Downregulation of Uncoupling Protein 2(UCP2) Mediated by MicroRNA-762 Confers Cardioprotection and Participates in the Regulation of Dynamic Mitochondrial Homeostasis of Dynamin Related Protein1 (DRP1) After Myocardial Infarction in Mice

Liu, Dehui; Zou, Shangrong; Li, Guangnan; Zhang, Qiyu; Chen, Chunlin; Li, Cuizhi; Song, Haiqu; Chen, Shaoxian; Wang, Jiawen; Wu, Yueheng; Liu, Youbin

doi:10.3389/fcvm.2021.764064

Cited by 6 publications

(3 citation statements)

References 26 publications

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“…This aligns with existing literature on hypoxia-responsive microRNAs, miR-212 and miR-132, which were previously described to regulate steroidogenesis (21,39). However, a number of microRNAs used in this study have not yet been implicated in the control of steroidogenesis (47)(48)(49). The induction of these miRNAs in our experimental settings is believed to lead to the repression of steroid biosynthesizing enzymes, thereby reducing steroid production -a hypothesis that was confirmed in Y1 cells in vitro and ex vivo cultured adrenal glands under acute hypoxia.…”

Section: Discussionsupporting

confidence: 90%

HIF1α controls steroidogenesis under acute hypoxic stress

Ariyeloye,

Watts,

Jaykar

et al. 2024

Preprint

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Background Hypoxia is a critical physiological and pathological condition known to influence various cellular processes, including steroidogenesis. While previous studies, including our own, have highlighted the regulatory effects of Hypoxia-Inducible Factor 1α (HIF1α) on steroid production, the specific molecular mechanisms remain poorly understood. This study investigates the role of hypoxia and HIF1α in steroid biosynthesis across multiple experimental models during acute exposure to low oxygen levels. Methods To assess the extent to which acute hypoxia modulates steroidogenesis, we employed several approaches, including the Y1 adrenocortical cell line, an ex vivo adrenal gland explant model, and a conditional HIF1α-deficient mouse line in the adrenal cortex. We focused on various regulatory patterns that may critically suppress steroidogenesis. Results In Y1 cells and adrenal gland explants, hypoxia induced the upregulation of specific microRNAs, leading to the suppression of mRNA levels of key steroidogenic enzymes and reduced steroid hormone production. The hypoxia/HIF1α-dependent induction of these microRNAs and the consequent modulation of steroid production were confirmed in vivo. Notably, using our conditional HIF1α-deficient mouse line, we found that the increase in miRNA expression under hypoxic conditions is directly dependent on HIF1α. Furthermore, the regulation of steroidogenic enzymes (e.g., StAR and Cyp11a1) and steroid production occurred at the level of protein translation, revealing an unexpected layer of control under hypoxic conditions in vivo. Conclusions These findings elucidate the molecular mechanisms underlying acute hypoxia-induced changes in steroid biosynthesis and may also be useful in developing new strategies for various steroid hormone pathologies.

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Section: Discussionsupporting

confidence: 90%

HIF1α controls steroidogenesis under acute hypoxic stress

Ariyeloye,

Watts,

Jaykar

et al. 2024

Preprint

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“…Secreted frizzled-related protein 5 (Sfrp5), a protective regulatory protein in coronary heart disease, decreases Drp1 Ser-616 phosphorylation levels and significantly diminishes infarct size [52]. Similarly to Sfrp5 action, uncoupling protein 2 (UCP2) overexpression during myocardial infarction inhibits Drp1 Ser-616 phosphorylation, thereby decreasing apoptosis and improving cardiac function [53]. By disrupting mitochondrial fission and activating AMPK, sirtuin 3 (SIRT3) delays myocardial injury after myocardial infarction by promoting Drp1 dephosphorylation and Drp1 phosphorylation [54].…”

Section: Phosphorylationmentioning

confidence: 99%

Post-Translational Modification of Drp1 is a Promising Target for Treating Cardiovascular Diseases

Ji¹,

Zhou²,

Chen³

et al. 2023

CVIA

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Mitochondria are essential for cell growth, fission, differentiation, and survival, particularly in undivided cells with high energy requirements, such as cardiomyocytes. The morphology and position of mitochondria change with the activity of mitochondrial fission proteins and mitochondrial fusion proteins. These regulatory mechanisms substantially affect cardiomyocyte energy supply and normal function. In mitochondrial fission, dynamin-related protein 1 (Drp1) is involved in the separation and degradation of damaged mitochondria, and accurately regulates mitochondrial renewal and number. Recent studies have revealed a variety of post-translational modification (PTMs) of Drp1, including phosphorylation, SUMOylation, acetylation, O-GlcNAcylation, and S-sulfhydration. These modifications ensure that Drp1 continues to function normally in various signaling pathways, by modulating its activity, stability, and subcellular localization. This article provides an overview of the relationship between Drp1 PTMs and cardiovascular diseases such as heart failure, myocardial infarction, and myocardial ischemia-reperfusion, and describes how these modifications can be targeted and regulated, to help guide cardiovascular disease treatment.

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“…Metformin prevents the DRP1-mediated mitochondrial fission that leads to atherosclerosis in diabetic mice via an AMP-activated protein kinase (AMPK)-dependent pathway [120]. DRP1 is essential in the pathogenesis of diabetic micro and macrovascular complications [121][122][123][124][125][126][127][128][129][130][131][132][133][134][135].…”

Section: Mitochondrial Dynamics In T2dmmentioning

confidence: 99%

The Complex Interplay between Imbalanced Mitochondrial Dynamics and Metabolic Disorders in Type 2 Diabetes

Huynh

Rethi

et al. 2023

Cells

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Type 2 diabetes mellitus (T2DM) is a global burden, with an increasing number of people affected and increasing treatment costs. The advances in research and guidelines improve the management of blood glucose and related diseases, but T2DM and its complications are still a big challenge in clinical practice. T2DM is a metabolic disorder in which insulin signaling is impaired from reaching its effectors. Mitochondria are the “powerhouses” that not only generate the energy as adenosine triphosphate (ATP) using pyruvate supplied from glucose, free fatty acid (FFA), and amino acids (AA) but also regulate multiple cellular processes such as calcium homeostasis, redox balance, and apoptosis. Mitochondrial dysfunction leads to various diseases, including cardiovascular diseases, metabolic disorders, and cancer. The mitochondria are highly dynamic in adjusting their functions according to cellular conditions. The shape, morphology, distribution, and number of mitochondria reflect their function through various processes, collectively known as mitochondrial dynamics, including mitochondrial fusion, fission, biogenesis, transport, and mitophagy. These processes determine the overall mitochondrial health and vitality. More evidence supports the idea that dysregulated mitochondrial dynamics play essential roles in the pathophysiology of insulin resistance, obesity, and T2DM, as well as imbalanced mitochondrial dynamics found in T2DM. This review updates and discusses mitochondrial dynamics and the complex interactions between it and metabolic disorders.

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Downregulation of Uncoupling Protein 2(UCP2) Mediated by MicroRNA-762 Confers Cardioprotection and Participates in the Regulation of Dynamic Mitochondrial Homeostasis of Dynamin Related Protein1 (DRP1) After Myocardial Infarction in Mice

Cited by 6 publications

References 26 publications

HIF1α controls steroidogenesis under acute hypoxic stress

HIF1α controls steroidogenesis under acute hypoxic stress

Post-Translational Modification of Drp1 is a Promising Target for Treating Cardiovascular Diseases

The Complex Interplay between Imbalanced Mitochondrial Dynamics and Metabolic Disorders in Type 2 Diabetes

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