NFATc3-dependent expression of miR-153-3p promotes mitochondrial fragmentation in cardiac hypertrophy by impairing mitofusin-1 expression

Abstract

Mitochondrial dysfunction is involved in the pathogenesis of various cardiovascular disorders. Although mitochondrial dynamics, including changes in mitochondrial fission and fusion, have been implicated in the development of cardiac hypertrophy, the underlying molecular mechanisms remain mostly unknown. Here, we show that NFATc3, miR-153-3p, and mitofusion-1 (Mfn1) constitute a signaling axis that mediates mitochondrial fragmentation and cardiomyocyte hypertrophy.Methods: Isoprenaline (ISO) was used to stimulate the hypertrophic response and mitochondrial fragmentation in cultured cardiomyocytes and in vivo. We performed immunoblotting, immunofluorescence, and quantitative real-time PCR to validate the function of Mfn1 in cardiomyocyte hypertrophy. Bioinformatic analyses, a luciferase reporter assay, and gain- and loss-of-function studies were used to demonstrate the biological function of miR-153-3p, which regulates mitochondrial fragmentation and hypertrophy by targeting Mfn1. Moreover, ChIP-qPCR and a luciferase reporter assay were performed to identify transcription factor NFATc3 as an upstream regulator to control the expression of miR-153-3p.Results: Our results show that ISO promoted mitochondrial fission and enhanced the expression of miR-153-3p in cardiomyocytes. Knockdown of miR-153-3p attenuated ISO-induced mitochondrial fission and hypertrophy in cultured primary cardiomyocytes. miR-153-3p suppression inhibited mitochondrial fragmentation in ISO-induced cardiac hypertrophy in a mouse model. We identified direct targeting of Mfn1, a key protein of the mitochondrial fusion process, by miR-153-3p. Also, miR-153-3p promoted ISO-induced mitochondrial fission by suppressing the translation of Mfn1. We further found that NFATc3 activated miR-153-3p expression. Knockdown of NFATc3 inhibited miR-153-3p expression and blocked mitochondrial fission and hypertrophic response in cardiomyocytes.Conclusions: Our data revealed a novel signaling pathway, involving NFATc3, miR-153-3p, and Mfn1, which could be a therapeutic target for the prevention and treatment of cardiac hypertrophy.

Klf5 down-regulation induces vascular senescence through eIF5a depletion and mitochondrial fission

“…Importantly, these effects can be attenuated by overexpression of Mfn1. [43,44]. Consistently, our results showed that chronic Ang II stimulation-induced Klf5 down-regulation contributed to low expression of eIF5a in VSMCs, which in turn decreased the expression of Mfn1 and thus attenuated the interaction of eIF5a with Mfn1, subsequently leading to excessive accumulation of ROS and VSMC senescence.…”

RETRACTED: Matrine Protects Cardiomyocytes Against Hyperglycemic Stress by Promoting Mitofusin 2-Induced Mitochondrial Fusion

“…For example, the activation of mitochondrial fusion was found to enhance myocardial resistance to ischemia-reperfusion injury ( Wang et al, 2020f ). Overexpression of Mfn1 upregulated mitochondrial fusion, protecting the heart against hypertrophy by circumventing the miR-153-3p signaling pathway ( Wang et al, 2020g ). Although enhancing mitochondrial dynamics has been reported as a therapeutic intervention in diabetic cardiomyopathy, most studies have focused on the effects of mitochondrial fission and mitophagy on mitochondrial homeostasis ( Zhou et al, 2019 ; Wang et al, 2020e ).…”

The lncRNA Malat1 regulates microvascular function after myocardial infarction in mice via miR-26b-5p/Mfn1 axis-mediated mitochondrial dynamics

“…Evidence noted Mfn1 overexpression inhibited mitochondrial fragmentation and thereby suppress mitophagy in skeletal muscle atrophy [ 27 ]. Mfn1 participates in different cardiovascular diseases, such as protecting myocardial cells against ischaemia-reperfusion injury and inhibiting the development of cardiac hypertrophy [ 28 , 29 ]. There are several lines of evidence that lncRNAs can modulate mitochondrial dynamics and, as a consequence, control mitochondrial functions and change disease prognosis.…”