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

Redox Biology, Journal Year: 2021, Volume and Issue: 45, P. 102049 - 102049

Published: June 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.

Language: Английский

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

Redox Biology, Journal Year: 2022, Volume and Issue: 52, P. 102288 - 102288

Published: March 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

Language: Английский

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Mitochondrial quality control mechanisms as molecular targets in diabetic heart

Metabolism, Journal Year: 2022, Volume and Issue: 137, P. 155313 - 155313

Published: Sept. 17, 2022

Language: Английский

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

Angiogenesis, Journal Year: 2022, Volume and Issue: 25(3), P. 307 - 329

Published: March 18, 2022

Language: Английский

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Therapeutic strategies in ischemic cardiomyopathy: Focus on mitochondrial quality surveillance

EBioMedicine, Journal Year: 2022, Volume and Issue: 84, P. 104260 - 104260

Published: Sept. 19, 2022

Language: Английский

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Myocardial ischemia-reperfusion injury; Molecular mechanisms and prevention

Microvascular Research, Journal Year: 2023, Volume and Issue: 149, P. 104565 - 104565

Published: June 10, 2023

Language: Английский

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Antioxidant Phytochemicals as Potential Therapy for Diabetic Complications

Antioxidants, Journal Year: 2023, Volume and Issue: 12(1), P. 123 - 123

Published: Jan. 4, 2023

The global prevalence of diabetes continues to increase partly due rapid urbanization and an in the aging population. Consequently, this is associated with a parallel diabetic vascular complications which significantly worsen burden diabetes. For these complications, there still unmet need for safe effective alternative/adjuvant therapeutic interventions. There also increasing urge options come from natural products such as plants. Hyperglycemia-induced oxidative stress central development complications. Furthermore, stress-induced inflammation insulin resistance are endothelial damage progression Human animal studies have shown that polyphenols could reduce stress, hyperglycemia, prevent including retinopathy, nephropathy, peripheral neuropathy. Part effects attributed their modulatory effect on endogenous antioxidant systems. This review attempts summarize established systems literature. Moreover, potential strategies harnessing benefits discussed.

Language: Английский

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

Archives of Toxicology, Journal Year: 2023, Volume and Issue: 97(12), P. 3023 - 3035

Published: Sept. 14, 2023

Language: Английский

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Mitochondrial dysfunction route as a possible biomarker and therapy target for human cancer

Biomedical Journal, Journal Year: 2024, Volume and Issue: unknown, P. 100714 - 100714

Published: March 1, 2024

Mitochondria are vital organelles found within living cells and have signalling, biosynthetic, bioenergetic functions. play a crucial role in metabolic reprogramming, which is characteristic of cancer allows them to assure steady supply proteins, nucleotides, lipids enable rapid proliferation development. Their dysregulated activities been associated with the growth metastasis different kinds human cancer, particularly ovarian carcinoma. In this review, we briefly demonstrated modified mitochondrial function including mutations mtDNA, reactive oxygen species production, dynamics, apoptosis cells, autophagy, calcium excess maintain genesis, progression, metastasis. Furthermore, dysfunction pathway for some genomic, proteomic, metabolomics modifications has studied. Additionally, linked targeted therapies biomarkers through various alteration processes underlying dysfunction, notably targeting species, metabolites, rewind pathways, chemo-resistant carcinoma cells.

Language: Английский

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Nuclear receptor subfamily 4 group A member 1 promotes myocardial ischemia/reperfusion injury through inducing mitochondrial fission factor-mediated mitochondrial fragmentation and inhibiting FUN14 domain containing 1-depedent mitophagy

International Journal of Biological Sciences, Journal Year: 2024, Volume and Issue: 20(11), P. 4458 - 4475

Published: Jan. 1, 2024

This study investigated the mechanism by which NR4A1 regulates mitochondrial fission factor (Mff)-related and FUN14 domain 1 (FUNDC1)-mediated mitophagy following cardiac ischemia-reperfusion injury(I/R). Our findings showed that damage regulation was positively correlated with pathological pan-apoptosis of myocardial cell mitochondria. Compared wild-type mice (WT), NR4A1-knockout exhibited resistance to injury fission, characterized activation. Results increased expression level, activating mediated Mff restoring phenotype FUNDC1. The inactivation FUNDC1 phosphorylation could not mediate normalization in a timely manner, leading an excessive stress response unfolded proteins imbalance homeostasis. process disrupted quality control network, accumulation damaged mitochondria activation pan-apoptotic programs. data indicate is novel critical target I/R exertsand negative regulatory effects Mff-mediated mito-fission inhibiting FUNDC1-mediated mitophagy. Targeting crosstalk balance between NR4A1-Mff-FUNDC1 potential approach for treating I/R.

Language: Английский

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