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:2.3.3.1 (citrate synthase)
4,488 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Chronic fatigue syndrome is characterized by muscle fatigue and pain at rest, symptoms which are usually exacerbated with exercise. Although various studies have shown minor, non-specific morphological and biochemical changes in muscle of patients with chronic fatigue syndrome, no consistent defect has been identified. Some have suggested that an enteroviral infection in muscle may cause the chronic muscle fatigue seen in patients with chronic fatigue syndrome, with acute infection directly and irreversibly impairing mitochondrial function, and persistent infection depressing muscle protein synthesis and metabolism. 2. To clarify the involvement of enterovirus infection in chronic fatigue syndrome, muscle biopsies from a group of patients with chronic fatigue syndrome were examined for the presence of enteroviral RNA by reverse transcriptase-polymerase chain reaction techniques in relation to functional studies of muscle mitochondria and the muscle RNA/DNA ratio. 3. Fifty-eight percent of patients reported an uncharacterized 'viral infection' before the onset of their illness, but none of the muscle samples from 34 patients contained detectable amounts of enteroviral RNA. Muscle tissue had a general reduction in the RNA/DNA ratio and mitochondrial enzyme activities with no specific abnormality in the activity of enzymes encoded partially on the mitochondrial genome (cytochrome-c oxidase) or nuclear genome (citrate synthase, succinate reductase). 4. These data provide no evidence of an enteroviral infection in muscle of patients with chronic fatigue syndrome, although this does not exclude a role of enterovirus in initiating the disease process. The general reduction in RNA/DNA ratio and mitochondrial enzyme activities is consistent with a general reduction in habitual activity.
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PMID:Investigation by polymerase chain reaction of enteroviral infection in patients with chronic fatigue syndrome. 877 36

We present a new approach for determining dynamical domains in large proteins, either based on a comparison of different experimental structures, or on a simplified normal mode calculation for a single conformation. In a first step, a deformation measure is evaluated for all residues in the protein; a high deformation indicates highly flexible interdomain regions. The sufficiently rigid parts of the protein are then classified into rigid domains and low-deformation interdomain regions on the basis of their global motion. We demonstrate the techniques on three proteins: citrate synthase, which has been the subject of earlier domain analyses, HIV-1 reverse transcriptase, which has a rather complex domain structure, and aspartate transcarbamylase as an example of a very large protein. These examples show that the comparison of conformations and the normal mode analysis lead to essentially the same domain identification, except for cases where the experimental conformations differ by the presence of a large ligand, such as a DNA strand. Normal mode analysis has the advantage of requiring only one experimental structure and of providing a more detailed picture of domain movements, e.g. the splitting of domains into subdomains at higher frequencies.
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PMID:Analysis of domain motions in large proteins. 1002 23

Endurance training induces, in female rats, alterations of oestrous cycle with decrease in plasma oestradiol levels. Moreover, it is well known that oestradiol concentrations modify oestrogen receptor levels. In order to further explain the effects of oestrogens on skeletal muscles, we hypothesized that endurance training modifies the levels of oestrogen receptor alpha messenger ribonucleic acid (ER alpha mRNA) in rat gastrocnemius muscle. Wistar rats were separated into four groups: male controls (C(m)) (n=7), female controls (C(f)) (n=6), male trained (E(m)) (n=7) and female trained (E(f)) (n=6). The endurance training programme was performed for 7 weeks, 5 days week-1 and consisted of 1 h of continuous running on an adapted motor-driven treadmill. At the end of the training session, the gastrocnemius muscle was isolated, weighed and semiquantification of ER alpha mRNA was performed using the reverse transcriptase-polymerase chain reaction (RT-PCR) technique. The citrate synthase (CS) activity of the gastrocnemius muscle was measured by a fluorimetric method. The CS activity of the male and female gastrocnemius muscle, respectively, 100 +/- 7% in C(m) (n=7) vs. 120 +/- 14% in E(m) (n=6, P < 0.01) and 100 +/- 13% in C(f) (n=6) vs. 138 +/- 23% in E(f) (n=6, P < 0.01) was significantly increased after 7 weeks of training. The ER alpha mRNA levels were significantly increased in E(f) compared with C(f) (0.49 +/- 0.15 vs. 0.31 +/- 0.11, P < 0.01) but not in E(m) compared with C(m) (0.37 +/- 0.15 vs. 0.37 +/- 0.13). In conclusion, these results demonstrate that 7 weeks of endurance training increased the level of transcripts encoding ER alpha in rats with the increase restricted to the females.
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PMID:Effect of endurance training on oestrogen receptor alpha transcripts in rat skeletal muscle. 1190 28

It is well known that oestrogens exert muscle anabolic and metabolic effects. Oestrogens act via specific oestrogen receptor (ER) proteins. The mainly represented oestrogen receptor alpha messenger ribonucleic acid subtype (ER(alpha) mRNA) was described in various tissues including the skeletal muscle. Moreover, it has been shown that endurance training significantly increases ER(alpha) mRNA levels in the female rat gastrocnemius muscle. The aim of this study was to determine if this training programme also modifies ER(alpha) mRNA levels in muscles with different typology, the soleus (slow twitch muscle), extensor digitorum longus (fast twitch muscle) and gastrocnemius (intermediate muscle). So far, two groups of Wistar female rats were set up: untrained (u) (n = 7), and trained (e) (n = 7). The endurance training programme was performed for 7 weeks, 5 days per week and consisted of 1 h of continuous running on an adapted motor-driven treadmill involving progressive intensity and gradient of the treadmill. Three different skeletal muscles, extensor digitorum longus (E), gastrocnemius (G) and soleus (S), were isolated and weighed in the untrained (Eu, Gu and Su) and trained group (Ee, Ge and Se). Semi-quantification of ER(alpha) mRNA levels was performed by the reverse transcriptase-polymerase chain reaction (RT-PCR) technique. In order to attest the efficiency of our endurance training programme, the citrate synthase activity (CS) of each muscle was measured by a fluorimetric method. The CS activity was significantly increased with training in the gastrocnemius [100.00 +/- 4.99% in Gu (n = 6) vs. 138.10 +/- 8.82% in Ge (n = 6), P < 0.01] and in the soleus [100.00 +/- 2.92% in Su (n = 7) vs. 115.90 +/- 3.71% in Se (n = 7), P < 0.01] but not in the extensor digitorum longus [100.00 +/- 1.87% in Eu (n = 7) vs. 96.90 +/- 1.55% in Ee (n = 7)]. Concerning the influence of muscle type on ER(alpha) mRNA level (1) in the untrained group, the ER(alpha) mRNA level was significantly higher in soleus muscle compared with gastrocnemius and extensor digitorum longus muscles [0.43 +/- 0.04 in Su (n = 7) compared with 0.31 +/- 0.03 in Gu (n = 6) and 0.21 +/- 0.03 in Eu (n = 7), P < 0.05; P < 0.05); 2] in the trained group, the ER(alpha) mRNA level was significantly higher insoleus and gastrocnemius muscles compared with extensor digitorum longus muscle [0.43 +/- 0.06 in Se (n = 7) and 0.49 +/- 0.05 in Ge (n = 6) vs. 0.12 +/- 0.01 in Ee (n = 7), P < 0.05; P < 0.05]. Indeed, after training, the ER(alpha) mRNA level significantly increased in gastrocnemius muscle [0.31 +/- 0.03 in Gu(n = 6) vs. 0.49 +/- 0.05 in Ge (n = 6), P < 0.01], significantly decreased in extensor digitorum longus [0.21 +/- 0.03 in Eu (n = 7) vs. 0.12 +/- 0.01 in Ee (n = 7), P < 0.01] and was not significantly modified in soleus [0.43 +/- 0.04 in Su (n = 7) vs. 0.43 +/- 0.06 in Se (n = 7)]. The differences in ER(alpha) mRNA level between trained and untrained animals indicate training-induced effects that are specific to the skeletal muscle type.
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PMID:Effect of endurance training on oestrogen receptor alpha expression in different rat skeletal muscle type. 1210 Mar 60

A decreased sperm motility has been reported in men treated with nucleoside analog reverse transcriptase inhibitors (NRTI). Sperm motility is correlated with enzymatic activities of the sperm mitochondrial respiratory chain (MRC), which may be impaired by NRTI. We compared sperm and skeletal muscle MRC and citrate synthase (CS) activities, sperm adenosine triphosphate (ATP) content and sperm motility between rats exposed to zidovudine (AZT) for 10 weeks and controls. Decreased levels of CS-normalized cytochrome c oxidase (COX, the MRC complex IV) activity were observed in the spermatozoa from AZT-treated rats, with no significant decrease in ATP content or motility. In muscle absolute COX activity increased after exposure to AZT but CS-normalized COX activity remained unchanged. These results suggest that exposure to NRTI can induce MRC dysfunction earlier in spermatozoa than in skeletal muscle.
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PMID:Deficit in cytochrome c oxidase activity induced in rat sperm mitochondria by in vivo exposure to zidovudine. 1451 Dec 19

In yeast, mitochondrial dysfunction activates a specific pathway, termed retrograde regulation, which alters the expression of specific nuclear genes and results in increased replicative life span. In mammalian cells, the specific nuclear genes induced in response to loss of mitochondrial function are less well defined. This study characterizes responses in nuclear gene expression to loss of mitochondrial DNA sequences in three different human cell types: T143B, an osteosarcoma-derived cell line; ARPE19, a retinal pigment epithelium cell line; and GMO6225, a fibroblast cell population from an individual with Kearns-Sayre syndrome (KSS). Quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) was used to measure gene expression of a selection of glycolysis, TCA cycle, mitochondrial, peroxisomal, extracellular matrix, stress response, and regulatory genes. Gene expression changes that were common to all three cell types included up-regulation of GCK (glucokinase), CS (citrate synthase), HOX1 (heme oxygenase 1), CKMT2 (mitochondrial creatine kinase 2), MYC (v-myc myelocytomatosis viral oncogene homolog), and WRN (Werner syndrome helicase), and down-regulation of FBP1 (fructose-1, 6-bisphosphatase 1) and COL4A1 (collagen, type IV, alpha 1). RNA interference experiments show that induction of MYC is important in rho0 cells for the up-regulation of glycolysis. In addition, a variety of cell type-specific gene changes was detected and most likely depended upon the differentiated functions of the individual cell types. These expression changes may help explain the response of different tissues to the loss of mitochondrial function due to aging or disease.
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PMID:Common and cell type-specific responses of human cells to mitochondrial dysfunction. 1556 Nov 7

Although it is well accepted that treatment with nucleoside reverse transcriptase inhibitors (NRTIs) modifies fat metabolism and fat distribution in humans, the mechanisms underlying these modifications are not yet known. The present investigation examines the effects of chronic oral administration of 3'-azido-3'-deoxythymidine (AZT) on the mitochondrial metabolism and the redox status management of rat white adipose tissues originating from two anatomical sites, as well as of the rat liver. Results showed that AZT treatment induced differential effects on the mitochondrial functions depending on the anatomical localisation. Indeed, in inguinal adipose tissue, a significant decrease in the cytochrome c oxidase activity and in the mitochondrial DNA (mtDNA) content was observed, whereas the activity of citrate synthase, a mitochondrial protein exclusively encoded by the nucleus, was not affected. In contrast, no significant change in these parameters could be detected for epididymal tissue and for liver. In parallel, no oxidative stress could be detected after treatment, for both white adipose tissues and for liver, even though treated liver exhibited several modifications in redox management. Taken together, these data demonstrate differential mitochondrial effects of AZT on subcutaneous versus visceral white adipose tissue. Moreover, the decrease in mitochondrial oxidative capacity of inguinal adipocyte consecutive to AZT treatment is not primarily due to an oxidative stress per se, but rather to a depletion of the mtDNA content per cell.
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PMID:Site specific alterations of adipose tissue mitochondria in 3'-azido-3'-deoxythymidine (AZT)-treated rats: an early stage in lipodystrophy? 1589 94

In spite of opposing changes in rates of adenosine triphosphate turnover, hypertrophy and atrophy of the heart are accompanied by the same changes in gene expression, resembling a fetal genotype. Fetal hearts are characterized by increased ischemia tolerance. We assessed respiratory capacity of mitochondrial subpopulations from unloaded and pressure-overloaded hearts before and after 15 minutes of normothermic ischemia. Unloading was achieved by heterotopic rat heart transplantation and overloading by aortic banding. Respiratory chain gene expression (NADH dehydrogenase, cytochrome c oxidase [COX]) were analyzed by reverse transcriptase-polymerase chain reaction. Subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM) were isolated by differential centrifugation. Citrate synthase was used as mitochondrial marker enzyme. Adenosine diphosphate-stimulated oxygen consumption (state 3) was measured with a Clark-type electrode. Unloading resulted in atrophy, overloading in hypertrophy. State 3 was reduced in atrophied hearts both in SSM and IFM (SSM: 204 +/- 79 vs 804 +/- 147 natoms oxygen min(-1) mL(-1), P < .001; IFM: 468 +/- 158 vs 1141 +/- 296 natoms oxygen min(-1) mL(-1), P < .05), but was unchanged in hypertrophied hearts. NADH dehydrogenase and COX expression was also decreased with atrophy and was unchanged with hypertrophy. Ischemia caused decreased recovery of citrate synthase in isolates of SSM (P < .05) but not of IFM. State 3 in control hearts was reduced in IFM (-41%, P < .01) and SSM (-19%, not significant). This ischemia-induced decrease was less pronounced in SSM (-2%) and IFM (-22%) of atrophied and IFM (-23%) of hypertrophied hearts. Subsarcolemmal mitochondria of hypertrophied hearts displayed the greatest ischemia-induced decrease of state 3 (-32%, P < .05). In conclusion, (1) long-term changes in workload differentially affect maximal respiratory capacity and ischemia tolerance of isolated mitochondria. The changes are not parallel to the changes in energy requirements. (2) Mitochondria of atrophied hearts appear to be more resistant against ischemia than controls.
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PMID:Differential changes in respiratory capacity and ischemia tolerance of isolated mitochondria from atrophied and hypertrophied hearts. 1683 47

Lipoatrophy is a prevalent side effect of antiretroviral treatment of human immunodeficiency virus (HIV) infection. Its mechanisms are still disputed but include mitochondrial toxicity and, in particular, mitochondrial DNA (mtDNA) depletion induced by nucleoside reverse transcriptase inhibitors. To obtain an integrated evaluation of the mitochondrial alteration in lipoatrophy, we investigated the DNA, RNA, and protein levels in 15 samples of abdominal subcutaneous adipose tissue from HIV-infected patients with peripheral lipoatrophy and compared the results with those for 15 samples from age- and body mass index-matched controls. The DNA and RNA analyses used PCR-based techniques, while proteins were quantified with enzyme-linked immunosorbent assay and measurement of activities with spectrophotometric assays. Depletion of mtDNA and mtDNA-encoded MT-CO2 mRNA was present, but normal levels of mtDNA-dependent activity (cytochrome c oxidase) and protein (MT-CO2p) showed that it was compensated for. An increase in nuclear-DNA-dependent mitochondrial activities (citrate synthase and malate dehydrogenase) and protein (COX4I1p), as well as transcriptional up-regulation of nuclear-DNA-encoded mitochondrial genes (COX4I1 and UCP2), demonstrated increased mitochondrial biogenesis. However, the expression of the known transcription factors of mitochondrial biogenesis (TFAM, NRF1, GABPA, PPARGC1A, PPARGC1B, and PPRC1) was normal or decreased. Increased amounts of activated caspase 3 and of DDIT3 mRNA showed the induction of apoptosis and oxidative stress, respectively. The mtDNA content did not correlate with any other mitochondrial parameter. In conclusion, mtDNA content does not appear to be an accurate biomarker of mitochondrial alteration in lipoatrophic adipose tissue. The preservation of mtDNA-dependent mitochondrial functions occurred despite severe mtDNA depletion. The presence of significant oxidative stress and apoptosis did not correlate with the mtDNA content.
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PMID:Mitochondrial DNA content, an inaccurate biomarker of mitochondrial alteration in human immunodeficiency virus-related lipodystrophy. 1833 66

Mitochondrial dysfunction as a consequence of mitochondrial DNA (mtDNA) depletion due to therapy with nucleoside analogue reverse transcriptase inhibitors (NRTI) has been proposed as a pathogenic mechanism leading to lipoatrophy in HIV-infected patients. The aim of our study was to investigate the impact of NRTI treatment on mtDNA abundance and the activities of respiratory chain complexes in primary human subcutaneous preadipocytes (phsPA). We studied adipocyte phenotypes, viability, and differentiation (CCAAT/enhancer-binding protein alpha [C/EBPalpha] and peroxisome proliferator-activated receptor gamma [PPARgamma] expression) and adiponectin production, mtDNA content, mitochondrial membrane potential, mitochondrial mass, and respiratory chain enzyme and citrate synthase activities in both proliferating and differentiating phsPA. Cells were exposed to zidovudine (6 microM), stavudine (d4T; 3 microM), and zalcitabine (ddC; 0.1 microM) for 8 weeks. NRTI-induced mtDNA depletion occurred in proliferating and differentiating phsPA after exposure to therapeutic drug concentrations of d4T and ddC. At these concentrations, ddC and d4T led to an almost 50% decrease in the number of mtDNA copies per cell without major impact on adipocyte differentiation. Despite mtDNA depletion by NRTI, the activities of the respiratory chain complexes, the mitochondrial membrane potential, and the mitochondrial mass were found to be unaffected. Severe NRTI-mediated mtDNA depletion in phsPA is not inevitably associated with impaired respiratory chain activity or altered mitochondrial membrane potential.
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PMID:Mitochondrial DNA depletion and respiratory chain activity in primary human subcutaneous adipocytes treated with nucleoside analogue reverse transcriptase inhibitors. 1980 55


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