Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.5.3 (complex I)
8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several lines of research suggest that mitochondria play a role in the etiopathogenesis of diabetic cardiomyopathy, although the mechanisms involved are still debated. In the present study, we report that State 3 oxygen consumption decreases by approximately 35% with glutamate and by approximately 30% with succinate in mitochondria from diabetic rat hearts compared to controls. In these mitochondria the enzymatic activities of complex I and complex II are also decreased to a comparable extent. Western blot analysis of mitochondrial protein pattern using antibodies recognizing proteins modified by the lipid peroxidation product 4-hydroxynonenal indicates the FAD-containing subunit of succinate dehydrogenase as one of the targets of this highly reactive aldehyde. In rats diabetic for 6 or 12 weeks, insulin supplementation for 2 weeks decreases the level of protein modified by 4-hydroxynonenal and restores mitochondrial respiration and enzyme activity to control level. Taken together, these results: (1) indicate that 4-hydroxynonenal is endogenously produced within diabetic mitochondria and forms an adduct with selective mitochondrial proteins, (2) identify one of these proteins as a subunit of succinate dehydrogenase, and (3) provide strong evidence that insulin treatment can reverse and ameliorate free radical damage and mitochondrial function under diabetic conditions.
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PMID:Decreased complex II respiration and HNE-modified SDH subunit in diabetic heart. 1652 Feb 40

1-Methyl-4-phenylpyridinium ion (MPP+), an inhibitor of mitochondrial complex I, has been widely used as a neurotoxin because it elicits a severe Parkinson's disease-like syndrome characterized by elevation of intracellular reactive oxygen species level and apoptotic death. Adiponectin, secreted from adipose tissue, mediates systemic insulin sensitivity with liver and muscle as target organs. Adiponectin can also suppress superoxide generation in endothelial cells. In the present study, we investigated the protective effects of adiponectin on MPP+-induced cytotoxicity in human neuroblastoma SH-SY5Y cells, as well as the underlying mechanism. Our results suggest that the protective effects of adiponectin on MPP+-induced apoptosis may be ascribed to its anti-oxidative properties, anti-apoptotic activity via inducing expression of SOD and catalase, and regulation of Bcl-2 and Bax expression. These data indicated that adiponectin might provide a useful therapeutic strategy for the treatment of progressive neurodegenerative diseases such as Parkinson's disease.
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PMID:Adiponectin protects human neuroblastoma SH-SY5Y cells against MPP+-induced cytotoxicity. 1655 29

Thiazolidinediones are synthetic agonists for the transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) and are therapeutically used as insulin sensitizers. Besides therapeutical benefits, potential side effects such as the induction of cell death by thiazolidinediones deserve consideration. Although PPARgamma-dependent and -independent cell death in response to thiazolidinediones has been described, we provide evidence supporting a new mechanism to account for thiazolidinedione-initiated but PPARgamma-independent cell demise. In Jurkat T cells, ciglitazone and troglitazone provoked rapid and dose-dependent cell death, whereas rosiglitazone did not alter cell viability. We found induction of apoptosis by troglitazone, whereas ciglitazone caused necrosis. Because preincubation with the reactive oxygen species (ROS) scavengers manganese (III) tetrakis(4-benzoic acid) porphyrin and vitamin C significantly inhibited ciglitazone- and partially troglitazone-mediated cell death, we suggest that ROS contribute to cytotoxicity. Assuming that ROS originate from mitochondria, studies in submitochondrial particles demonstrated that all thiazolidinediones inhibited complex I of the mitochondrial respiratory chain. However, only ciglitazone and troglitazone lowered complex II activity as well. Pharmacological inhibition of complexes I and II documented that complex II inhibition in Jurkat cells caused massive apoptotic cell death, whereas inhibition of complex I provoked only marginally apoptosis after 4-h treatment. Therefore, inhibition of complex II by ciglitazone and troglitazone is the main trigger of cell death. ATP depletion by ciglitazone, in contrast to troglitazone, is responsible for induction of necrosis. Our results demonstrate that despite their similar molecular structure, thiazolidinediones differently affect cell death, which might help to explain some adverse effects occurring during thiazolidinedione-based therapies.
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PMID:Mechanism of thiazolidinedione-dependent cell death in Jurkat T cells. 1732 28

Individually, exercise and the drug metformin have been shown to prevent or delay type 2 diabetes. Metformin mildly inhibits complex I of the electron transport system and may impact aerobic capacity in people exercising while taking metformin. The purpose of the study was to evaluate the effects of metformin on maximal aerobic capacity in healthy individuals without mitochondrial dysfunction. Seventeen healthy, normal-weight men (n=11) and women (n=6) participated in a double-blind, placebo-controlled, cross-over design. Peak aerobic capacity was measured twice using a continuous, incrementally graded protocol; once after 7-9 d of metformin (final dose=2000 mg/d) and once with placebo, with 1 week between tests. The order of the conditions was counterbalanced. Peak oxygen uptake (VO2 peak), heart rate (HR), ventilation (VE), respiratory exchange ratio (RER), rating of perceived exertion (RPE), and test duration were compared across conditions using paired t tests with the R statistical program. VO2 peak (-2.7%), peak heart rate (-2.0%), peak ventilation (-6.2%), peak RER (-3.0%), and exercise duration (-4.1%) were all reduced slightly, but significantly, with metformin (all p<0.05). There was no effect of metformin on RPE or ventilatory breakpoint. Correlations between the decrement in VO2 peak and any of the other outcome variables were weak (r2<0.20) and not significant. Short-term treatment with metformin has statistically significant, but physiologically subtle, effects that reduce key outcomes related to maximal exercise capacity. Whether this small but consistent effect is manifested in people with insulin resistance or diabetes who already have some degree of mitochondrial dysfunction remains to be determined.
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PMID:Impact of metformin on peak aerobic capacity. 1834 54

It is known that dietary restriction (DR) increases maximum longevity in rodents, but the mechanisms involved remain unknown. Among the possible mechanisms, several lines of evidence support the idea that decreases in mitochondrial oxidative stress and in insulin signaling are involved but it is not known if they are interconnected. It has been reported that when C57BL/6 mice are maintained on an every other day (EOD) feeding their overall food intake is only slightly decreased and plasma insulin-like growth factor (IGF)-1 is even somewhat increased. In spite of this, their maximum longevity is increased, analogously to what occurs in classic DR. Thus, this model dissociates the increase in longevity from the decrease in IGF-1 observed in classic DR. Based on these facts, we have studied the effect of EOD DR on the rate of mitochondrial reactive oxygen species (ROS) production, oxygen consumption, and the percent free radical leak (FRL) of well-coupled liver mitochondria, the marker of mtDNA oxidative damage 8-oxo-7,8-dihydro-2'deoxyguanosine (8-oxodG), the content of complexes I to IV of the respiratory chain, the apoptosis inducing factor (AIF), PGC1-alpha, UCP2, five different markers of oxidative damage to proteins and the full fatty acid composition on C57BL/6 mice liver. It was found that EOD DR decreased ROS production in complex I but not in complex III without changes in oxygen consumption. As a result, FRL was decreased in complex I. Oxidative damage to mtDNA (8-oxodG) and protein oxidation, glycoxidation and lipoxidation were also lower in the EOD restricted group in comparison with the control one while the degree of fatty acid unsaturation was held constant. The EOD group also showed decreases in AIF, PGC1-alpha, and UCP2. These results support the possibility that EOD DR increases maximum life span at least in part through decreases in mitochondrial oxidative stress which are independent from insulin/IGF-1-like signaling.
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PMID:Effect of every other day feeding on mitochondrial free radical production and oxidative stress in mouse liver. 1859 80

Pancreatic islets express the superoxide-producing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system, but its role remains unknown. To address this, we studied the mechanisms of impaired insulin secretion induced by diphenyleneiodium (DPI), an NADPH oxidase inhibitor. We investigated the effects of DPI on glucose- and nonfuel-stimulated insulin secretion, islet glucose metabolism, and intracellular Ca2+ concentration ([Ca2+]i) dynamics in rat islets and beta-cell line RINm5F cells. DPI did not affect insulin secretion at 3.3 mm glucose but totally suppressed insulin secretion stimulated by 16.7 mm glucose (percentage of control, 9.2 +/- 1.2%; P <0.001). DPI also inhibited insulin release by high K+-induced membrane depolarization (percentage of control, 36.0 +/- 5.3%; P <0.01) and protein kinase C activation (percentage of control, 30.2 +/- 10.6% in the presence of extracellular Ca2+, P <0.01; percentage of control, 42.0 +/- 4.7% in the absence of extracellular Ca2+, P <0.01). However, DPI had no effect on mastoparan-induced insulin secretion at 3.3 and 16.7 mm glucose under Ca2+-free conditions. DPI significantly suppressed islet glucose oxidation and ATP content through its known inhibitory action on complex I in the mitochondrial respiratory chain. On the other hand, DPI altered [Ca2+]i dynamics in response to high glucose and membrane depolarization, and DPI per se dose-dependently increased [Ca2+]i. The DPI-induced [Ca2+]i rise was associated with a transient increase in insulin secretion and was attenuated by removal of extracellular Ca2+, by L-type voltage-dependent Ca2+ channel blockers, by mitochondrial inhibitors, or by addition of 0.1 or 1.0 microm H2O2 exogenously. Our results showed that DPI impairment of insulin secretion involved altered Ca2+ signaling, suggesting that NADPH oxidase may modulate Ca2+ signaling in beta-cells.
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PMID:Impaired insulin secretion by diphenyleneiodium associated with perturbation of cytosolic Ca2+ dynamics in pancreatic beta-cells. 1861 20

Mitochondrial reactive oxygen species have been implicated in both diabetic complications and the progression of the underlying diabetic state. However, it is not clear whether mitochondria of diabetic origin are intrinsically altered to generate excess reactive oxygen species independent of the surrounding diabetic milieu. Mitochondria were isolated from gastrocnemius, heart, and liver of 2-wk and 2-month streptozotocin diabetic rats and controls. We rigidly quantified mitochondrial superoxide, respiration and ATP production, respiratory coupling, the expression of several proteins with antioxidant properties, and the redox state of glutathione. Both fluorescent assessment and electron paramagnetic spectroscopy revealed that superoxide production was unchanged or reduced in the 2-month diabetic mitochondria compared with controls. Kinetic analysis of the proton leak showed that diabetic heart and muscle mitochondria were actually more coupled compared with control despite an approximate 2- to 4-fold increase in uncoupling protein-3 content. Adenine nucleotide translocator type 1 expression was reduced by approximately 50% in diabetic muscle mitochondria. Catalase was significantly up-regulated in muscle and heart tissue and in heart mitochondria, whereas glutathione peroxidase expression was increased in liver mitochondria of diabetic rats. We conclude that gastrocnemius, heart, and liver mitochondria of streptozotocin diabetic rats are not irrevocably altered toward excess superoxide production either by complex I or complex III. Moreover, gastrocnemius and heart mitochondria demonstrate increased, not decreased, respiratory coupling. Mitochondria of insulin-deficient diabetic rats do show signs of adaptation to antecedent oxidative stress manifested as tissue-specific enzyme and uncoupling protein expression but remain remarkably robust with respect to superoxide production.
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PMID:Superoxide and respiratory coupling in mitochondria of insulin-deficient diabetic rats. 1877 40

4-Methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione (oltipraz), a prototype drug candidate containing a 1,2-dithiole-3-thione moiety, has been widely studied as a cancer chemopreventive agent. Oltipraz and other novel 1,2-dithiole-3-thione congeners have the capability to prevent insulin resistance via AMP-activated protein kinase (AMPK) activation. Arachidonic acid (AA, a proinflammatory fatty acid) exerts a deleterious effect on mitochondria and promotes reactive oxygen species (ROS) production. This study investigated whether AA alone or in combination with iron (catalyst of autooxidation) causes ROS-mediated mitochondrial impairment, and if so, whether oltipraz and synthetic 1,2-dithiole-3-thiones protect mitochondria and cells against excess ROS produced by AA + iron. Oltipraz treatment effectively inhibited mitochondrial permeability transition promoted by AA + iron in HepG2 cells, thereby protecting cells from ROS-induced apoptosis. Oltipraz was found to attenuate apoptosis induced by rotenone (complex I inhibitor), but not that by antimycin A (complex III inhibitor), suggesting that the inhibition of AA-induced apoptosis by oltipraz might be associated with the electron transport system. AMPK activation by oltipraz contributed to cell survival, which was supported by the reversal of oltipraz's restoration of mitochondrial membrane potential by concomitant treatment of compound C. By the same token, an AMPK activator inhibited AA + iron-induced mitochondrial permeability transition with an increase in cell viability. Moreover, new 1,2-dithiole-3-thiones with the capability of AMPK activation protected cells from mitochondrial permeability transition and ROS overproduction induced by AA + iron. Our results demonstrate that oltipraz and new 1,2-dithiole-3-thiones are capable of protecting cells from AA + iron-induced ROS production and mitochondrial dysfunction, which may be associated with AMPK activation.
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PMID:Inhibition of arachidonic acid and iron-induced mitochondrial dysfunction and apoptosis by oltipraz and novel 1,2-dithiole-3-thione congeners. 1894 20

Insulin resistance or diabetes is associated with limited exercise capacity, which can be caused by the abnormal energy metabolism in skeletal muscle. Oxidative stress is involved in mitochondrial dysfunction in diabetes. We hypothesized that increased oxidative stress could cause mitochondrial dysfunction in skeletal muscle and make contribution to exercise intolerance in diabetes. C57/BL6J mice were fed on normal diet or high fat diet (HFD) for 8 wk to induce obesity with insulin resistance and diabetes. Treadmill tests with expired gas analysis were performed to determine the exercise capacity and whole body oxygen uptake (Vo(2)). The work (vertical distance x body weight) to exhaustion was reduced in the HFD mice by 36%, accompanied by a 16% decrease of peak Vo(2). Mitochondrial ADP-stimulated respiration, electron transport chain complex I and III activities, and mitochondrial content in skeletal muscle were decreased in the HFD mice. Furthermore, superoxide production and NAD(P)H oxidase activity in skeletal muscle were significantly increased in the HFD mice. Intriguingly, the treatment of HFD-fed mice with apocynin [10 mmol/l; an inhibitor of NAD(P)H oxidase activation] improved exercise intolerance and mitochondrial dysfunction in skeletal muscle without affecting glucose metabolism itself. The exercise capacity and mitochondrial function in skeletal muscle were impaired in type 2 diabetes, which might be due to enhanced oxidative stress. Therapies designed to regulate oxidative stress and maintain mitochondrial function could be beneficial to improve the exercise capacity in type 2 diabetes.
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PMID:Oxidative stress in skeletal muscle impairs mitochondrial respiration and limits exercise capacity in type 2 diabetic mice. 1961 6

Obesity and mild hyperglycemia are characteristic of early or "prediabetes." The associated increase in fatty acid flux is posited to enhance substrate delivery to mitochondria, leading to enhanced superoxide production that results in mitochondrial dysfunction and progressive worsening of the hyperglycemic state. We quantified superoxide production by gastrocnemius muscle, heart, and liver mitochondria in a rodent model that mimics the pathophysiology of prediabetes by administering low-dose streptozotocin to rats fed high fat (HF). Superoxide was rigorously determined indirectly as H(2)O(2) largely released from the matrix and by electron paramagnetic resonance spectroscopy that directly detects superoxide released externally. Both HF and low-dose streptozotocin mildly increased glycemia (P < .05 by 2-way analysis of variance). Matrix and external superoxide production by gastrocnemius mitochondria respiring on the complex II substrate succinate and matrix superoxide production by liver mitochondria respiring on the complex I substrates glutamate plus malate were significantly reduced by HF feeding but not affected by mild hyperglycemia. Superoxide production was not significantly altered by either treatment in heart mitochondria fueled by either complex I or II substrates. The functional status of the mitochondria was assayed as simultaneous respiration and membrane potential that were not affected by HF or mild hyperglycemia. Comparison of substrate and inhibitor effects on superoxide release implied marked differences in the redox mechanisms regulating mitochondrial superoxide production from liver mitochondria compared with muscle and heart. In summary, superoxide production from mitochondria of different insulin-sensitive tissues differs mechanistically. However, in any case, excess superoxide production as an intrinsic property of mitochondria of insulin-sensitive tissues does not result from conditions mimicking the pathophysiology of pre- or early diabetes.
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PMID:Superoxide production by mitochondria of insulin-sensitive tissues: mechanistic differences and effect of early diabetes. 1976 76


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