Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat

Hicks, Steven D.; Labinskyy, Nazar; Piteo, Brian; Laurent, Dimitri; Mathew, Jamie; Gupte, Sachin A.; Edwards, John G.

doi:10.1152/ajpheart.00567.2012

Cited by 18 publications

(23 citation statements)

References 131 publications

(147 reference statements)

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“…Further, Herlein et al have argued that in mild diabetes or prediabetes, mitochondrial superoxide may not be elevated in contrast to its decided presence in more severe diabetic states [31]. More recently our investigations suggest that separate from a direct effect of mtROS on mtDNA, mitochondrial topoisomerase dysfunction increased mtDNA strand breakage [37,40]. Collectively these studies suggest that more than just mtROS promotes mtDNA damage leading to mitochondrial and cellular degradation within the heart.…”

supporting

confidence: 51%

Myocardial Mitochondria at the Intersection of Health and Disease

2013

J Clin Exp Cardiolog

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The air that we breathe and the food that we eat reach their confluency in the mitochondria to derive the energy that the cell is dependent upon. The heart is the most aerobic of organs and has little anaerobic reserve compared to the constant demands placed upon it. At rest the arterial-venous oxygen extraction from the blood is the greatest from the heart and this only goes up with exercise. Common to all cell types residing in the heart is the need for energy and mitochondrial dysfunction is a significant contributor to cell death across the spectrum of cardiac disorders. Mitochondrial failure within any one cell type creates varying complications that eventually manifest as heart failure.The field of mitochondrial biology has under gone several paradigms shifts since the early nineties. The pioneering work of Krebs, Chance, and others had brought the field to a plateau with the focus on ATP generation. It was not until the implications of mitochondria's role in apoptosis and the cell's health, was there a strong resurgence of interest in mitochondrial biology [1,2]. Since then, a second major road of significance, dug predominantly by D. Wallace, has been in identifying the participation of mitochondria DNA (mtDNA) alterations and damage as a common pathology in unrelated symptoms [3,4]. And third avenue, that mitochondria are not just the isolated organelles pictured in electron micrographs, but dynamic entities that undergo significant morphological changes as a course of their normal function [5].The mitochondrial genome is a circular double-stranded DNA of more than 16 Kb in humans. It codes for 37 genes including 13 of the more than 1000 proteins indigenous to the mammalian mitochondria. Mitochondrial disorders are a heterogeneous group of diseases that may be characterized by maternal inheritance, heteroplasmy, and threshold effect. Mitochondrial dysfunction and mtDNA damage has been reported in diabetes, alcoholism, cancer, skeletal muscle disorders, and neurodegenerative diseases such as Barth Syndrome, MELAS, ALS, or LHON [6-9]. As one example, several mtDNA mutations have been identified that represent a high risk for the development of diabetes [10][11][12][13]. Mutations may take the form of deletions, rearrangements, or missense mutations that interfere with protein synthesis. The etiology for the accumulation of mtDNA mutations and deletions is not completely understood [14][15][16].This is an open

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confidence: 51%

Myocardial Mitochondria at the Intersection of Health and Disease

2013

J Clin Exp Cardiolog

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“…In particular, mitochondrial DNA (mtDNA) appears at increased susceptibility to oxidative damage, which may be attributable to low mtDNA repair capacity and lack of histones, the close proximity to the ETC, or oxidative damage to mitochondrial proteins and lipids. This increased susceptibility has been observed in patients or animals with diabetes or obesity and in vitro models (8,20,24,25). Mitochondrial ROS also impair mitochondrial respiration via oxidative post-translational modifications of complex I and complex II of the ETC, whereas scavenging of mitochondrial ROS inhibited cardiac hypertrophy and improved diastolic function in a preclinical model of obesity (26).…”

Section: Obesity Diabetes and Oxidative Stressmentioning

confidence: 79%

Oxidative Stress and Cardiovascular Risk: Obesity, Diabetes, Smoking, and Pollution

Niemann

Rohrbach

Miller

et al. 2017

Journal of the American College of Cardiology

281

177

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Oxidative stress occurs whenever the release of reactive oxygen species (ROS) exceeds endogenous antioxidant capacity. In this paper, we review the specific role of several cardiovascular risk factors in promoting oxidative stress, namely diabetes, obesity, smoking, and excessive pollution. Specifically, the risk of developing heart failure is higher in patients with diabetes or obesity, even with optimal medical treatment, and the increased release of ROS from cardiac mitochondria and other sources likely contributes to the development of cardiac dysfunction in this setting. Here, we explore the role of different ROS sources arising in obesity and diabetes, and the impact of excessive ROS production on the development of cardiac lipotoxicity. In parallel, contaminants in the air that we breathe pose a significant threat to human health. This paper provides an overview of cigarette smoke and urban air pollution, considering how their composition and biological effects have detrimental effects on cardiovascular health.

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“…Despite current optimal therapy, the mortality rate of acute myocardial infarction in diabetic patients is more than double that of nondiabetic patients [ 20 ]. Uncontrolled chronic hyperglycemia with mitochondrial bioenergetics deficit and increased oxidative stress led to an inadequate physiological reserve in the myocardium when challenged by MI/R insult [ 21 – 24 ]. Diabetes also attenuates the endogenous antiapoptosis signaling pathways, thus invalidating powerful therapeutic programs, such as ischemic pre- and postconditioning [ 25 – 27 ].…”

Section: Introductionmentioning

confidence: 99%

Suppression of Excessive Histone Deacetylases Activity in Diabetic Hearts Attenuates Myocardial Ischemia/Reperfusion Injury via Mitochondria Apoptosis Pathway

Leng

Meng

et al. 2017

Journal of Diabetes Research

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Background. Histone deacetylases (HDACs) play a pivotal role in signaling modification and gene transcriptional regulation that are essential for cardiovascular pathophysiology. Diabetic hearts with higher HDACs activity were more vulnerable to myocardial ischemia/reperfusion (MI/R) injury compared with nondiabetic hearts. We are curious about whether suppression of excessive HDACs activity in diabetic heart protects against MI/R injury. Methods. Diabetic rats were subjected to 45 min of ischemia, followed by 3 h of reperfusion. H9C2 cardiomyocytes were exposed to high glucose for 24 h, followed by 4 h of hypoxia and 2 h of reoxygenation (H/R). Results. Both MI/R injury and diabetes mellitus elevated myocardium HDACs activity. MI/R induced apoptotic cell death was significantly decreased in diabetic rats treated with HDACs inhibitor trichostatin A (TSA). TSA administration markedly moderated dissipation of mitochondrial membrane potential, protected the integrity of mitochondrial permeability transition pore (mPTP), and decreased cell apoptosis. Notably, cotreatment with Akt inhibitor partly or absolutely inhibited the protective effect of TSA in vivo and in vitro. Furthermore, TSA administration activated Akt/Foxo3a pathway, leading to Foxo3a cytoplasm translocation and attenuation proapoptosis protein Bim expression. Conclusions. Both diabetes mellitus and MI/R injury increased cardiac HDACs activity. Suppression of HDACs activity triggered protective effects against MI/R and H/R injury under hyperglycemia conditions through Akt-modulated mitochondrial apoptotic pathways via Foxo3a/Bim.

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Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat

Cited by 18 publications

References 131 publications

Myocardial Mitochondria at the Intersection of Health and Disease

Myocardial Mitochondria at the Intersection of Health and Disease

Oxidative Stress and Cardiovascular Risk: Obesity, Diabetes, Smoking, and Pollution

Suppression of Excessive Histone Deacetylases Activity in Diabetic Hearts Attenuates Myocardial Ischemia/Reperfusion Injury via Mitochondria Apoptosis Pathway

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