by producing sufficient cellular energy and performing crucial roles in maintaining metabolic balance through intracellular Ca2+ homeostasis, oxidative stress, axonal development. Depression is a prevalent psychiatric disorder with an unclear pathophysiology. Damage to hippocampal neurons key component plasticity regulation synapses plays critical role mechanism depression. There evidence suggesting that mitochondrial dysfunction associated synaptic impairment. The maintenance homeostasis includes quantitative quality control mitochondria. Mitochondrial biogenesis produces new healthy mitochondria, dynamics cooperates mitophagy remove damaged These processes population stability exert neuroprotective effects against early In contrast, observed various brain regions patients major depressive disorders. accumulation defective mitochondria accelerates dysfunction. addition, impaired aggravate alterations microenvironment, promoting neuroinflammation depletion, thereby exacerbating development This review summarizes influence underlying molecular pathways on pathogenesis Additionally, we discuss as potential therapeutic strategy for

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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