Mitochondrial Dynamics and Heart Failure

Knowlton, Anne A; Liu, Tingting

doi:10.1002/cphy.c150022

Cited by 31 publications

(21 citation statements)

References 203 publications

(273 reference statements)

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“…The balance between fission and fusion regulate the morphology of mitochondria. Defective mitochondrial dynamics has also been identified as a feature of heart failure (Knowlton and Liu, ) and diabetic cardiomyopathy (Galloway and Yoon, ). Hausenloy and colleagues have further reported that the promotion of fusion (and inhibition of fission) is cardioprotetive against ischaemia reperfusion injury (Ong et al, ).…”

Section: Cryo‐em and Spa Techniques Enter A New Era For Protein Strucmentioning

confidence: 99%

Three‐dimensional electron microscopy techniques for unravelling mitochondrial dysfunction in heart failure and identification of new pharmacological targets

Daghistani

Rajab

Kitmitto

2018

British J Pharmacology

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A hallmark of heart failure is mitochondrial dysfunction leading to a bioenergetics imbalance in the myocardium. Consequently, there is much interest in targeting mitochondrial abnormalities to attenuate the pathogenesis of heart failure. This review discusses (i) how electron microscopy (EM) techniques have been fundamental for the current understanding of mitochondrial structure–function, (ii) the paradigm shift in resolutions now achievable by 3‐D EM techniques due to the introduction of direct detection devices and phase plate technology, and (iii) the application of EM for unravelling mitochondrial pathological remodelling in heart failure. We further consider the tremendous potential of multi‐scale EM techniques for the development of therapeutics, structure‐based ligand design and for delineating how a drug elicits nanostructural effects at the molecular, organelle and cellular levels. In conclusion, 3‐D EM techniques have entered a new era of structural biology and are poised to play a pivotal role in discovering new therapies targeting mitochondria for treating heart failure. Linked Articles This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc

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Section: Cryo‐em and Spa Techniques Enter A New Era For Protein Strucmentioning

confidence: 99%

Three‐dimensional electron microscopy techniques for unravelling mitochondrial dysfunction in heart failure and identification of new pharmacological targets

Daghistani

Rajab

Kitmitto

2018

British J Pharmacology

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“…14 The mitochondrial dysfunction that has been correlated to the bioenergetic collapse seen in heart failure derives largely from studies in LV disease, 15 and is characterized by depressed oxidative phosphorylation, 16,17 a metabolic switch from fatty acid oxidation (FAO) to glycolysis, 18 lipid accumulation and lipotoxicity, 19 and changes in mitochondrial morphology and dynamics. [20][21][22] Some of these changes have been recapitulated in models of RV failure, particularly the switch from FAO to glycolysis. [23][24][25] Beyond this, few studies directly compare the metabolic differences between the LV and RV in health and disease.…”

Section: Introductionmentioning

confidence: 99%

Differential Bioenergetics in Adult Rat Cardiomyocytes Isolated From the Right Versus Left Ventricle

Nguyen

Rao

Mullett

et al. 2020

Preprint

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The right and left ventricle of the heart have distinctly different developmental origins and are affected differently by similar pathological stimuli. Though it is well established that the heart relies almost entirely on mitochondrial function to sustain energy production, it remains unclear whether bioenergetics differ in the two ventricles. Herein, we define a novel methodology to optimize the isolation of intact cardiomyocytes from the right versus the left ventricle. We demonstrate that this segmental Langendorff-free methodology yields viable cardiomyocytes with intact mitochondrial function. Further, we compare bioenergetics in right versus left ventricle cardiomyocytes and show that cardiomyocytes from the right ventricle have a greater maximal capacity for respiration and enhanced glycolytic rate. This increase in respiration was concomitant with increased fatty acid oxidation and levels of fatty acid oxidation proteins, but no change in mitochondrial electron transport complex expression. These data validate a potentially powerful tool to evaluate differences in right and left ventricular function and advance the understanding of cardiac bioenergetic differences. These data will be discussed in the context of differential responses by the right versus ventricle in pathology.

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“…This imbalance leads to cellular dysfunction ( van der Bliek et al ., 2013 ). In recent studies, the association between mitochondrial dynamics and cardiovascular disease has been explored ( Knowlton and Liu, 2015 ), and mitochondrial dysfunction as a major cause of various diseases has been postulated ( Archer, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

High Glucose Causes Human Cardiac Progenitor Cell Dysfunction by Promoting Mitochondrial Fission: Role of a GLUT1 Blocker

Choi

Park

Jang

et al. 2016

Biomolecules & Therapeutics

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Cardiovascular disease is the most common cause of death in diabetic patients. Hyperglycemia is the primary characteristic of diabetes and is associated with many complications. The role of hyperglycemia in the dysfunction of human cardiac progenitor cells that can regenerate damaged cardiac tissue has been investigated, but the exact mechanism underlying this association is not clear. Thus, we examined whether hyperglycemia could regulate mitochondrial dynamics and lead to cardiac progenitor cell dysfunction, and whether blocking glucose uptake could rescue this dysfunction. High glucose in cardiac progenitor cells results in reduced cell viability and decreased expression of cell cycle-related molecules, including CDK2 and cyclin E. A tube formation assay revealed that hyperglycemia led to a significant decrease in the tube-forming ability of cardiac progenitor cells. Fluorescent labeling of cardiac progenitor cell mitochondria revealed that hyperglycemia alters mitochondrial dynamics and increases expression of fission-related proteins, including Fis1 and Drp1. Moreover, we showed that specific blockage of GLUT1 improved cell viability, tube formation, and regulation of mitochondrial dynamics in cardiac progenitor cells. To our knowledge, this study is the first to demonstrate that high glucose leads to cardiac progenitor cell dysfunction through an increase in mitochondrial fission, and that a GLUT1 blocker can rescue cardiac progenitor cell dysfunction and downregulation of mitochondrial fission. Combined therapy with cardiac progenitor cells and a GLUT1 blocker may provide a novel strategy for cardiac progenitor cell therapy in cardiovascular disease patients with diabetes.

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Mitochondrial Dynamics and Heart Failure

Cited by 31 publications

References 203 publications

Three‐dimensional electron microscopy techniques for unravelling mitochondrial dysfunction in heart failure and identification of new pharmacological targets

Three‐dimensional electron microscopy techniques for unravelling mitochondrial dysfunction in heart failure and identification of new pharmacological targets

Differential Bioenergetics in Adult Rat Cardiomyocytes Isolated From the Right Versus Left Ventricle

High Glucose Causes Human Cardiac Progenitor Cell Dysfunction by Promoting Mitochondrial Fission: Role of a GLUT1 Blocker

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