Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.5.3 (complex I)
 8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 70 kD protein, which we have named mitoskelin, is highly enriched in cytoskeletal preparations from bovine cardiac muscle. Mitoskelin has three main variants with isoelectric points between 5.6 and 5.8. Immunoblotting with polyclonal antibodies directed against mitoskelin shows that, like intermediate filament proteins, the majority of mitoskelin resists solubilization from a myocardial homogenate by a series of extraction solutions ranging from very low salt to 0.6 M KI buffers and by 0.1-1% Nonidet P-40 detergent. By double-label immunofluorescence on cells and tissues, mitoskelin is colocalized with the mitochondrial marker cytochrome c oxidase. Mitoskelin is associated with the inner membranes of mitochondria as shown by immunoelectron microscopy and immunoblotting. Immunological cross-reactivity and similarities of molecular weight, pI, distribution, and chromatographic properties indicate that mitoskelin is the 70 kD component of complex I (NADH: ubiquinone oxidoreductase), a portion of the mitochondrial oxidative phosphorylation system. No function or activity has yet been demonstrated for the 70 kD component of the 25-polypeptide complex I. Dialysis against physiological buffers allows purified, urea-solubilized mitoskelin to form 10 nm wide filamentous structures that do not closely resemble intermediate filaments. These results suggest the exciting possibility that mitochondria may contain a membrane-associated filamentous skeleton.
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PMID:Mitoskelin: a mitochondrial protein found in cytoskeletal preparations. 267 50

This experiment was designed to evaluate whether or not liposomal encapsulated-doxorubicin and combination therapy of free doxorubicin with coenzyme Q10, an antioxidant, mitigate the delayed adverse effects on cardiac muscle mitochondria. Rats aged 7 weeks were divided into the following four groups; rats were injected with doxorubicin or liposomal encapsulated-doxorubicin, total dose 15 mg/kg. The doxorubicin group consisted of two subgroups depending on diet, i.e., standard diet or 0.2% coenzyme Q10 diet. Mitochondria from cardiac muscles were prepared from rats aged 13 and 35 weeks. No significant decrease in the activity of complex I of the mitochondrial electron transport chain was observed in rats aged 13 weeks among the groups, however, significant decreases in the activity in rats aged 35 weeks were observed in the doxorubicin and liposomal doxorubicin groups compared with the corresponding control rats. In contrast, no significant change in complex I activity was observed in rats fed with coenzyme Q10 diet irrespective of doxorubicin treatment. From these results, not liposomal encapsulation of doxorubicin but combination therapy with antioxidant might be expected to reduce the delayed adverse effects of doxorubicin on heart mitochondria.
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PMID:Approaches that mitigate doxorubicin-induced delayed adverse effects on mitochondrial function in rat hearts; liposome-encapsulated doxorubicin or combination therapy with antioxidant. 758 Sep 95

Defects of the mitochondrial respiratory chain in cardiac muscle are an important, yet still overlooked cause of heart failure. In 16 of 32 endocardial biopsies from infants affected by "idiopathic" hypertrophic cardiomyopathy we demonstrated a remarkable decrease of activity of either complex I, or complex IV, or both, relative to complex II + III activity which was taken as an index of mitochondrial proliferation. At the molecular level, several mtDNA mutations have been associated with cardiomyopathy. For instance, MIMyCa is a maternally inherited syndrome presenting with a variable combination of skeletal and heart muscle failure associated with a heteroplasmic A3260G transition in the tRNALeu(UUR) gene. To study the effects of the mutation in a controlled system, we prepared clones of transmitochondrial cybrids by fusing mutant cytoplasts with mtDNA-less tumor cells. Two groups of clones were identified: nearly 100% mutant (M group) and nearly 100% wild-type (WT group). The means of complex I and IV in the M group were 63% and 67% relative to the WT group. The O2 consumption in the M group was 36%, and the lactate production was 218% of that in the WT group. MtDNA-specific translation was defective in M clones. The study of transmitochondrial cybrids is an important clue to test the pathogenicity of mtDNA mutations.
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PMID:OXPHOS defects and mitochondrial DNA mutations in cardiomyopathy. 760 20

The effects of BRB-I-28 and its derivatives (GLG-V-13, SAZ-VII-22 and SAZ-VII-23), a novel group of antiarrhythmic agents, were investigated on the rat heart mitochondrial respiratory chain. The results indicate that BRB-I-28 and its derivatives have concentration-dependent inhibitory effects on NADH oxidase and NADH-CoQ reductase (complex I), but they have no significant effects on succinate oxidase, succinate dehydrogenase (complex II), CoQ-cytochrome c reductase (complex III), cytochrome c oxidase (complex IV), and NADH-K3Fe(CN)6 reductase. The site of inhibition of BRB-I-28 and its derivatives on the respiratory chain was localized between flavoprotein n (FPn) and CoQ, which is similar to the effect of rotenone and several other antiarrhythmic drugs such as amiodarone, propranolol, etc. BRB-I-28 and its derivatives also have significant inhibitory effects on mitochondrial ATPase activity as reported for other antiarrhythmic drugs such as amiodarone, propranolol, quinidine, and lidocaine. However, BRB-I-28 and its derivatives have no direct effects on sarcoplasmic reticulum Ca(2+)-ATPase activity. The inhibitory effects of BRB-I-28 and its derivatives on mitochondrial oxidative phosphorylation may result in the depletion of ATP. This effect, in combination with their effects on Na+,K(+)-ATPase, could possibly produce an increase in Ca2+ concentration in cytosol. This may be another mechanism by which these DHBCN derivatives produce an increase in systemic arterial blood pressure and contractile force of isolated cardiac muscle. On the other hand, inhibition on mitochondrial respiration may account for some of the potential toxic effects of these diheterabicyclo[3.3.1]nonane derivatives.
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PMID:Effects of novel antiarrhythmic agents, BRB-I-28 and its derivatives, on the heart mitochondrial respiratory chain and sarcoplasmic reticulum Ca(2+)-ATPase. 799 64

The redox state of the carriers of electron-transport chain of cardiac mitochondria was studied in the conditions of normal perfusion, global ischemia and reoxygenation of the myocardial tissue. Experiments were performed on isolated rat hearts perfused at 37 degrees C by the "working heart" procedure. The EPR spectra of the freeze-clamped hearts were measured at 6-30 K. An analysis of the main values of g-tensor, line-shape, line-width and relaxation parameters of the components of low-temperature EPR spectra allowed to distinguish the signals from Fe-S centers of NADH-CoQ reductase and succinate-CoQ reductase, and the signals from free radical species of coenzyme Q and flavin coenzymes. The EPR spectra of hearts that were fixed during control perfusion and reperfusion contained predominantly the signal of oxidized S3 center of succinate-CoQ reductase. The free radical signal in these conditions was mainly due to ubisemiquinones. Besides the intensive signal of S3 center, the low-temperature EPR spectra contained also signals from different Fe-S centers paramagnetic in reduced state. The global ischemia of cardiac muscle caused essential reduction of the Fe-S clusters of the mitochondrial electron-transport chain. In ischemic condition the free radical EPR signal was mainly due to flavosemiquinones. The changes of the redox state of carriers of the mitochondrial respiratory chain correlated with the changes of the physiological parameters of cardiac muscle.
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PMID:[Redox state of the electron-transport carriers in cardiac mitochondria: a study by the method of low-temperature EPR spectroscopy]. 949 Jan 10

NADH:ubiquinone oxidoreductase (complex I) is the first and largest complex in the electron transport chain of mitochondria. The bovine complex purified from cardiac muscle consists of at least 42 different subunits with a combined molecular mass of about 890 kDa. The three-dimensional structure of the complex was determined at 22 A from single particles embedded in vitrified ice using electron cryo-microscopy. The structure was calculated using a new program to align particles, to correct for the contrast transfer function of the microscope, and to carry out the three-dimensional reconstruction of the complex. The bovine complex has the overall L-shaped appearance found in earlier studies of the closely related complex I from Neurospora crassa, but it differs by having a thin stalk region linking the membrane-bound globular arm with the intrinsic membrane domain. Thus, the stalk which measures about 30 A in diameter is likely to contain part of the electron transfer pathway linking the NADH binding site in the globular arm with the ubiquinone binding site in the membrane domain. The globular domain of bovine complex I is significantly bigger than that of the N. crassa enzyme, suggesting that the apparent additional subunit complexity of the bovine enzyme is associated with the globular part.
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PMID:Three-dimensional structure of bovine NADH:ubiquinone oxidoreductase (complex I) at 22 A in ice. 957 Oct 20

Although cyclosporin (CsA) is considered to be the best immunosuppressive molecule in transplantation, it has been suspected to alter mitochondrial respiration of various tissues. We evaluated the acute effect of CsA and its vehicle on maximal oxidative capacity (V(max)) of cardiac, soleus and gastrocnemius muscles of rats by an oxygraphic method in saponin skinned muscle fibres. The effects of Sandimmun (a formulation of CsA), vehicle of Sandimmun (cremophor and ethanol (EtOH)), CsA in EtOH and EtOH alone were tested. Increasing concentrations (5 - 20 - 50 - 100 microM) of CsA (or vehicles) were used. Sandimmun profoundly altered the V(max) of all muscles. For example, at 20 microM, inhibition reached 18+/-3, 23+/-5, 45+/-5%, for heart, soleus and gastrocnemius respectively. There were only minor effects of CsA diluted in EtOH and EtOH alone on V(max) of cardiac muscle. Because the effects of vehicle on V(max) were similar or higher than those of Sandimmun, the inhibition of oxidative capacity could be entirely attributed to the vehicle for all muscles. Next, we investigated the potential sites of action of the vehicle on the different complexes of the mitochondrial respiratory chain by using specific substrates and inhibitors. The vehicle affected mitochondrial respiration mainly at the level of complex I ( approximately -85% in skeletal muscles, and -32% in heart), but also at complex IV ( approximately -26% for all muscles). The mechanism of action of the vehicle on the mitochondrial membrane and the implications for the clinical use of immunosuppressive drugs are discussed.
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PMID:Effect of cyclosporin A and its vehicle on cardiac and skeletal muscle mitochondria: relationship to efficacy of the respiratory chain. 1145 50

Dilated cardiomyopathy (DCM) is widely accepted as a pluricausal or multifactorial disease. Because of the linkage between energy metabolism in the mitochondria and cardiac muscle contraction, it is reasonable to assume that mitochondrial abnormalities may be responsible for some forms of DCM. We analysed the whole mitochondrial genome in a series of 45 patients with DCM for alterations and compared the findings with those of 62 control subjects. A total of 458 sequence changes could be identified. These sequence changes were distributed among the whole mitochondrial DNA (mtDNA). An increased number of novel missense mutations could be detected nearly in all genes encoding for protein subunits in DCM patients. In genes coding for NADH dehydrogenase subunits the number of mtDNA mutations detected in patients with DCM was significantly increased (p < 0.05) compared with control subjects. Eight mutations were found to occur in conserved amino acids in the above species. The c.5973G > A (Ala-Trp) and the c.7042T > G (Val-Asp) mutations were located in highly conserved domains of the gene coding for cytochrome c oxidase subunit. Two tRNA mutations could be detected in the mtDNA of DCM patients alone. The T-C transition at nt 15,924 is connected with respiratory enzyme deficiency, mitochondrial myopathy, and cardiomyopathy. The c.16189T > C mutation in the D-loop region that is associated with susceptibility to DCM could be detected in 15.6% of patients as well as in 9.7% of controls. Thus, mutations altering the function of the enzyme subunits of the respiratory chain can be relevant for the pathogenesis of dilated cardiomyopathy.
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PMID:Novel point mutations in the mitochondrial DNA detected in patients with dilated cardiomyopathy by screening the whole mitochondrial genome. 1512 Jun 34

A genetic mice model of glutaric acidemia type I (GAI) has recently been developed, however affected animals do not develop the striatal damage characteristic of patients with this disorder. Therefore, the initial aim of the present work was to induce high glutaric acid (GA) concentrations in rat brain similar to those found in GAI patients through subcutaneous injection of GA. High brain GA concentrations (up to 0.60 micromol/g congruent with 0.60mM) were achieved by a single subcutaneous injection of saline-buffered GA (5 micromol/g body weight) to Wistar rats of 7-22 days of life. GA brain levels were about 10-fold lower than in plasma and 5-fold lower than in skeletal and cardiac muscles, indicating that the permeability of the blood brain barrier to GA is low. We also aimed to use this model to investigate neurochemical parameters in the animals. Thus, we evaluated the effect of this model on energy metabolism parameters in midbrain, in which the striatum is localized, as well as in peripheral tissues (skeletal and cardiac muscles) of 22-day-old rats. Control rats were treated with saline in the same volumes. We verified that CO2 production from glucose was not altered in midbrain of rats treated with GA, indicating a normal functioning of the tricarboxylic acid cycle. Creatine kinase activity was also not changed in midbrain, skeletal and cardiac muscles. In contrast, complex I-III activity of the respiratory chain was inhibited in midbrain (25%), while complexes I-III (25%) and II-III (15%) activities were reduced in skeletal muscle, with no alterations found in cardiac muscle. These data indicate that GA administration moderately impairs cellular energy metabolism in midbrain and skeletal muscle of young rats.
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PMID:Glutaric acid administration impairs energy metabolism in midbrain and skeletal muscle of young rats. 1629 5

AMP-activated protein kinase (AMPK) plays an important role in controlling energy homeostasis and is envisioned as a promising target to treat metabolic disorders. In the heart, AMPK is involved in short-term regulation and in transcriptional control of proteins involved in energy metabolism. Here, we investigated whether deletion of AMPKalpha2, the main cardiac catalytic isoform, alters mitochondrial function and biogenesis. Body weight, heart weight, and AMPKalpha1 expression were similar in control littermate and AMPKalpha2(-/-) mice. Despite normal oxygen consumption in perfused hearts, maximal oxidative capacity, measured using saponin permeabilized cardiac fibers, was approximately 30% lower in AMPKalpha2(-/-) mice with octanoate, pyruvate, or glutamate plus malate but not with succinate as substrates, showing an impairment at complex I of the respiratory chain. This effect was associated with a 25% decrease in mitochondrial cardiolipin content, the main mitochondrial membrane phospholipid that is crucial for complex I activity, and with a 13% decrease in mitochondrial content of linoleic acid, the main fatty acid of cardiolipins. The decrease in cardiolipin content could be explained by mRNA downregulation of rate-limiting enzymes of both cardiolipin synthesis (CTP:PA cytidylyltransferase) and remodeling (acyl-CoA:lysocardiolipin acyltransferase 1). These data reveal a new role for AMPKalpha2 subunit in the regulation of cardiac muscle oxidative capacity via cardiolipin homeostasis.
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PMID:AMP-activated protein kinase alpha2 deficiency affects cardiac cardiolipin homeostasis and mitochondrial function. 1732 49


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