Down-regulation of the mitochondrial fusion protein Opa1/Mfn2 promotes cardiomyocyte hypertrophy in Su5416/hypoxia-induced pulmonary hypertension rats

Luo, Fangmei; Fu, Minyi; Wang, Ting; Qi, Yanan; Zhong, Xuefeng; Li, Dai; Liu, Bin

doi:10.1016/j.abb.2023.109743

Cited by 3 publications

(3 citation statements)

References 36 publications

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“…However, Opa1 and Mfn1 levels remained unchanged. Interestingly, in the Su5416/hypoxia-induced PH rat model, both Opa1 and Mfn2 were significantly down-regulated in right ventricular tissues [58]. This suggests that although a delicate mitochondrial fusion/fission balance is maintained by the fusion and fission mediators crucial for cell survival and optimal functioning, they cannot compensate for the loss of individual mediators in PH as seen in different tissue types and organisms.…”

Section: Discussionmentioning

confidence: 99%

Novel Relationship between Mitofusin 2-Mediated Mitochondrial Hyperfusion, Metabolic Remodeling, and Glycolysis in Pulmonary Arterial Endothelial Cells

Yegambaram,

Sun,

Flores

et al. 2023

IJMS

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The disruption of mitochondrial dynamics has been identified in cardiovascular diseases, including pulmonary hypertension (PH), ischemia-reperfusion injury, heart failure, and cardiomyopathy. Mitofusin 2 (Mfn2) is abundantly expressed in heart and pulmonary vasculature cells at the outer mitochondrial membrane to modulate fusion. Previously, we have reported reduced levels of Mfn2 and fragmented mitochondria in pulmonary arterial endothelial cells (PAECs) isolated from a sheep model of PH induced by pulmonary over-circulation and restoring Mfn2 normalized mitochondrial function. In this study, we assessed the effect of increased expression of Mfn2 on mitochondrial metabolism, bioenergetics, reactive oxygen species production, and mitochondrial membrane potential in control PAECs. Using an adenoviral expression system to overexpress Mfn2 in PAECs and utilizing 13C labeled substrates, we assessed the levels of TCA cycle metabolites. We identified increased pyruvate and lactate production in cells, revealing a glycolytic phenotype (Warburg phenotype). Mfn2 overexpression decreased the mitochondrial ATP production rate, increased the rate of glycolytic ATP production, and disrupted mitochondrial bioenergetics. The increase in glycolysis was linked to increased hypoxia-inducible factor 1α (HIF-1α) protein levels, elevated mitochondrial reactive oxygen species (mt-ROS), and decreased mitochondrial membrane potential. Our data suggest that disrupting the mitochondrial fusion/fission balance to favor hyperfusion leads to a metabolic shift that promotes aerobic glycolysis. Thus, therapies designed to increase mitochondrial fusion should be approached with caution.

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Section: Discussionmentioning

confidence: 99%

Novel Relationship between Mitofusin 2-Mediated Mitochondrial Hyperfusion, Metabolic Remodeling, and Glycolysis in Pulmonary Arterial Endothelial Cells

Yegambaram,

Sun,

Flores

et al. 2023

IJMS

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“…Fusion is coordinated primarily by the proteins mitofusin (MFN) 1 and 2 located on the outer mitochondrial membrane and optic atrophy (OPA) 1 located on the inner mitochondrial membrane whereas mitochondrial fission is mediated primarily by dynamin-related protein1 (Drp1), a pro-fission protein that opposes Mfn2 and is also of importance in the mitophagic process. Prevention of mitochondrial fusion or fission has been shown to enhance cardiac hypertrophy and overall pathology, strongly suggesting that an imbalance between mitochondrial fission and fusion leads to a cardiac pathological response [113][114][115][116].…”

Section: Mitochondrial Function and Dynamics In The Development Of Ca...mentioning

confidence: 99%

“…atrophy (OPA) 1 located on the inner mitochondrial membrane whereas mitochondrial fission is mediated primarily by dynamin-related protein1 (Drp1), a pro-fission protein that opposes Mfn2 and is also of importance in the mitophagic process. Prevention of mitochondrial fusion or fission has been shown to enhance cardiac hypertrophy and overall pathology, strongly suggesting that an imbalance between mitochondrial fission and fusion leads to a cardiac pathological response [113][114][115][116]. In theory, leptin may participate in the modulation of mitochondrial function and structure via two processes, first by stimulating cell signalling, which targets mitochondria, and secondly by directly targeting mitochondria, which can occur through intracellularly derived leptin.…”

Section: Mitochondrial Function and Dynamics In The Development Of Ca...mentioning

confidence: 99%

Molecular and Cellular Mechanisms Underlying the Cardiac Hypertrophic and Pro-Remodelling Effects of Leptin

Karmazyn,

Gan

2024

IJMS

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Since its initial discovery in 1994, the adipokine leptin has received extensive interest as an important satiety factor and regulator of energy expenditure. Although produced primarily by white adipocytes, leptin can be synthesized by numerous tissues including those comprising the cardiovascular system. Cardiovascular function can thus be affected by locally produced leptin via an autocrine or paracrine manner but also by circulating leptin. Leptin exerts its effects by binding to and activating specific receptors, termed ObRs or LepRs, belonging to the Class I cytokine family of receptors of which six isoforms have been identified. Although all ObRs have identical intracellular domains, they differ substantially in length in terms of their extracellular domains, which determine their ability to activate cell signalling pathways. The most important of these receptors in terms of biological effects of leptin is the so-called long form (ObRb), which possesses the complete intracellular domain linked to full cell signalling processes. The heart has been shown to express ObRb as well as to produce leptin. Leptin exerts numerous cardiac effects including the development of hypertrophy likely through a number of cell signaling processes as well as mitochondrial dynamics, thus demonstrating substantial complex underlying mechanisms. Here, we discuss mechanisms that potentially mediate leptin-induced cardiac pathological hypertrophy, which may contribute to the development of heart failure.

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A novel nomogram to predict the impact of polymorphism and plasma level of Mfn2 on risk of ischemic cardiomyopathy

Naman,

Aimaier,

Abudourexiti

et al. 2024

Preprint

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Objectives In this study, we aimed to investigate the relation of polymorphism as well as plasma level of Mitofusion2(Mfn2) and occurrence of ischemic cardiomyopathy (ICM), then develop a predictive model which can predict the risk of ICM. Methods A total of 2052 participants were included in this study. These participants were randomly assigned to the training group [n = 1412 (70%)] and the validation group [n = 640 (30%)]. Univariable analysis was performed in the training group. Then, least absolute shrinkage and selection operator (LASSO) regression model were adopted, then, a multivariable logistic regression was performed to build the predictive model. We then constructed a nomogram incorporating the variables regarded as independent predictive factors using multivariable logistic regression analysis. Evaluated the model by Receiver operating characteristic (ROC) curves, calibration plot and decision curve analysis (DCA). Results The independent predicting factors incorporated into this nomogram were age, hemoglobin concentration, diabetes, ejection fraction, left-ventricular diastolic-end diameter, plasma Mfn2 concentration, and mutation in rs1042842 and rs2295281. Our constructed nomogram displayed favorable discrimination ability, Besides, the Hosmer–Lemshow test suggested that the model exhibited good consistency (P training group = 0.2655; P validation group = 0.3315). DCA revealed that our constructed ICM nomogram showed clinical benefits. Conclusions The plasma level of Mfn2 is a protective factor of ICM. Mutations of rs1042842 and rs2295281 are risk factors for ICM.

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Down-regulation of the mitochondrial fusion protein Opa1/Mfn2 promotes cardiomyocyte hypertrophy in Su5416/hypoxia-induced pulmonary hypertension rats

Cited by 3 publications

References 36 publications

Novel Relationship between Mitofusin 2-Mediated Mitochondrial Hyperfusion, Metabolic Remodeling, and Glycolysis in Pulmonary Arterial Endothelial Cells

Novel Relationship between Mitofusin 2-Mediated Mitochondrial Hyperfusion, Metabolic Remodeling, and Glycolysis in Pulmonary Arterial Endothelial Cells

Molecular and Cellular Mechanisms Underlying the Cardiac Hypertrophic and Pro-Remodelling Effects of Leptin

A novel nomogram to predict the impact of polymorphism and plasma level of Mfn2 on risk of ischemic cardiomyopathy

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