Mitochondria respiration and susceptibility to ischemia–reperfusion injury in diabetic hearts

Lashin, Ossama; Romani, Andrea

doi:10.1016/j.abb.2003.09.024

Cited by 13 publications

(13 citation statements)

References 51 publications

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“…The results of this study extended these finding by demonstrating reduced respiratory function of electron transport chain complexes II-IV (Table 3). We hypothesized that state IV respiration would be increased, as demonstrated recently by Lashin and Romani (31,32) in ketotic diabetic rats; however, we observed a significant decrease with pyruvate 1 malate but not with palmitoylcarnitine (Table 1), consistent with the well-documented decreased activity of pyruvate dehydrogenase in the diabetic heart (47). How et al (30) did not find any difference in state IV respiration between normal and diabetic mice with either pyruvate or palmitoylcarnitine as substrate, yet they observed decreased cardiac mechanical efficiency (external power generation/myocardial energy expenditure) in working hearts at both low and high fatty acid concentrations.…”

Section: Discussionsupporting

confidence: 65%

“…Previous studies demonstrated a similar reduction in state III respiration with either glutamate and succinate (31,32) or pyruvate (30) with diabetes. The results of this study extended these finding by demonstrating reduced respiratory function of electron transport chain complexes II-IV (Table 3).…”

Section: Discussionmentioning

confidence: 88%

“…We hypothesized that PPARa stimulation with diabetes, and pharmacologically with fenofibrate, would increase the protein expression and activity of MTE-I and the export of fatty acid anions from isolated mitochondria. Because diabetes decreases cardiac mechanical efficiency by increasing myocardial oxygen consumption (30), we also investigated whether diabetes or treatment with fenofibrate would decrease the ADP-to-oxygen ratio (P/O) or increase state IV respiration in the mitochondria (31,32). Experiments were performed in established rat models of fenofibrate treatment and streptozotocin-induced diabetes that have previously shown upregulation of the mRNA of MTE-I and UCP3.…”

mentioning

confidence: 99%

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Diabetes or peroxisome proliferator-activated receptor α agonist increases mitochondrial thioesterase I activity in heart

King

Young

Kerner

et al. 2007

Journal of Lipid Research

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Peroxisome proliferator-activated receptor a (PPARa) is a transcriptional regulator of the expression of mitochondrial thioesterase I (MTE-I) and uncoupling protein 3 (UCP3), which are induced in the heart at the mRNA level in response to diabetes. Little is known about the regulation of protein expression of MTE-I and UCP3 or about MTE-I activity; thus, we investigated the effects of diabetes and treatment with a PPARa agonist on these parameters. Rats were either made diabetic with streptozotocin (55 mg/kg ip) and maintained for 10-14 days or treated with the PPARa agonist fenofibrate (300 mg/kg/day) for 4 weeks. MTE-I and UCP3 protein expression, MTE-1 activity, palmitate export, and oxidative phosphorylation were measured in isolated cardiac mitochondria. Diabetes and fenofibrate increased cardiac MTE-I mRNA, protein, and activity (?4-fold compared with controls). This increase in activity was matched by a 6-fold increase in palmitate export in fenofibrate-treated animals, despite there being no effect in either group on UCP3 protein expression. Both diabetes and fenofibrate caused significant decreases in state III respiration of isolated mitochondria with pyruvate 1 malate as the substrate, but only diabetes reduced state III rates with palmitoylcarnitine. Both diabetes and specific PPARa activation increased MTE-I protein, activity, and palmitate export in the heart, with little effect on UCP3 protein expres-

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 88%

mentioning

confidence: 99%

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Diabetes or peroxisome proliferator-activated receptor α agonist increases mitochondrial thioesterase I activity in heart

King

Young

Kerner

et al. 2007

Journal of Lipid Research

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“…These similarities to type 2 diabetic models prompted us to investigate in this study whether mitochondrial uncoupling also contributes to impaired cardiac efficiency and contractile dysfunction in type 1 diabetic models. To date, measurements of cardiac state 4 respiration rates and ADP-to-O ratios performed in streptozotocin-injected animals have yielded conflicting results, making it difficult to make any conclusions about the presence or absence of mitochondrial uncoupling in this model of type 1 diabetes (8,(13)(14)(15).…”

mentioning

confidence: 99%

Type 1 Diabetic Akita Mouse Hearts Are Insulin Sensitive but Manifest Structurally Abnormal Mitochondria That Remain Coupled Despite Increased Uncoupling Protein 3

et al. 2008

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OBJECTIVE-Fatty acid-induced mitochondrial uncoupling and oxidative stress have been proposed to reduce cardiac efficiency and contribute to cardiac dysfunction in type 2 diabetes. We hypothesized that mitochondrial uncoupling may also contribute to reduced cardiac efficiency and contractile dysfunction in the type 1 diabetic Akita mouse model (Akita). RESEARCH DESIGN AND METHODS-Cardiac function andsubstrate utilization were determined in isolated working hearts and in vivo function by echocardiography. Mitochondrial function and coupling were determined in saponin-permeabilized fibers, and proton leak kinetics was determined in isolated mitochondria. Hydrogen peroxide production and aconitase activity were measured in isolated mitochondria, and total reactive oxygen species (ROS) were measured in heart homogenates. RESULTS-Resting cardiac function was normal in Akita mice, and myocardial insulin sensitivity was preserved. Although Akita hearts oxidized more fatty acids, myocardial O 2 consumption was not increased, and cardiac efficiency was not reduced. ADP-stimulated mitochondrial oxygen consumption and ATP synthesis were decreased, and mitochondria showed grossly abnormal morphology in Akita. There was no evidence of oxidative stress, and despite a twofold increase in uncoupling protein 3 (UCP3) content, ATP-to-O ratios and proton leak kinetics were unchanged, even after perfusion of Akita hearts with 1 mmol/l palmitate.

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“…in the electron transport chain (ETC) are particularly prone to the formation of ROS and include oxidizable electron carriers in the inner mitochondrial membrane (12,32). This has implications for ETC proteins because a major constituent of these structures is their iron-sulphur centers (39), which can react with ROS such as superoxide (O 2…”

mentioning

confidence: 99%

Diabetic cardiomyopathy-associated dysfunction in spatially distinct mitochondrial subpopulations

Dabkowski¹,

Williamson²,

Bukowski³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

129

169

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Peer CJ, Callery PS, Hollander JM. Diabetic cardiomyopathy-associated dysfunction in spatially distinct mitochondrial subpopulations. Am J Physiol Heart Circ Physiol 296: H359 -H369, 2009. First published December 5, 2008 doi:10.1152/ajpheart.00467.2008.-Diabetic cardiomyopathy is the leading cause of heart failure among diabetic patients, and mitochondrial dysfunction has been implicated as an underlying cause in the pathogenesis. Cardiac mitochondria consist of two spatially, functionally, and morphologically distinct subpopulations, termed subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM). SSM are situated beneath the plasma membrane, whereas IFM are embedded between myofibrils. The goal of this study was to determine whether spatially distinct cardiac mitochondrial subpopulations respond differently to a diabetic phenotype. Swiss-Webster mice were subjected to intraperitoneal injections of streptozotocin or citrate saline vehicle. Five weeks after injections, diabetic hearts displayed decreased rates of contraction, relaxation, and left ventricular developed pressures (P Ͻ 0.05 for all three). Both mitochondrial size (forward scatter, P Ͻ 0.01) and complexity (side scatter, P Ͻ 0.01) were decreased in diabetic IFM but not diabetic SSM. Electron transport chain complex II respiration was decreased in diabetic SSM (P Ͻ 0.05) and diabetic IFM (P Ͻ 0.01), with the decrease being greater in IFM. Furthermore, IFM complex I respiration and complex III activity were decreased with diabetes (P Ͻ 0.01) but were unchanged in SSM. Superoxide production was increased only in diabetic IFM (P Ͻ 0.01). Oxidative damage to proteins and lipids, indexed through nitrotyrosine residues and lipid peroxidation, were higher in diabetic IFM (P Ͻ 0.05 and P Ͻ 0.01, respectively). The mitochondria-specific phospholipid cardiolipin was decreased in diabetic IFM (P Ͻ 0.01) but not SSM. These results indicate that diabetes mellitus imposes a greater stress on the IFM subpopulation, which is associated, in part, with increased superoxide generation and oxidative damage, resulting in morphological and functional abnormalities that may contribute to the pathogenesis of diabetic cardiomyopathy. diabetes; free radical; mitochondria

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Mitochondria respiration and susceptibility to ischemia–reperfusion injury in diabetic hearts

Cited by 13 publications

References 51 publications

Diabetes or peroxisome proliferator-activated receptor α agonist increases mitochondrial thioesterase I activity in heart

Diabetes or peroxisome proliferator-activated receptor α agonist increases mitochondrial thioesterase I activity in heart

Type 1 Diabetic Akita Mouse Hearts Are Insulin Sensitive but Manifest Structurally Abnormal Mitochondria That Remain Coupled Despite Increased Uncoupling Protein 3

Diabetic cardiomyopathy-associated dysfunction in spatially distinct mitochondrial subpopulations

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