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Abstract
Maintaining proper mitochondrial respiratory function is crucial for alleviating cardiac metabolic disorders during obesity, and mitophagy is critically involved in this process. Long non-coding RNA H19 (H19) is crucial for metabolic regulation, but its roles in cardiac disorders, mitochondrial respiratory function, and mitophagy during obesity are largely unknown. In this study, palmitic acid (PA)-treated H9c2 cell and Lep−/− mice were used to investigate cardiac metabolic disorders in vitro and in vivo, respectively. The effects of H19 on metabolic disorders, mitochondrial respiratory function, and mitophagy were investigated. Moreover, the regulatory mechanisms of PA, H19, mitophagy, and respiratory function were examined. The models tested displayed a reduction in H19 expression, respiratory function and mitochondrial number and volume, while the expression of mitophagy- and Pink1/Parkin signaling-related proteins was upregulated, as indicated using quantitative real-time PCR, Seahorse mitochondrial stress test analyzer, transmission electron microscopy, fluorescence indicators and western blotting. Forced expression of H19 helped to the recoveries of respiratory capacity and mitochondrial number while inhibited the levels of mitophagy- and Pink1/Parkin signaling-related proteins. Pink1 knockdown also attenuated PA-induced mitophagy and increased respiratory capacity. Mechanistically, RNA pull-down, mass spectrometry, and RNA-binding protein immunoprecipitation assays showed that H19 could hinder the binding of eukaryotic translation initiation factor 4A, isoform 2 (eIF4A2) with Pink1 mRNA, thus inhibiting the translation of Pink1 and attenuation of mitophagy. PA significantly increased the methylation levels of the H19 promoter region by upregulation Dnmt3b methylase levels, thereby inhibiting H19 transcription. Collectively, these findings suggest that DNA methylation-mediated the downregulation of H19 expression plays a crucial role in cardiomyocyte or H9c2 cells metabolic disorders and induces cardiac respiratory dysfunction by promoting mitophagy. H19 inhibits excessive mitophagy by limiting Pink1 mRNA translation, thus alleviating this cardiac defect that occurs during obesity.
Highlights
Obesity is a worldwide health problem imposing risk for many serious diseases, cardiovascular disease, which is the leading cause of death all around the world[1,2]
Poor expression of Long non-coding RNAs (lncRNAs) H19 was responsible for the reduced mitochondrial respiration and cardiac dysfunction in obesity Mitochondrial respiratory function, as represented by basal/maximal respiration capacity and adenosinetriphosphate (ATP) production, analyzed using the Seahorse XF mitochondrial stress test analyzer, was significantly reduced in H9c2 cells upon palmitic acid (PA) administration (Fig. 1A)
These results indicated that suppressed the expression of H19 in cardiomyocytes or H9c2 cells are critical for cardiac dysfunction and impaired mitochondrial respiration in obesity
Summary
Obesity is a worldwide health problem imposing risk for many serious diseases, cardiovascular disease, which is the leading cause of death all around the world[1,2]. Chronic obesity directly impairs cardiac structure and function[4,5]. Official journal of the Cell Death Differentiation Association. Wang et al Cell Death and Disease (2021)12:557. Obesity-induced cardiac impairments are considered to occur due to the alterations in myocardial lipid metabolism[6,7]. Other factors, such as mitochondrial dysfunction, autophagy, and inflammation, have been reported to be critically involved[8]. The precise cues of obesity-induced cardiac function impairment remain elusive
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