Uncoupling proteins as a therapeutic target to protect the diabetic heart

Dludla, Phiwayinkosi V.; Nkambule, Bongani B.; Tiano, Luca; Louw, Johan; Jastroch, Martin; Mazibuko-Mbeje, Sithandiwe E.

doi:10.1016/j.phrs.2018.09.013

Cited by 28 publications

(22 citation statements)

References 161 publications

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“…However, enhanced UCP3 expression has been associated with the mitigation of oxidative stress, and in line with this there is evidence to suggest a relationship between increased mitochondrial ROS and UCP3 deficiency . In intact cell systems, mild mitochondrial uncoupling, due to a decrease in ∆Ψm, has been proposed to be a protective strategy under conditions of oxidative stress such as diabetes and obesity . However, this situation may only apply at the extremes of high redox potential, which is further elaborated within the R‐ORB hypothesis (Redox‐Optimized ROS Balance) …”

Section: Pathophysiology Of Disturbances In Mitochondrial Metabolism mentioning

confidence: 87%

“…Increased expression of UCP3 has been described in the hearts of animals with streptozotocin‐induced diabetes . Other studies have demonstrated an association with UCP3 and enhanced myocardial FAO during insulin resistance and diabetes, and in humans increased concentrations of circulating free FAs correlate with expression of both UCP2 and UCP3 . However, FA‐induced leak respiration can occur without alterations in UCP3 protein content (eg as in ob/ob hearts).…”

Section: Pathophysiology Of Disturbances In Mitochondrial Metabolism mentioning

confidence: 99%

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Altered mitochondrial metabolism in the insulin‐resistant heart

et al. 2019

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Obesity‐induced insulin resistance and type 2 diabetes mellitus can ultimately result in various complications, including diabetic cardiomyopathy. In this case, cardiac dysfunction is characterized by metabolic disturbances such as impaired glucose oxidation and an increased reliance on fatty acid (FA) oxidation. Mitochondrial dysfunction has often been associated with the altered metabolic function in the diabetic heart, and may result from FA‐induced lipotoxicity and uncoupling of oxidative phosphorylation. In this review, we address the metabolic changes in the diabetic heart, focusing on the loss of metabolic flexibility and cardiac mitochondrial function. We consider the alterations observed in mitochondrial substrate utilization, bioenergetics and dynamics, and highlight new areas of research which may improve our understanding of the cause and effect of cardiac mitochondrial dysfunction in diabetes. Finally, we explore how lifestyle (nutrition and exercise) and pharmacological interventions can prevent and treat metabolic and mitochondrial dysfunction in diabetes.

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Section: Pathophysiology Of Disturbances In Mitochondrial Metabolism mentioning

confidence: 87%

Section: Pathophysiology Of Disturbances In Mitochondrial Metabolism mentioning

confidence: 99%

Altered mitochondrial metabolism in the insulin‐resistant heart

et al. 2019

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“…In a morbidly obese state, adipocytes utilize FFAs derived from triglyceride stores via excessive lipolysis for energy production, as a result of glucose deprivation due to insulin resistance [64]. Excessive FFAs lead to an overflow of electrons in the electron transport chain during oxidative phosphorylation, resulting in their leakage and generation of O 2 • − followed by the production of other ROS molecules [64,70]. Excess production of mitochondrial derived ROS is associated with aggravation of inflammation and development of insulin resistance in adipocytes through the activation of the NF-κB [71].…”

Section: Oxidative Stress In Adipose Tissuementioning

confidence: 99%

Inflammation and Oxidative Stress in an Obese State and the Protective Effects of Gallic Acid

et al. 2018

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Metabolic complications in an obese state can be aggravated by an abnormal inflammatory response and enhanced production of reactive oxygen species. Pro-inflammatory response is known to be associated with the formation of toxic reactive oxygen species and subsequent generation of oxidative stress. Indeed, adipocytes from obese individuals display an altered adipokine profile, with upregulated expression and secretion of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin (IL-6). Interestingly, natural compounds, including phenolic enriched foods are increasingly explored for their ameliorative effects against various metabolic diseases. Of interest is gallic acid, a trihydroxybenzoic acid that has progressively demonstrated robust anti-obesity capabilities in various experimental models. In addition to reducing excessive lipid storage in obese subjects, gallic acid has been shown to specifically target the adipose tissue to suppress lipogenesis, improve insulin signaling, and concomitantly combat raised pro-inflammatory response and oxidative stress. This review will revise mechanisms involved in the pathophysiological effects of inflammation and oxidative stress in an obese state. To better inform on its therapeutic potential and improvement of human health, available evidence reporting on the anti-obesity properties of gallic acid and its derivatives will be discussed, with emphases on its modulatory effect on molecular mechanisms involved in insulin signaling, inflammation and oxidative stress.

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“…200 Mitochondrial uncoupling proteins (three known UCP paralogues: UCP 1, UCP 2, UCP 3; UCP2 and UCP3 confirmed in the heart) are inner membrane carrier proteins expressed within the myocardium that can protect against free radical damage by regulating mitochondrial respiration, leading to decreased ROS formation under conditions of stress, such as acute myocardial I/R injury. 56,201 Overexpression of UCPs protects the myocardium against acute I/R injury. Several UCP activators have been described, including antioxidant biofactor, aspalathin, ghrelin, losartan, ramipril, melatonin, resveratrol, and some antihyperglycemic agents (metformin, glitazones, sitagliptin).…”

Section: Mitochondrial Ion Channelsmentioning

confidence: 99%

Mitochondrial dysfunction in cardiovascular disease: Current status of translational research/clinical and therapeutic implications

Manolis¹,

Manolis

et al. 2020

Medicinal Research Reviews

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Mitochondria provide energy to the cell during aerobic respiration by supplying ~95% of the adenosine triphosphate (ATP) molecules via oxidative phosphorylation. These organelles have various other functions, all carried out by numerous proteins, with the majority of them being encoded by nuclear DNA (nDNA). Mitochondria occupy ~1/3 of the volume of myocardial cells in adults, and function at levels of high‐efficiency to promptly meet the energy requirements of the myocardial contractile units. Mitochondria have their own DNA (mtDNA), which contains 37 genes and is maternally inherited. Over the last several years, a variety of functions of these organelles have been discovered and this has led to a growing interest in their involvement in various diseases, including cardiovascular (CV) diseases. Mitochondrial dysfunction relates to the status where mitochondria cannot meet the demands of a cell for ATP and there is an enhanced formation of reactive‐oxygen species. This dysfunction may occur as a result of mtDNA and/or nDNA mutations, but also as a response to aging and various disease and environmental stresses, leading to the development of cardiomyopathies and other CV diseases. Designing mitochondria‐targeted therapeutic strategies aiming to maintain or restore mitochondrial function has been a great challenge as a result of variable responses according to the etiology of the disorder. There have been several preclinical data on such therapies, but clinical studies are scarce. A major challenge relates to the techniques needed to eclectically deliver the therapeutic agents to cardiac tissues and to damaged mitochondria for successful clinical outcomes. All these issues and progress made over the last several years are herein reviewed.

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Uncoupling proteins as a therapeutic target to protect the diabetic heart

Cited by 28 publications

References 161 publications

Altered mitochondrial metabolism in the insulin‐resistant heart

Altered mitochondrial metabolism in the insulin‐resistant heart

Inflammation and Oxidative Stress in an Obese State and the Protective Effects of Gallic Acid

Mitochondrial dysfunction in cardiovascular disease: Current status of translational research/clinical and therapeutic implications

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