METTL3 boosts mitochondrial fission and induces cardiac fibrosis by enhancing LncRNA GAS5 methylation

Tu, Bin; Song, Kai; Zhou, Yang; Sun, He; Liu, Zhiyan; Li, Lin; Ding, Ji-Fei; Sha, Ji-Ming; Yan, Shuhua; Yang, Jingjing; Li, Rui; Zhang, Ye; Zhao, Jin; Tao, Hui

doi:10.1016/j.phrs.2023.106840

Cited by 27 publications

(4 citation statements)

References 41 publications

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“…However, controversy persists regarding the enzymes that play major roles in the proliferation and differentiation of cardiac. METTL3 [7,9,29], WTAP [30] and FTO [6] reportedly regulate CF proliferation and differentiation. Our study found that in cardiac fibrotic tissue post-MI, the expression of METTL3 and ALKBH5 increased, whereas that of FTO decreased with the extension of ischemia time.…”

Section: Discussionmentioning

confidence: 95%

“…Inhibition of FTO, an m6A demethylase, attenuates the antifibrotic effect of leonurine in rat cardiac fibroblasts [6]. METTL3 catalyzes m6A methylation of GAS5 in a YTHDF2-dependent manner to boost mitochondrial fission and cardiac fibroblast proliferation and fibroblast migration [7]. Overexpression of methyltransferase METTL3 in CFs could upregulate the expression of fibrosis-related genes and activate the TGF-β/Smad2/3 signalling pathway to promote the development of myocardial fibrosis [8].…”

Section: Introductionmentioning

confidence: 99%

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METTL3 silencing suppresses cardiac fibrosis via m6A modification of SMOC2

He,

Pan,

Tao

et al. 2024

Preprint

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Cardiac fibrosis leads to decreased cardiac compliance, impaired systolic and diastolic function, resulting in heart failure. M6A methylation plays a role in fibrosis development. However, its underlying mechanism remain poorly understood. This study explores the role and molecular mechanisms of m6A methylation in regulating cardiac fibrosis after myocardial infarction (MI). A mouse myocardial fibrosis model post-MI was established by ligating the left coronary artery. Corresponding gene knockdown was achieved in vitro or in vivo using short hairpin RNA or fibroblast-specific AAV9 virus. Echocardiography assessed cardiac function in mice, while Masson staining determined the degree of collagen deposition post-MI. The meRIP-Seq kit detected mRNA methylation levels in myocardial tissue and hypoxia-treated cardiac fibroblasts. Expression of RNA methylation-related enzymes, fibrosis-related proteins, and SMOC2 expression in the myocardial tissue or cardiac fibroblasts was detected using western blotting. Actinomycin D assessed SMOC2 mRNA stability. Results demonstrated increased levels of m6A methylation and METTL3 expression in myocardial fibrosis tissue post-MI and in hypoxia-treated cardiac fibroblasts. In vivo METTL3 downregulation reduced the fibrotic area and improved cardiac function, while METTL3 downregulation in vitro can alleviate cardiac fibroblast proliferation and differentiation after hypoxia. Per bioinformatic analysis, SMOC2 may be differentially expressed, regulated by RNA methylation during cardiac fibroblast proliferation and differentiation. SMOC2 is significantly elevated in myocardial fibrotic tissue post-MI and hypoxia-induced cardiac fibroblasts. SMOC2 downregulation alleviates cardiac fibroblast proliferation and differentiation. Mechanistically, METTL3 promoted SMOC2 mRNA stability by increasing its m6A methylation level, thereby regulating cardiac fibroblast proliferation and differentiation. Conclusively, METTL3 participates in cardiac fibroblasts proliferation and differentiation post-MI by increasing the m6A methylation level of SMOC2 mRNA, thereby promoting its stability.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

METTL3 silencing suppresses cardiac fibrosis via m6A modification of SMOC2

He,

Pan,

Tao

et al. 2024

Preprint

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“…Similar to our findings, a previous study showed that METTL3 promoted GC development wherein METTL3 catalysed the m6A methylation of growth arrest specific 5 (GAS5) in a YTHDF2‐mediated manner to enhance Drp1‐mediated mitochondrial fission. 39 , 40 Furthermore, PX‐478 can alleviate the m6A modification mediated by the HIF‐1α/METTL3/IGF2BP3 pathway to inhibit the interaction between Drp1 and Fis1 and mitochondrial fission/dysfunction. In addition, METTL3 mutation or IGF2BP3 knocking down inhibited m6A modification and decreased Drp1 protein levels to rescue mitochondrial function in PHT and GC nude mouse models.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction induced by HIF‐1α under hypoxia contributes to the development of gastric mucosal lesions

Xiao,

Liu,

Xie

et al. 2024

Clinical & Translational Med

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IntroductionHypoxia is an important characteristic of gastric mucosal diseases, and hypoxia‐inducible factor‐1α (HIF‐1α) contributes to microenvironment disturbance and metabolic spectrum abnormalities. However, the underlying mechanism of HIF‐1α and its association with mitochondrial dysfunction in gastric mucosal lesions under hypoxia have not been fully clarified.ObjectivesTo evaluate the effects of hypoxia‐induced HIF‐1α on the development of gastric mucosal lesions.MethodsPortal hypertensive gastropathy (PHG) and gastric cancer (GC) were selected as representative diseases of benign and malignant gastric lesions, respectively. Gastric tissues from patients diagnosed with the above diseases were collected. Portal hypertension (PHT)‐induced mouse models in METTL3 mutant or NLRP3‐deficient littermates were established, and nude mouse gastric graft tumour models with relevant inhibitors were generated. The mechanisms underlying hypoxic condition, mitochondrial dysfunction and metabolic alterations in gastric mucosal lesions were further analysed.ResultsHIF‐1α, which can mediate mitochondrial dysfunction via upregulation of METTL3/IGF2BP3‐dependent dynamin‐related protein 1 (Drp1) N6‐methyladenosine modification to increase mitochondrial reactive oxygen species (mtROS) production, was elevated under hypoxic conditions in human and mouse portal hypertensive gastric mucosa and GC tissues. While blocking HIF‐1α with PX‐478, inhibiting Drp1‐dependent mitochondrial fission via mitochondrial division inhibitor 1 (Mdivi‐1) treatment or METTL3 mutation alleviated this process. Furthermore, HIF‐1α influenced energy metabolism by enhancing glycolysis via lactate dehydrogenase A. In addition, HIF‐1α‐induced Drp1‐dependent mitochondrial fission also enhanced glycolysis. Drp1‐dependent mitochondrial fission and enhanced glycolysis were associated with alterations in antioxidant enzyme activity and dysfunction of the mitochondrial electron transport chain, resulting in massive mtROS production, which was needed for activation of NLRP3 inflammasome to aggravate the development of the PHG and GC.ConclusionsUnder hypoxic conditions, HIF‐1α enhances mitochondrial dysfunction via Drp1‐dependent mitochondrial fission and influences the metabolic profile by altering glycolysis to increase mtROS production, which can trigger NLRP3 inflammasome activation and mucosal microenvironment alterations to contribute to the development of benign and malignant gastric mucosal lesions.

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“…For example, METTL3 has been shown to influence mitochondrial metabolism by affecting the expression of genes involved in energy production and mitochondrial respiration 13 , 42 . Additionally, METTL3 has been implicated in mitochondrial dynamics, where its RNA methylation activity may modulate the expression of genes associated with mitochondrial fission and fusion processes 43 . Moreover, METTL3 has been found to interact with mitochondrial RNA and potentially regulate the stability and translation of mitochondrial-encoded transcripts 13 .…”

Section: Discussionmentioning

confidence: 99%

METTL3 boosts mitochondrial fission and induces cardiac fibrosis after ischemia/reperfusion injury

Ma,

Chang,

Gao

et al. 2024

Int. J. Biol. Sci.

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METTL3, an RNA methyltransferase enzyme, exerts therapeutic effects on various cardiovascular diseases. Myocardial ischemia-reperfusion injury (MIRI) and subsequently cardiac fibrosis is linked to acute cardiomyocyte death or dysfunction induced by mitochondrial damage, particularly mitochondrial fission. Our research aims to elucidate the potential mechanisms underlying the therapeutic actions of METTL3 in MIRI, with focus on mitochondrial fission. When compared with Mettl3 flox mice subjected to MIRI, Mettl3 cardiomyocyte knockout ( Mettl3 Cko ) mice have reduced infarct size, decreased serum levels of myocardial injury-related factors, limited cardiac fibrosis, and preserved myocardial ultrastructure and contractile/relaxation capacity. The cardioprotective actions of Mettl3 knockout were associated with reduced inflammatory responses, decreased myocardial neutrophil infiltration, and suppression of cardiomyocyte death. Through signaling pathway validation experiments and assays in cultured HL-1 cardiomyocytes exposed to hypoxia/reoxygenation, we confirmed that Mettl3 deficiency interfere with DNA-PKcs phosphorylation, thereby blocking the downstream activation of Fis1 and preventing pathological mitochondrial fission. In conclusion, this study confirms that inhibition of METTL3 can alleviate myocardial cardiac fibrosis inflammation and prevent cardiomyocyte death under reperfusion injury conditions by disrupting DNA-PKcs/Fis1-dependent mitochondrial fission, ultimately improving cardiac function. These findings suggest new approaches for clinical intervention in patients with MIRI.

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METTL3 boosts mitochondrial fission and induces cardiac fibrosis by enhancing LncRNA GAS5 methylation

Cited by 27 publications

References 41 publications

METTL3 silencing suppresses cardiac fibrosis via m6A modification of SMOC2

METTL3 silencing suppresses cardiac fibrosis via m6A modification of SMOC2

Mitochondrial dysfunction induced by HIF‐1α under hypoxia contributes to the development of gastric mucosal lesions

METTL3 boosts mitochondrial fission and induces cardiac fibrosis after ischemia/reperfusion injury

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