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:3.6.3.14 (ATP synthase)
7,042 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The influence of the fungicidic compound beta-thujaplicin (beta-isopropyl-tropolone) on the energy transformation processes of oxidative phosphorylation was investigated in isolated rat liver mitochondria with succinate (plus rotenone) as substrate. To elucidate the observed strong inhibition of active respiration by beta-thujaplicin three possibilities were assayed: the inhibition of 1) transport processes across the inner mitochondrial membrane for inorganic phosphate, adenine nucleotides, or succinate, 2) electron flux along the respiratory chain, and 3) mitochondrial ATPase. In this respect a remarkable inhibition of both Pi transport and the translocation of adenine nucleotides could not be observed. However, the effective suppression of the DNP-induced ATPase by beta-thujaplicin explains the pronounced inhibition of active respiration. An impairment of succinate transport and the measured partial inhibition of the terminal respiratory chain at the level of cytochrome oxidase contribute to the less marked inhibition of the uncoupled respiration. The ability of beta-thujaplicin to extract mitochondrial Mg++ and the prevention of the effects of beta-thujaplicin by an excess of Mg++ in the medium suggest a common mode of action of beta-thujaplicin as a lipophilic chelator of Mg++ and other divalent cations.
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PMID:The multifunctional actions of beta-thujaplicin on the oxidative energy transformations as a consequence of its lipophilic and chelating properties. 678 24

The RCA1 (YTA12) and AFG3 (YTA10) genes of Saccharomyces cerevisiae code for homologous mitochondrial proteins that belong to the recently described AAA protein-family [Kunau et al. (1993) Biochimie 75,209-224]. Mutations in either gene have been shown to induce a respiratory defect. In the case of rca1 mutants this phenotype has been ascribed to defective assembly of cytochrome oxidase and ubiquinol-cytochrome c reductase. In the present study we show that the respiratory defect of afg3 mutants, like that of rca1 mutants, is also caused by an arrest in assembly of cytochrome oxidase and ubiquinol-cytochrome c reductase. In addition to the absence of the respiratory complexes, rca1 and afg3 mutants exhibit reduced mitochondrial ATPase activity. As a first step to an understanding of the biochemical basis for the ATPase defect we have examined the assembly of the F1 and F0 constituents of the ATPase complex. We present evidence that the ATPase lesion stems at least in part from the failure of rca1 and afg3 mutants to assemble F1. Although the mutants also display lower steady-state concentrations of some F0 subunits, this could be a secondary effect of defective F1 assembly.
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PMID:Mutations in RCA1 and AFG3 inhibit F1-ATPase assembly in Saccharomyces cerevisiae. 758 36

Metabolic control analysis was applied to describe the control of mitochondrial oxidative phosphorylation in calcium (approximately 2 microM free calcium) activated saponin-skinned rat musculus soleus fibers oxidizing glutamate and malate. Under these circumstances approximately 80% of mitochondrial active-state respiration was reached due to the activation of ATP turnover by actomyosin ATPase. The flux control coefficients of H(+)-ATPase, adenine-nucleotide translocase, phosphate transporter, NADH:ubiquinone oxidoreductase and cytochrome-c oxidase were determined to be equal to 0.16 +/- 0.08 (n = 6), 0.34 +/- 0.12 (n = 5), 0.08 +/- 0.03 (n = 5), 0.01 +/- 0.006 (n = 4) and 0.09 +/- 0.03 (n = 3) using inhibitor titrations with the specific inhibitors oligomycin, carboxyatractyloside, mersalyl, rotenone and cyanide, respectively, and applying non-linear regression of the entire titration curve. The flux control coefficient of actomyosin ATPase was determined with vanadate to be equal to 0.50 +/- 0.09 (n = 6), measuring independently the vanadate-caused inhibition of fiber respiration and ATP-splitting activity. In contrast to results with isolated rat skeletal muscle mitochondria reconstituted with soluble F1-ATPase the decrease in phosphate concentration from 10 mM to 1 mM only slightly affected the distribution of flux control coefficients. This difference is caused by different kinetic properties of soluble F1-ATPase and actomyosin ATPase. Therefore, phosphate seems to be in skeletal muscle in vivo only a modest modulator of control of oxidative phosphorylation.
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PMID:Distribution of flux control among the enzymes of mitochondrial oxidative phosphorylation in calcium-activated saponin-skinned rat musculus soleus fibers. 760 28

Subunit c is normally present as an inner mitochondrial membrane component of the F0 sector of the ATP synthase complex, but in the late infantile form of neuronal ceroid-lipofuscinosis (NCL) it was also found in lysosomes in high concentrations. The rate of degradation of subunit c as measured by pulse-chase and immunoprecipitation showed a marked delay of degradation in patients' fibroblasts with late infantile form of NCL. There were no significant differences between control cells and cells with disease in the degradation of cytochrome oxidase subunit IV, an inner membrane protein of mitochondria. Measurement of labeled subunit c in mitochondrial and lysosomal fractions showed that the accumulation of labeled subunit c in the mitochondrial fraction can be detected before lysosomal appearance of radioactive subunit c, suggesting that subunit c accumulated as a consequence of abnormal catabolism in the mitochondrion and is transferred to lysosomes through an autophagic process. The biosynthetic rate of subunit c and mRNA levels for P1 and P2 genes that code for it were almost the same in both control and patient cells. These findings suggest that a specific failure in the degradation of subunit c after its normal inclusion in mitochondria and its consequent accumulation in lysosomes.
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PMID:Abnormal degradative pathway of mitochondrial ATP synthase subunit c in late infantile neuronal ceroid-lipofuscinosis (Batten disease). 766 41

In this study we have examined (1) the integrated function of the mitochondrial respiratory chain by polarographic measurements and (2) the activities of the respiratory chain complexes I, II-III, and IV as well as the ATP synthase (complex V) in free mitochondria and synaptosomes isolated from gerbil brain, after a 30-min period of graded cerebral ischaemia. These data have been correlated with cerebral blood flow (CBF) values as measured by the hydrogen clearance technique. Integrated functioning of the mitochondrial respiratory chain, using both NAD-linked and FAD-linked substrates, was initially affected at CBF values of approximately 35 ml 100 g-1 min-1, and declined further as the CBF was reduced. The individual mitochondrial respiratory chain complexes, however, showed differences in sensitivity to graded cerebral ischaemia. Complex I activities decreased sharply at blood flows below approximately 30 ml 100 g-1 min-1 (mitochondria and synaptosomes) and complex II-III activities decreased at blood flows below 20 ml 100 g-1 min-1 (mitochondria) and 35-30 ml 100 g-1 min-1 (synaptosomes). Activities declined further as CBF was reduced below these levels. Complex V activity was significantly affected only when the blood flow was reduced below 15-10 ml 100 g-1 min-1 (mitochondria and synaptosomes). In contrast, complex IV activity was unaffected by graded cerebral ischaemia, even at very low CBF levels.
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PMID:Changes of respiratory chain activity in mitochondrial and synaptosomal fractions isolated from the gerbil brain after graded ischaemia. 772 7

Subunit c is normally present as an inner mitochondrial membrane component of the F0 section of the ATP synthase complex, but in the late infantile form of neuronal ceroid lipofuscinosis (NCL) it was also found in lysosomes in high concentrations. To explore the mechanism of storage of subunit c, the rates of degradation and synthesis of subunit c were measured in fibroblast cell types from controls and patients with the late infantile form of NCL. The radiolabel from subunit c decreased with time in control cells, whereas no apparent loss of radioactivity of subunit c was found in patients' cells. There were no significant differences between control cells and cells with disease in the degradation of cytochrome oxidase subunit IV, an inner membrane protein of mitochondria. A combination of pulse-chase and subcellular fractionation analysis showed that a delay of intramitochondrial loss from prelabeled subunit c was seen in all diseased cells tested. Lysosomal appearance of labeled subunit c could be detected after chase for more than 1 week and its radioactivities were variable among diseased cell types. The biosynthetic rate of subunit c was almost the same in both control and patient cells. Northern blotting analyses showed that mRNAs for P1 and P2 genes had no significant difference in lengths and amounts between control and patient cells. Results suggest a specific failure in the degradation of subunit c after its normal inclusion in mitochondria and its consequent accumulation in lysosomes. This is the first direct evidence to show a delay of subunit c degradation in the cells from the late infantile form of NCL.
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PMID:Specific delay of degradation of mitochondrial ATP synthase subunit c in late infantile neuronal ceroid lipofuscinosis (Batten disease). 783 67

Some analytical and functional parameters of rat heart mitochondrial have been investigated at six different periods of ageing from 2 to 26 months. The fatty acid composition of the mitochondrial membranes reveals a percentage increase of polyunsaturated fatty acids (20:4 n-6, 22:6 n-3) up to 12 months, followed by a decrease; however, fluorescence polarization of the membrane probe diphenylhexatriene is not changed, revealing that membrane fluidity is not significantly affected. No major change in ubiquinone-9 and in cytochrome content is apparent, indicating that the relative ratio of the respiratory chain components is unmodified. Nevertheless, significant changes in enzyme specific activities are detected: NADH cytochrome c reductase and cytochrome oxidase activities increase up to 12 months, then decrease at 18-26 months; ubiquinol cytochrome c reductase exhibits a peak at 18 months, followed by a decrease. All these activities follow a similar trend during the whole life span of the rat, even though the 'maximum' is different. No significant changes have been found in ATP synthase. Succinate-cytochrome c reductase steadily increases over the whole life span. The results, showing activity decreases in the respiratory enzymes having subunits encoded by mitochondrial DNA, are compatible with the 'mitochondrial' theory of ageing.
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PMID:Mitochondrial activities of rat heart during ageing. 788 68

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

We have performed experiments which demonstrate that puromycin inhibits the import of proteins into mitochondria in in vitro reactions containing mitochondria isolated from the yeast Saccharomyces cerevisiae and precursor proteins synthesized in a nuclease-treated rabbit reticulocyte lysate. Puromycin inhibited the import of several precursor proteins including; a fusion protein consisting of the first 22 N-terminal residues of yeast cytochrome oxidase subunit IV fused to mouse dihydrofolate reductase, both a destabilized and truncated form of this same fusion protein, the beta-subunit of the yeast mitochondrial F1-ATPase and yeast alcohol dehydrogenase III. The insertion of the yeast outer mitochondrial protein porin was not inhibited by puromycin. Puromycin-induced import inhibition could be overcome by adding additional ATP to the import reactions. However, if access of ATP to the mitochondrial matrix was prevented by blocking the adenine nucleotide translocase with carboxyatractyloside, ATP addition was unable to overcome the inhibitory effect of puromycin on protein import. Collectively, these results demonstrate that puromycin inhibits protein import into mitochondria by interfering with an ATP-dependent step in the import process and that the ATP-dependent component in the reaction is located inside the inner mitochondrial membrane. In addition to supporting the view that ATP is required in the matrix for efficient protein import, these results may provide a useful tool for identifying the ATP-binding components of the import apparatus.
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PMID:Puromycin inhibits protein import into mitochondria by interfering with an intramitochondrial ATP-dependent reaction. 833 41

We have utilized a homologous cell-free mitochondrial protein import system derived from the yeast Saccharomyces cerevisiae, in addition to performing a series of in vivo experiments in yeast, to investigate the coupling between cytosolic protein synthesis and protein transport into mitochondria. We found that the import of bulk mitochondrial proteins was inhibited in both the homologous in vitro reaction and in vivo upon arrest of cytosolic protein synthesis with the addition of cycloheximide. Tight coupling of synthesis and import was also demonstrated in vivo for the beta subunit of the mitochondrial F1-ATPase. We also investigated the effect of the antifolate methotrexate on the import of a fusion protein consisting of the mitochondrial targeting signal of yeast cytochrome oxidase subunit IV fused to mouse dihydrofolate reductase (the COXIV-DHFR fusion protein). Methotrexate has previously been shown to inhibit posttranslational import of COXIV-DHFR by preventing the DHFR moiety from unfolding. However, we found that antifolate addition had no inhibitory effect on the import of COXIV-DHFR in vivo, suggesting that its import into mitochondria in yeast cells occurs cotranslationally. Further, when we treated yeast with the proton ionophore carbonyl cyanide m-chlorophenylhydrazone to collapse the mitochondrial membrane potential and induce the accumulation of extramitochondrial precursor pools, we found that the ability to be imported by a strictly posttranslational mechanism upon reestablishing the membrane potential varied from one precursor to another, suggesting that cotranslational import may be mandatory for the import of some proteins in vivo. In summary, our findings are entirely consistent with the notion that import of proteins into yeast mitochondria occurs cotranslationally under normal conditions in vivo.
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PMID:Coupling of cytosolic protein synthesis and mitochondrial protein import in yeast. Evidence for cotranslational import in vivo. 838 May 82


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