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:1.3.5.1 (succinate dehydrogenase)
8,177 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

'Myofibrillar myopathy' defines a myopathic condition with focal myofibrillar destruction and accumulation of degraded myofibrillar elements. Despite the fact that a number of mutations in different genes as well as cytotoxic agents lead to the disease, abnormal accumulation of desmin is a typical, common feature. Pathological changes of mitochondrial morphology and function have been observed in animal models with intermediate filament pathology. Therefore, in the present study we tested for mitochondrial pathology in skeletal muscle of five patients with the pathohistological diagnosis of myofibrillar myopathy. Screening for large-scale mtDNA deletions and the frequent MERRF (myoclonic epilepsy; ragged red fibres) and MELAS (mitochondrial encephalomyopathy; lactic acidosis; stroke) point mutations was negative in all patients. Histologically, all muscle biopsies showed nonspecific abnormalities of the oxidative/mitochondrial enzyme stainings (histochemistry for reduced nicotinamide adenine dinucleotide, succinic dehydrogenase, cytochrome c oxidase), only one of them had ragged red fibres and a significant number of cytochrome c oxidase-negative fibres. Upon biochemical investigation, four of our patients showed pathologically low respiratory chain complex I activities. Only one of our patients had a pathologically low complex IV activity, while the measurements of the others were within low normal range. The single patient with pathological values for both complex I and IV was the one with the clear histological hallmarks (ragged red and cytochrome c oxidase-negative fibres) of mitochondrial pathology. She also was the only patient with clinical signs hinting at a mitochondrial disorder. Together with data from observations in desmin- and plectin-deficient mice, our results support the view that desmin intermediate filament pathology in these cases is closely linked to mitochondrial dysfunction in skeletal muscle.
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PMID:Mitochondrial dysfunction in myofibrillar myopathy. 1258 39

Rigid spine syndrome (RSS) is a rare myopathic ailment characterized by mild axial and proximal muscle weakness. Muscle contraction in these patients causes limitation of neck and trunk flexion, scoliosis, and mild joint deformity. We report the case of a 30-year-old man with RSS who presented with severe restrictive ventilatory defect (forced vital capacity, 1.53 L, 39% of predicted), mild scoliosis (Cobb's angle 12), proximal muscle weakness and stiff back. Creatine phosphokinase was 986 IU/L. Muscle biopsy of the right vastus lateralis revealed increased variation in muscle fiber diameter, proliferation of endomysium, and type I fiber atrophy. Round and whorled fibers indicating myopathic change were found on sections stained with nicotinamide adenine dinucleotide dehydrogenase and succinate dehydrogenase. RSS was diagnosed based on myopathic findings and clinical presentation. Nocturnal chronic respiratory failure and fragmented sleep developed. He was treated with continuous positive airway pressure and had recovered his normal daily activity by 1-year follow-up. We suggest that patients with RSS should be assessed for possible ventilatory failure; treatment with nasal continuous positive airway pressure or bilevel continuous positive airway pressure therapy should be considered.
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PMID:Rigid spine syndrome with chronic respiratory failure. 1264 94

A 9-month-old male German Shepherd dog was referred for evaluation of progressive exercise intolerance. Clinical examination revealed a stiff, stilted gait and marked atrophy and hypotonia of skeletal muscle. The dog had raised creatine kinase (181 U/liter), lactate dehydrogenase (510 U/liter), and aspartate aminotransferase (123.6 U/liter) levels, suggesting a muscle disease. Histochemical evaluation of muscle biopsies revealed the presence of subsarcolemmal oxidative activity, reduced nicotinamide adenine dinucleotide, and succinate dehydrogenase, and the absence of cytochrome oxidase activity. Ragged red fibers were demonstrated with Gomori trichrome stain. Ultrastructural examination of the muscle confirmed the presence of subsarcolemmal accumulations of mitochondria and morphologically atypical mitochondria.
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PMID:Mitochondrial myopathy in a german shepherd dog. 1294 7

The effects of increasing mitochondrial oxidative phosphorylation (OXPHOS), by enhancing electron transport chain components, were evaluated on 1-methyl-4-phenylpyridinium (MPP+) toxicity in brain neuroblastoma cells. Although glucose is a direct energy source, ultimately nicotinamide and flavin reducing equivalents fuel ATP produced through OXPHOS. The findings indicate that cell respiration/mitochondrial O(2) consumption (MOC) (in cells not treated with MPP+) is not controlled by the supply of glucose, coenzyme Q(10) (Co-Q(10)), NADH+, NAD or nicotinic acid. In contrast, MOC in whole cells is highly regulated by the supply of flavins: riboflavin, flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), where cell respiration reached up to 410% of controls. In isolated mitochondria, FAD and FMN drastically increased complex I rate of reaction (1300%) and (450%), respectively, having no effects on complex II or III. MPP+ reduced MOC in whole cells in a dose-dependent manner. In isolated mitochondria, MPP+ exerted mild inhibition at complex I, negligible effects on complexes II-III, and extensive inhibition of complex IV. Kinetic analysis of complex I revealed that MPP+ was competitive with NADH, and partially reversible by FAD and FMN. Co-Q(10) potentiated complex II ( approximately 200%), but not complex I or III. Despite positive influence of flavins and Co-Q(10) on complexes I-II function, neither protected against MPP+ toxicity, indicating inhibition of complex IV as the predominant target. The nicotinamides and glucose prevented MPP+ toxicity by fueling anaerobic glycolysis, evident by accumulation of lactate in the absence of MOC. The data also define a clear anomaly of neuroblastoma, indicating a preference for anaerobic conditions, and an adverse response to aerobic. An increase in CO(2), CO(2)/O(2) ratio, mitochondrial inhibition or O(2) deprivation was not directly toxic, but activated metabolism through glycolysis prompting depletion of glucose and starvation. In conclusion, the results of this study indicate that the mechanism of action for MPP+, involves the inhibition of complex I and and more specifically complex IV, leading to impaired OXPHOS and MOC. Moreover, flavin dervatives control the rate of complex I/cellular respiration and Co-Q10 augments complex II [corrected].
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PMID:Effects of enhancing mitochondrial oxidative phosphorylation with reducing equivalents and ubiquinone on 1-methyl-4-phenylpyridinium toxicity and complex I-IV damage in neuroblastoma cells. 1500 52

1. Herein we study the effects of the mitochondrial complex II inhibitor malonate on its primary target, the mitochondrion. 2. Malonate induces mitochondrial potential collapse, mitochondrial swelling, cytochrome c (Cyt c) release and depletes glutathione (GSH) and nicotinamide adenine dinucleotide coenzyme (NAD(P)H) stores in brain-isolated mitochondria. 3. Although, mitochondrial potential collapse was almost immediate after malonate addition, mitochondrial swelling was not evident before 15 min of drug presence. This latter effect was blocked by cyclosporin A (CSA), Ruthenium Red (RR), magnesium, catalase, GSH and vitamin E. 4. Malonate added to SH-SY5Y cell cultures produced a marked loss of cell viability together with the release of Cyt c and depletion of GSH and NAD(P)H concentrations. All these effects were not apparent in SH-SY5Y cells overexpressing Bcl-xL. 5. When GSH concentrations were lowered with buthionine sulphoximine, cytoprotection afforded by Bcl-xL overexpression was not evident anymore. 6. Taken together, all these data suggest that malonate causes a rapid mitochondrial potential collapse and reactive oxygen species production that overwhelms mitochondrial antioxidant capacity and leads to mitochondrial swelling. Further permeability transition pore opening and the subsequent release of proapoptotic factors such as Cyt c could therefore be, at least in part, responsible for malonate-induced toxicity.
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PMID:Malonate induces cell death via mitochondrial potential collapse and delayed swelling through an ROS-dependent pathway. 1565 18

Doxorubicin causes a chronic cardiomyopathy. Although the exact pathogenesis is unknown, recent animal data suggest that somatically acquired alterations of mitochondrial DNA (mtDNA) and concomitant mitochondrial dysfunction play an important role in its onset. In this study, skeletal and myocardial muscles were examined from human autopsies. Compared to controls (n = 8), doxorubicin-exposed hearts (n = 6) showed low absolute enzyme activity of mtDNA-encoded nicotinamide adenine dinucleotide hydrogen dehydrogenase (NADH DH, 79% residual activity, p = 0.03) and cytochrome c oxidase (COX, 59% residual activity, p < 0.001), but not of succinate dehydrogenase (SDH), which is encoded exclusively by nuclear DNA. NADH DH/SDH and COX/SDH ratios were 37% (p < 0.001) and 27% (p < 0.001) of controls. Expression of the mtDNA-encoded subunit II of COX was reduced (82%, p = 0.04), compared to its unchanged nucleus-encoded subunit IV. MtDNA-content was diminished (56%, p = 0.02), but the 'common' mtDNA-deletion was increased (9.2-fold, p = 0.004). Doxorubicin-exposed hearts harboured numerous additional mtDNA rearrangements lacking direct repeats. They contained elevated levels of malondialdehyde (MDA) (p = 0.006, compared to controls), which correlated inversely with the COX/SDH ratio (r = -0.45, p = 0.02) and the mtDNA-content (r = -0.75, p = 0.002), and correlated positively with the levels of the 'common' deletion (r = 0.80, p < 0.001). Doxorubicin-exposed hearts also contained the highest levels of superoxide (p < 0.001, compared to controls), which correlated negatively with the mtDNA-encoded respiratory chain activities, such as the COX/SDH ratio (r = -0.57, p = 0.02) and the NADH/SDH ratio (r = -0.52, p = 0.04), as well as with the mtDNA content (r = -0.69, p = 0.003), and correlated positively with the frequency of the 'common' deletion (r = 0.76, p < 0.001) and the MDA levels (r = 0.86, p < 0.001). Doxorubicin-exposed hearts contained electron-dense deposits within mitochondria. Hearts exposed to other anthracyclines (n = 6) or skeletal muscle (all groups) had no mitochondrial dysfunction. Doxorubicin, unlike other anthracyclines, augments lipid peroxidation, induces mtDNA mutations and decreases mtDNA content in human hearts. These lesions have an impact on mitochondrial function and could be of importance in the pathogenesis of clinical cardiomyopathy.
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PMID:Tissue-specific mtDNA lesions and radical-associated mitochondrial dysfunction in human hearts exposed to doxorubicin. 1627 10

The alkaloid veratrine is a lipid-soluble neurotoxin, which target voltage-gated Na+ channels for their primary action. Recently, we showed that this alkaloid may cause myonecrosis and evidences suggest mitochondria as one of its cell targets. Herein, we investigate the effects caused by variable concentration of veratrine (250 and 550 microg/mL) on mitochondrial oxygen consumption, respiratory chain enzymes activities, and ultrastructure, combining electron microscopy with cytochemical and biochemical approaches. The results showed different sort of ultrastructural changes, both in isolated and intramuscular mitochondria. Veratrine decreased mitochondrial nicotinamide adenine dinucleotide dehydrogenase (NADH-d), succinic dehydrogenase (SDH), and cytochrome oxidase (COX) activities, significantly and dose-dependently inhibited the state 3 respiration rate, respiratory control ratio (RCR), and ADP/O on isolated rat skeletal muscle mitochondria, whereas state 4 was unaffected. A tendency of increase in mitochondria diameter was seen with 250 microg/mL veratrine. We conclude that the alkaloid would probably act on mitochondrial membrane phospholipid configuration, which would explain the changes observed.
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PMID:Effects of veratrine on skeletal muscle mitochondria: ultrastructural, cytochemical, and morphometrical studies. 1645 34

Mitochondria isolated from cotyledons of germinating wax beans (Phaseolus vulgaris L.) showed fairly good respiratory control on days 1 and 2 after planting. The respiratory control was completely lost from days 3 to 5. During this period mitochondria were shown to be very leaky, losing about 88% of their total nicotinamide adenine dinucleotide to the suspending medium in a short time. The respiratory control was partially recovered by day 7, after which it completely disappeared again. By the use of differential centrifugation, the mitochondria were divided into subfractions by sequential centrifugation: 10,000g for 5 minutes, 25,000g for 5 minutes, and 40,000g for 5 minutes. The 10,000g subfraction was responsible for the recovery of mitochondrial activity (respiratory control value, adenosine diphosphate to oxygen ratio, and rate of oxygen utilization), on day 7. Activities of succinate dehydrogenase, cytochrome oxidase, pyruvate dehydrogenase, and isocitrate dehydrogenase from different mitochondrial subfractions of aging cotyledons were determined. In general, the enzyme activities, adenosine diphosphate to oxygen ratios, and the ability of mitochondria to swell and contract followed the same pattern as for respiratory control.
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PMID:Changes in the Respiratory, Enzymatic, and Swelling and Contraction Properties of Mitochondria from Colytedons of Phaseolus vulgaris L. during Germination. 1665 19

Central core disease is a nonprogressive or slowly progressive congenital myopathy with a variable degree of hypotonia and axial and proximal muscle weakness that is histologically characterized by areas devoid of oxidative enzyme activity, resulting from an absence or low numbers of mitochondria in these regions (central core). A 10-month-old, male, pony foal was examined because of stiff gait, marked contractures of the distal portion of the limbs, flexion deformities of the hooves, and moderate hypotonia that had been present from birth. The foal had increased creatine kinase (282 U/liter; reference interval 10-135 U/liter), lactate dehydrogenase (1,188 U/liter; reference interval 150-450 U/liter), and aspartate transaminase (377 U/liter; reference interval <290 U/liter) activities, suggesting muscle disease. Muscle biopsy was performed. In cytochrome oxidase-, succinate dehydrogenase-, and reduced nicotinamide adenine dinucleotide tetrazolium reductase-reacted sections, the dominant morphologic feature was the absence of oxidative enzyme activity in the cores. By use of immunohistochemical technique with a monoclonal antibody against desmin, the cores were clearly delineated and a desmin network was present within the cores. Ultrastructurally, the core areas were characterized by preserved sarcomeres with irregular Z-lines, with some streaming or zigzag appearance and abnormal sarcoplasmic reticulum profiles and T-tubules. Lack of mitochrondria within central cores was observed. Diagnosis of myopathy with central cores was made.
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PMID:Myopathy with central cores in a foal. 1684 6

The epidermis of vertebrates is the body's principal barrier against environment and its possible contaminants. The presence of keratins, as well as specific detoxifying molecules or enzyme activities, in the various epidermis layers is believed to be involved in providing protection from harmful environmental influences. Anuran integument is poorly hornified and thus permeable to some endogenous and exogenous compounds and thus serves as a good bioindicator of overall environmental conditions. In the present investigation, we studied the epidermis of Rana kl. esculenta adult specimens collected at two different rice fields, relatively unpolluted and heavily polluted, respectively. Environmental pollution was assayed by chemical analysis performed on both sediments and animals. We evaluated the structural aspects of the epidermis at both light and electron microscopy levels and the pattern of keratinization by immunohistochemistry. Furthermore, we studied the activities of some enzymes (acid and alkaline phosphatase, nitric oxide synthase-related nicotinamide adenine dinucleotide phosphate dehydrogenase, glucose-6-phosphate dehydrogenase, catalase, nonspecific esterases, and succinic dehydrogenase) involved mainly in membrane transport, xenobiotics, and oxidative metabolism. Compared with controls, in polluted animals we found the following results: (1) an increase in pollutant levels (i.e., cadmium, mercury, and lead); (2) less keratinized superficial cells in the epidermis; and (3) changes in most enzyme activities in keratinocytes and mitochondria-rich cells (particularly glucose-6-phosphate dehydrogenase and esterases, both important to counteract oxidative and toxic stress). Taken as a whole, the present data indicate the morphofunctional plasticity of the frog epidermis in response to environmental contamination.
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PMID:Morphofunctional evidence of changes in principal and mitochondria-rich cells in the epidermis of the frog Rana kl. esculenta living in a polluted habitat. 1699 33


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