Melatonin alleviates doxorubicin-induced mitochondrial oxidative damage and ferroptosis in cardiomyocytes by regulating YAP expression

Sun, Xiao Wei; Park, Sun; Zhen, Dong Kai; Xu, Xiao; Yang, Li; Fu, Danni; Wei, Cheng‐Xi; Niu, Xiaofeng; Tian, Jiawei; Li, Hairu

doi:10.1016/j.taap.2022.115902

Cited by 59 publications

(60 citation statements)

References 52 publications

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“…Mitochondria also participates in apoptosis via lipid peroxidation [93]. Many mitochondria-targeted ROS scavengers, such as mitoquinone (MitoQ) [94], SkQ1 [95], and melatonin [96] can prevent mitochondrial ROS formation and inhibit ferropotosis.…”

Section: Discussionmentioning

confidence: 99%

Evidence of pyroptosis and ferroptosis extensively involved in autoimmune diseases at the single-cell transcriptome level

Zhang

et al. 2022

J Transl Med

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Background Approximately 8–9% of the world’s population is affected by autoimmune diseases, and yet the mechanism of autoimmunity trigger is largely understudied. Two unique cell death modalities, ferroptosis and pyroptosis, provide a new perspective on the mechanisms leading to autoimmune diseases, and development of new treatment strategies. Methods Using scRNA-seq datasets, the aberrant trend of ferroptosis and pyroptosis-related genes were analyzed in several representative autoimmune diseases (psoriasis, atopic dermatitis, vitiligo, multiple sclerosis, systemic sclerosis-associated interstitial lung disease, Crohn’s disease, and experimental autoimmune orchitis). Cell line models were also assessed using bulk RNA-seq and qPCR. Results A substantial difference was observed between normal and autoimmune disease samples involving ferroptosis and pyroptosis. In the present study, ferroptosis and pyroptosis showed an imbalance in different keratinocyte lineages of psoriatic skinin addition to a unique pyroptosis-sensitive keratinocyte subset in atopic dermatitis (AD) skin. The results also revealed that pyroptosis and ferroptosis are involved in epidermal melanocyte destruction in vitiligo. Aberrant ferroptosis has been detected in multiple sclerosis, systemic sclerosis-associated interstitial lung disease, Crohn’s disease, and autoimmune orchitis. Cell line models adopted in the study also identified pro-inflammatory factors that can drive changes in ferroptosis and pyroptosis. Conclusion These results provide a unique perspective on the involvement of ferroptosis and pyroptosis in the pathological process of autoimmune diseases at the scRNA-seq level. IFN-γ is a critical inducer of pyroptosis sensitivity, and has been identified in two cell line models.

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Section: Discussionmentioning

confidence: 99%

Evidence of pyroptosis and ferroptosis extensively involved in autoimmune diseases at the single-cell transcriptome level

Zhang

et al. 2022

J Transl Med

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“…EGCG up-regulated AMP-activated protein kinaseα2 (AMPKα2), activated adaptive autophagy, reduced iron deposition, inhibited reactive oxygen species (ROS) overproduction and rectified abnormal lipid metabolism, thereby reversing ferroptosis in DIC. Similarly, in a recent article, Sun et al ( 25 ) demonstrated potent antioxidant melatonin inhibited mitochondrial lipid peroxidation and ameliorated doxorubicin-induced cardiac ferroptosis. In summary, we know that many forms of cell death are involved in DIC, among which ferroptosis is a pivotal one.…”

Section: Ferroptosis and Cardiovascular Diseasesmentioning

confidence: 80%

Roles of Ferroptosis in Cardiovascular Diseases

Guo

Zhang

Zhou

et al. 2022

Front. Cardiovasc. Med.

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Ferroptosis is an iron-dependent regulated cell death characterized by lipid peroxidation and iron overload, which is different from other types of programmed cell death, including apoptosis, necroptosis, autophagy, and pyroptosis. Over the past years, emerging studies have shown a close relation between ferroptosis and various cardiovascular diseases such as atherosclerosis, acute myocardial infarction, ischemia/reperfusion injury, cardiomyopathy, and heart failure. Herein, we will review the contributions of ferroptosis to multiple cardiovascular diseases and the related targets. Further, we discuss the potential ferroptosis-targeting strategies for treating different cardiovascular diseases.

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“…Pharmacological inhibition of ACSL4 can prevent ferroptosis-related diseases ( 38 ). In doxorubicin-induced myocardial damage models, YAP could decrease the expression level of ACSL4 ( 22 ). In lung adenocarcinoma, YAP diminished intracellular iron levels by promoting FTL transcription through transcription factor CP2 (TRCP2) ( 39 ).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the positive effect of YAP1 on pulmonary epithelial cells has already been reported. Research on the intervention of YAP1 in ferroptosis springs up gradually, and the newest study found that YAP depletion could abolish the myocardial protective effect of melatonin by upregulating acyl-CoA synthetase long-chain family member 4 (ACSL4) expression ( 22 ). Based on these reports, our study aimed to investigate whether YAP1 was involved in pulmonary epithelial cell ferroptosis in response to LPS stimulation and to explore the underlying mechanism of ferroptosis in sepsis-induced ALI.…”

Section: Introductionmentioning

confidence: 99%

YAP1 alleviates sepsis-induced acute lung injury via inhibiting ferritinophagy-mediated ferroptosis

et al. 2022

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Ferroptosis is a phospholipid peroxidation-mediated and iron-dependent cell death form, involved in sepsis-induced organ injury and other lung diseases. Yes-associated protein 1 (YAP1), a key regulator of the Hippo signaling pathway, could target multiple ferroptosis regulators. Herein, this study aimed to explore the involvement of ferroptosis in the etiopathogenesis of sepsis-induced acute lung injury (ALI) and demonstrate that YAP1 could disrupt ferritinophagy and moderate sepsis-induced ALI. Cecal ligation and puncture (CLP) models were constructed in wild-type (WT) and pulmonary epithelium-conditional knockout (YAP1f/f) mice to induce ALI, while MLE-12 cells with or without YAP1 overexpression were stimulated by lipopolysaccharide (LPS) in vitro. In-vivo modes showed that YAP1 knockout aggravated CLP-induced ALI and also accelerated pulmonary ferroptosis, as presented by the downregulated expression of GPX4, FTH1, and SLC7A11, along with the upregulated expression of SFXN1 and NCOA4. Transcriptome research identified these key genes and ferroptosis pathways involved in sepsis-induced ALI. In-vitro modes consistently verified that YAP1 deficiency boosted the ferrous iron accumulation and mitochondrial dysfunction in response to LPS. Furthermore, the co-IP assay revealed that YAP1 overexpression could prevent the degradation of ferritin to a mass of Fe2+ (ferritinophagy) via disrupting the NCOA4–FTH1 interaction, which blocked the transport of cytoplasmic Fe2+ into the mitochondria via the mitochondrial membrane protein (SFXN1), further reducing the generation of mitochondrial ROS. Therefore, these findings revealed that YAP1 could inhibit ferroptosis in a ferritinophagy-mediated manner, thus alleviating sepsis-induced ALI, which may provide a new approach to the therapeutic orientation for sepsis-induced ALI.

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Melatonin alleviates doxorubicin-induced mitochondrial oxidative damage and ferroptosis in cardiomyocytes by regulating YAP expression

Cited by 59 publications

References 52 publications

Evidence of pyroptosis and ferroptosis extensively involved in autoimmune diseases at the single-cell transcriptome level

Evidence of pyroptosis and ferroptosis extensively involved in autoimmune diseases at the single-cell transcriptome level

Roles of Ferroptosis in Cardiovascular Diseases

YAP1 alleviates sepsis-induced acute lung injury via inhibiting ferritinophagy-mediated ferroptosis

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