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BRD4 inhibition by JQ1 prevents high-fat diet-induced diabetic cardiomyopathy by activating PINK1/Parkin-mediated mitophagy in vivo.

ABSTRACT: BRD4 is a member of the BET family of epigenetic regulators. Inhibition of BRD4 by the selective bromodomain inhibitor JQ1, alleviates thoracic aortic constriction-induced cardiac hypertrophy and heart failure. However, whether BRD4 inhibition by JQ1 has therapeutic effect on diabetic cardiomyopathy, a major cause of heart failure in patients with Type 2 diabetes, remains unknown. Here, we discover a novel link between BRD4 and PINK1/Parkin-mediated mitophagy during diabetic cardiomyopathy. Upregulation of BRD4 in diabetic mouse hearts inhibits PINK1/Parkin-mediated mitophagy, resulting in accumulation of damaged mitochondria and subsequent impairment of cardiac structure and function. BRD4 inhibition by JQ1 improves mitochondrial function, and repairs the cardiac structure and function of the diabetic heart. These effects depended on rewiring of the BRD4-driven transcription and repression of PINK1. Deletion of Pink1 suppresses mitophagy, exacerbates cardiomyopathy, and abrogates the therapeutic effect of JQ1 on diabetic cardiomyopathy. Our results illustrate a valid therapeutic strategy for treating diabetic cardiomyopathy by inhibition of BRD4.

SUBMITTER: Mu J

PROVIDER: S-EPMC7736123 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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BRD4 inhibition by JQ1 prevents high-fat diet-induced diabetic cardiomyopathy by activating PINK1/Parkin-mediated mitophagy in vivo.

Mu Jing J Zhang Donghong D Tian Yunli Y Xie Zhonglin Z Zou Ming-Hui MH

Journal of molecular and cellular cardiology 20200915

BRD4 is a member of the BET family of epigenetic regulators. Inhibition of BRD4 by the selective bromodomain inhibitor JQ1, alleviates thoracic aortic constriction-induced cardiac hypertrophy and heart failure. However, whether BRD4 inhibition by JQ1 has therapeutic effect on diabetic cardiomyopathy, a major cause of heart failure in patients with Type 2 diabetes, remains unknown. Here, we discover a novel link between BRD4 and PINK1/Parkin-mediated mitophagy during diabetic cardiomyopathy. Upre ...[more]

PMID: 32941882

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Project description:BackgroundIncreased fatty acid oxidation (FAO) has long been considered a culprit in the development of obesity/diabetes mellitus-induced cardiomyopathy. However, enhancing cardiac FAO by removing the inhibitory mechanism of long-chain fatty acid transport into mitochondria via deletion of acetyl coenzyme A carboxylase 2 (ACC2) does not cause cardiomyopathy in nonobese mice, suggesting that high FAO is distinct from cardiac lipotoxicity. We hypothesize that cardiac pathology-associated obesity is attributable to the imbalance of fatty acid supply and oxidation. Thus, we here seek to determine whether further increasing FAO by inducing ACC2 deletion prevents obesity-induced cardiomyopathy, and if so, to elucidate the underlying mechanisms.MethodsWe induced high FAO in adult mouse hearts by cardiac-specific deletion of ACC2 using a tamoxifen-inducible model (ACC2 iKO). Control and ACC2 iKO mice were subjected to high-fat diet (HFD) feeding for 24 weeks to induce obesity. Cardiac function, mitochondria function, and mitophagy activity were examined.ResultsDespite both control and ACC2 iKO mice exhibiting a similar obese phenotype, increasing FAO oxidation by deletion of ACC2 prevented HFD-induced cardiac dysfunction, pathological remodeling, and mitochondria dysfunction, as well. Similarly, increasing FAO by knockdown of ACC2 prevented palmitate-induced mitochondria dysfunction and cardiomyocyte death in vitro. Furthermore, HFD suppressed mitophagy activity and caused damaged mitochondria to accumulate in the heart, which was attenuated, in part, in the ACC2 iKO heart. Mechanistically, ACC2 iKO prevented HFD-induced downregulation of parkin. During stimulation for mitophagy, mitochondria-localized parkin was severely reduced in control HFD-fed mouse heart, which was restored, in part, in ACC2 iKO HFD-fed mice.ConclusionsThese data show that increasing cardiac FAO alone does not cause cardiac dysfunction, but protects against cardiomyopathy in chronically obese mice. The beneficial effect of enhancing cardiac FAO in HFD-induced obesity is mediated, in part, by the maintenance of mitochondria function through regulating parkin-mediated mitophagy. Our findings also suggest that targeting the parkin-dependent mitophagy pathway could be an effective strategy against the development of obesity-induced cardiomyopathy.

Project description:MitoNEET, a mitochondrial outer membrane protein containing the Asn-Glu-Glu-Thr (NEET) sequence, controls the formation of intermitochondrial junctions and confers autophagy resistance. Moreover, mitoNEET as a mitochondrial substrate undergoes ubiquitination by activated Parkin during the initiation of mitophagy. Therefore, mitoNEET is linked to the regulation of autophagy and mitophagy. Mitophagy is the selective removal of the damaged or unnecessary mitochondria, which is crucial to sustaining mitochondrial quality control. In numerous human diseases, the accumulation of damaged mitochondria by impaired mitophagy has been observed. However, the therapeutic strategy targeting of mitoNEET as a mitophagy-enhancing mediator requires further research. Herein, we confirmed that mitophagy is indeed activated by mitoNEET inhibition. CCCP (carbonyl cyanide m-chlorophenyl hydrazone), which leads to mitochondrial depolarization, induces mitochondrial dysfunction and superoxide production. This, in turn, contributes to the induction of mitophagy; mitoNEET protein levels were initially increased before an increase in LC3-Ⅱ protein following CCCP treatment. Pharmacological inhibition of mitoNEET using mitoNEET Ligand-1 (NL-1) promoted accumulation of Pink1 and Parkin, which are mitophagy-associated proteins, and activation of mitochondria-lysosome crosstalk, in comparison to CCCP alone. Inhibition of mitoNEET using NL-1, or mitoNEET shRNA transfected into RAW264.7 cells, abrogated CCCP-induced ROS and mitochondrial cell death; additionally, it activated the expression of PGC-1α and SOD2, regulators of oxidative metabolism. In particular, the increase in PGC-1α, which is a major regulator of mitochondrial biogenesis, promotes mitochondrial quality control. These results indicated that mitoNEET is a potential therapeutic target in numerous human diseases to enhance mitophagy and protect cells by maintaining a network of healthy mitochondria. [BMB Reports 2022; 55(7): 354-359].

Dataset Information

BRD4 inhibition by JQ1 prevents high-fat diet-induced diabetic cardiomyopathy by activating PINK1/Parkin-mediated mitophagy in vivo.

Publications

BRD4 inhibition by JQ1 prevents high-fat diet-induced diabetic cardiomyopathy by activating PINK1/Parkin-mediated mitophagy in vivo.

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