MOTS-c repairs myocardial damage by inhibiting the CCN1/ERK1/2/EGR1 pathway in diabetic rats

Wang, Manda; Wang, Gangqiang; Pang, Xiaoli; Ma, Jiacheng; Yuan, Jinghan; Pan, Yanrong; Fu, Yu; Laher, Ismail; Li, Shunchang

doi:10.3389/fnut.2022.1060684

Cited by 8 publications

(5 citation statements)

References 57 publications

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“…MOTS-c is a mitochondria-derived peptide encoded in the 12S rRNA region of the mitochondrial genome (Figure 6 A). Reduced MOTS-c levels have been regarded as an early sign of mitochondrial dysfunction in a range of cardiovascular diseases, including heart failure 17 , diabetic cardiomyopathy 41 , and coronary artery disease 42 . Thus, we asked whether the mitochondrial protective effects of DNA-PKcs ablation were followed by MOTS-c upregulation.…”

Section: Resultsmentioning

confidence: 99%

The DNA-dependent protein kinase catalytic subunit exacerbates endotoxemia-induced myocardial microvascular injury by disrupting the MOTS-c/JNK pathway and inducing profilin-mediated lamellipodia degradation

Zou,

Shi,

Chang

et al. 2024

Theranostics

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Rationale: The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) promotes pathological mitochondrial fission during septic acute kidney injury. The mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c) is a mitochondria-derived peptide that exhibits anti-inflammatory properties during cardiovascular illnesses. We explored whether endotoxemia-induced myocardial microvascular injury involved DNA-PKcs and MOTS-c dysregulation. Methods: To induce endotoxemia in vivo, endothelial cell-specific DNA-PKcs- knockout mice were injected intraperitoneally with a single dose of lipopolysaccharide (10 mg/kg) and evaluated after 72 h. Results: Lipopolysaccharide exposure increased DNA-PKcs activity in cardiac microvascular endothelial cells, while pharmacological inhibition or endothelial cell-specific genetic ablation of DNA-PKcs reduced lipopolysaccharide-induced myocardial microvascular dysfunction. Proteomic analyses showed that endothelial DNA-PKcs ablation primarily altered mitochondrial protein expression. Verification assays confirmed that DNA-PKcs drastically repressed MOTS-c transcription by inducing mtDNA breaks via pathological mitochondrial fission. Inhibiting MOTS-c neutralized the endothelial protective effects of DNA-PKcs ablation, whereas MOTS-c supplementation enhanced endothelial barrier function and myocardial microvascular homeostasis under lipopolysaccharide stress. In molecular studies, MOTS-c downregulation disinhibited c-Jun N-terminal kinase (JNK), allowing JNK to phosphorylate profilin-S173. Inhibiting JNK or transfecting cells with a profilin phosphorylation-defective mutant improved endothelial barrier function by preventing F-actin depolymerization and lamellipodial degradation following lipopolysaccharide treatment. Conclusions: DNA-PKcs inactivation during endotoxemia could be a worthwhile therapeutic strategy to restore MOTS-c expression, prevent JNK-induced profilin phosphorylation, improve F-actin polymerization, and enhance lamellipodial integrity, ultimately ameliorating endothelial barrier function and reducing myocardial microvascular injury.

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Section: Resultsmentioning

confidence: 99%

The DNA-dependent protein kinase catalytic subunit exacerbates endotoxemia-induced myocardial microvascular injury by disrupting the MOTS-c/JNK pathway and inducing profilin-mediated lamellipodia degradation

Zou,

Shi,

Chang

et al. 2024

Theranostics

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“…Especially its protective effect on the heart seems worth further attention (Wang et al. 2023 ; Zhong et al. 2022 ; Li et al.…”

Section: Discussionmentioning

confidence: 99%

MOTS-c regulates pancreatic alpha and beta cell functions in vitro

Bień,

Pruszyńska-Oszmałek,

Kołodziejski

et al. 2024

Histochem Cell Biol

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The aim of this study is to determine the influence of the mitochondrial open-reading-frame of the twelve S rRNA-c (MOTS-c) peptide on pancreatic cell physiology. Moreover, in this study, we examined the changes in MOTS-c secretion and expression under different conditions. Our experiments were conducted using laboratory cell line cultures, specifically the INS-1E and αTC-1 cell lines, which represent β and α pancreatic cells, respectively. As the pancreas is an endocrine organ, we also tested its hormone regulation capabilities. Furthermore, we assessed the secretion of MOTS-c after incubating the cells with glucose and free fatty acids. Additionally, we examined key cell culture parameters such as cell viability, proliferation, and apoptosis. The results obtained from this study show that MOTS-c has a significant impact on the physiology of pancreatic cells. Specifically, it lowers insulin secretion and expression in INS-1E cells and enhances glucagon secretion and expression in αTC-1 cells. Furthermore, MOTS-c affects cell viability and apoptosis. Interestingly, insulin and glucagon affect the MOTS-c secretion as well as glucose and free fatty acids. These experiments clearly show that MOTS-c is an important regulator of pancreatic metabolism, and there are numerous properties of MOTS-c yet to be discovered.

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“…The above-mentioned calcium homeostasis is not the only factor that influences cardiomyocyte death; mitochondrial metabolic homeostasis is also important. In cardiomyocytes, Ca 2+ ions enter the mitochondria via the mitochondrial Ca 2+ (MCU), which stimulates the tricarboxylic acid (TCA) cycle to increase ATP production ( 32 , 33 , 35 , 75 – 78 ). An Egr-1 -mediated gene that codes for MICU1 (Mitochondrial Calcium Uptake 1), the gatekeeper of the mitochondrial calcium uniporter, is transcriptionally upregulated by the mitochondria in response to metabolic balance.…”

Section: Egr-1 Is Involved In Cardiac Cell Deathmentioning

confidence: 99%

Early growth response-1: Key mediators of cell death and novel targets for cardiovascular disease therapy

Xie

Chen

et al. 2023

Front. Cardiovasc. Med.

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SignificanceCardiovascular diseases are seen to be a primary cause of death, and their prevalence has significantly increased across the globe in the past few years. Several studies have shown that cell death is closely linked to the pathogenesis of cardiovascular diseases. Furthermore, many molecular and cellular mechanisms are involved in the pathogenesis of the cardiac cell death mechanism. One of the factors that played a vital role in the pathogenesis of cardiac cell death mechanisms included the early growth response-1 (Egr-1) factor.Recent AdvancesStudies have shown that abnormal Egr-1 expression is linked to different animal and human disorders like heart failure and myocardial infarction. The biosynthesis of Egr-1 regulates its activity. Egr-1 can be triggered by many factors such as serum, cytokines, hormones, growth factors, endotoxins, mechanical injury, hypoxia, and shear stress. It also displays a pro-apoptotic effect on cardiac cells, under varying stress conditions. EGR1 mediates a broad range of biological responses to oxidative stress and cell death by combining the acute changes occurring in the cellular environment with sustained changes in gene expression.Future DirectionsThe primary regulatory role played by the Egr-1-targeting DNAzymes, microRNAs, and oligonucleotide decoy strategies in cardiovascular diseases were identified to provide a reference to identify novel therapeutic targets for cardiovascular diseases.

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MOTS-c repairs myocardial damage by inhibiting the CCN1/ERK1/2/EGR1 pathway in diabetic rats

Cited by 8 publications

References 57 publications

The DNA-dependent protein kinase catalytic subunit exacerbates endotoxemia-induced myocardial microvascular injury by disrupting the MOTS-c/JNK pathway and inducing profilin-mediated lamellipodia degradation

The DNA-dependent protein kinase catalytic subunit exacerbates endotoxemia-induced myocardial microvascular injury by disrupting the MOTS-c/JNK pathway and inducing profilin-mediated lamellipodia degradation

MOTS-c regulates pancreatic alpha and beta cell functions in vitro

Early growth response-1: Key mediators of cell death and novel targets for cardiovascular disease therapy

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