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 mitochondrial oxidative phosphorylation involves five multimeric complexes imbedded in the inner membrane: complex I (Nicotinamide Adenine Dinucleotide (NADH) quinone oxidoreductase), II (succinate dehydrogenase), III (ubiquinol cytochrome c oxido reductase or bc1 complex), IV (cytochrome c oxidase), and V (ATP synthase). These respiratory complexes are conserved from the yeast Saccharomyces cerevisiae to human with the exception of complex I, which is replaced by three NADH dehydrogenases in S. cerevisiae. Here, we provide several protocols allowing an exhaustive characterization of each yeast complex: this chapter describes procedures from mitochondria preparation to measurement of the activity of each complex and analysis of their subunit composition and provides information on the interactions between different complexes.
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PMID:Preparation of respiratory chain complexes from Saccharomyces cerevisiae wild-type and mutant mitochondria : activity measurement and subunit composition analysis. 1837 11

The procyclic form of Trypanosoma brucei is a parasitic protozoan that normally dwells in the midgut of its insect vector. In vitro, this parasite prefers d-glucose to l -proline as a carbon source, although this amino acid is the main carbon source available in its natural habitat. Here, we investigated how l -proline is metabolized in glucose-rich and glucose-depleted conditions. Analysis of the excreted end products of (13)C-enriched l -proline metabolism showed that the amino acid is converted into succinate or l -alanine depending on the presence or absence of d-glucose, respectively. The fact that the pathway of l -proline metabolism was truncated in glucose-rich conditions was confirmed by the analysis of 13 separate RNA interference-harboring or knock-out cell lines affecting different steps of this pathway. For instance, RNA interference studies revealed the loss of succinate dehydrogenase activity to be conditionally lethal only in the absence of d-glucose, confirming that in glucose-depleted conditions, l -proline needs to be converted beyond succinate. In addition, depletion of the F(0)/F(1)-ATP synthase activity by RNA interference led to cell death in glucose-depleted medium, but not in glucose-rich medium. This implies that, in the presence of d-glucose, the importance of the F(0)/F(1)-ATP synthase is diminished and ATP is produced by substrate level phosphorylation. We conclude that trypanosomes develop an elaborate adaptation of their energy production pathways in response to carbon source availability.
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PMID:Glucose-induced remodeling of intermediary and energy metabolism in procyclic Trypanosoma brucei. 1843 Jul 32

Mitochondrial (m) KATP channel opening has been implicated in triggering cardiac preconditioning. Its consequence on mitochondrial respiration, however, remains unclear. We investigated the effects of two different KATP channel openers and antagonists on mitochondrial respiration under two different energetic conditions. Oxygen consumption was measured for complex I (pyruvate/malate) or complex II (succinate with rotenone) substrates in mitochondria from fresh guinea pig hearts. One of two mKATP channel openers, pinacidil or diazoxide, was given before adenosine diphosphate in the absence or presence of an mKATP channel antagonist, glibenclamide or 5-hydroxydecanoate. Without ATP synthase inhibition, both mKATP channel openers differentially attenuated mitochondrial respiration. Neither mKATP channel antagonist abolished these effects. When ATP synthase was inhibited by oligomycin to decrease [ATP], both mKATP channel openers accelerated respiration for both substrate groups. This was abolished by mKATP channel blockade. Thus, under energetically more physiological conditions, the main effect of mKATP channel openers on mitochondrial respiration is differential inhibition independent of mKATP channel opening. In contrast, under energetically less physiological conditions, mKATP channel opening can be evidenced by accelerated respiration and blockade by antagonists. Therefore, the effects of mKATP channel openers on mitochondrial function likely depend on the experimental conditions and the cell's underlying energetic state.
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PMID:KATP channel openers have opposite effects on mitochondrial respiration under different energetic conditions. 1843 94

We investigated the organization of photosystem II (PSII) in agranal bundle sheath thylakoids from a C(4) plant maize. Using blue native/SDS-PAGE and single particle analysis, we show for the first time that PSII in the bundle sheath (BS) chloroplasts exists in a dimeric form and forms light-harvesting complex II (LHCII).PSII supercomplexes. We also demonstrate that a similar set of photosynthetic membrane complexes exists in mesophyll and agranal BS chloroplasts, including intact LHCI.PSI supercomplexes, PSI monomers, PSII core dimers, PSII monomers devoid of CP43, LHCII trimers, LHCII monomers, ATP synthase, and cytochrome b(6)f complex. Fluorescence functional measurements clearly indicate that BS chloroplasts contain PSII complexes that are capable of performing charge separation and are efficiently sensitized by the associated LHCII. We identified a fraction of LHCII present within BS thylakoids that is weakly energetically coupled to the PSII reaction center; however, the majority of BS LHCII is shown to be tightly connected to PSII. Overall, we demonstrate that organization of the photosynthetic apparatus in BS agranal chloroplasts of a model C(4) plant is clearly distinct from that of the stroma lamellae of the C(3) plants. In particular, supramolecular organization of the dimeric LHCII.PSII in the BS thylakoids strongly suggests that PSII in the BS agranal membranes may donate electrons to PSI. We propose that the residual PSII activity may supply electrons to poise cyclic electron flow around PSI and prevent PSI overoxidation, which is essential for the CO(2) fixation in BS cells, and hence, may optimize ATP production within this compartment.
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PMID:Structural organization of photosynthetic apparatus in agranal chloroplasts of maize. 1863 64

The neurotoxic compound methylmercury (MeHg) is a commonly encountered pollutant in the environment, and constitutes a hazard for human health through fish eating. To study the impact of MeHg on mitochondrial structure and function, we contaminated the model fish species Danio rerio with food containing 13 microg of MeHg per gram, an environmentally relevant dose. Mitochondria from contaminated zebrafish muscles presented structural abnormalities under electron microscopy observation. In permeabilized muscle fibers, we observed, a strong inhibition of both state 3 mitochondrial respiration and functionally isolated maximal cytochrome c oxidase (COX) activity after 49 days of MeHg exposure. However, the state 4 respiratory rate remained essentially unchanged. This suggested a defect at the level of ATP synthesis. Accordingly, we measured a dramatic decrease in the rate of ATP release by skinned muscle fibers using either pyruvate and malate or succinate as respiratory substrates. However, the amount and the assembly of the ATP synthase were identical in both control and contaminated muscle mitochondrial fractions. This suggests that MeHg induced a decoupling of mitochondrial oxidative phosphorylation in the skeletal muscle of zebrafish. Western blot analysis showed a 30% decrease of COX subunit IV levels, a 50% increase of ATP synthase subunit alpha, and a 40% increase of the succinate dehydrogenase Fe/S protein subunit in the contaminated muscles. This was confirmed by the analysis of gene expression levels, using RT-PCR. Our study provides a basis for further analysis of the deleterious effect of MeHg on fish health via mitochondrial impairment.
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PMID:At environmental doses, dietary methylmercury inhibits mitochondrial energy metabolism in skeletal muscles of the zebra fish (Danio rerio). 1876 95

Indirubin, a red colored 3,2'-bisindole isomer, is a component of Indigo naturalis and is an active ingredient used in traditional Chinese medicine for the treatment of chronic diseases. The family of indirubin derivatives, such as indirubin-3'-oxime, has been suggested for various therapeutic indications. However, potential toxic interactions such as indirubin effects on mitochondrial bioenergetics are still unknown. This study evaluated the action of indirubin-3'-oxime on the function of isolated rat liver mitochondria contributing to a better understanding of the biochemical mechanisms underlying the multiple effects of indirubin. Indirubin-3'-oxime incubated with isolated rat liver mitochondria, at concentrations above 10microM, significantly depresses the phosphorylation efficiency of mitochondria as inferred from the decrease in the respiratory control and ADP/O ratios, the perturbations in mitochondrial membrane potential and in the phosphorylative cycle induced by ADP. Furthermore, indirubin-3'-oxime at up to 25microM stimulates the rate of state 4 respiration and inhibits state 3 respiration. The increased lag phase of repolarization was associated with a direct inhibition of the mitochondrial ATPase. Indirubin-3'-oxime significantly inhibited the activity of complex II and IV thus explaining the decreased FCCP-stimulated mitochondrial respiration. Mitochondria pre-incubated with indirubin-3'-oxime exhibits decreased susceptibility to calcium-induced mitochondrial permeability transition. This work shows for the first time multiple effects of indirubin-3'-oxime on mitochondrial bioenergetics thus indicating a potential mechanism for indirubin-3'-oxime effects on cell function.
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PMID:Indirubin-3'-oxime impairs mitochondrial oxidative phosphorylation and prevents mitochondrial permeability transition induction. 1878 56

We defined the transcriptomic and proteomic profiles of rat ageing skeletal muscle using a combined cDNA array, 2D- and Blue native-PAGE approach. This was allowed to obtain an overview of the interrelated events leading to the transcriptome/proteome/mitoproteome changes likely to underlie the structural/metabolic features of aged skeletal muscle. The main differences were found in genes/proteins related to energy metabolism, mitochondrial pathways, myofibrillar filaments, and detoxification. Concerning the abundance of mitochondrial OXPHOS complexes as well as their supramolecular organization and activity, mitochondria from old rats, when compared with those from young rats, contained significantly lower amounts of complex I (NADH:ubiquinone oxidoreductase), V (FoF1-ATP synthase), and III (ubiquinol:cytochrome c oxidoreductase). The same mitochondria contained a significantly larger amount of complex II (succinate:ubiquinone oxidoreductase), but an unchanged amount of complex IV (cytochrome c oxidase, COX). When comparing the supercomplex profiles between young and old muscle mitochondria, the densitometric analysis revealed that lighter supercomplexes were significantly reduced in older mitochondria, and that in the older group the major supercomplex bands were those representing heavier supercomplexes, likely suggesting a compensatory mechanism that, in ageing muscle, is functionally directed towards substrate channeling and catalytic enhancement advantaging the respirosome.
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PMID:Defining the transcriptomic and proteomic profiles of rat ageing skeletal muscle by the use of a cDNA array, 2D- and Blue native-PAGE approach. 1926 20

Two splice variants of the Marek's disease virus phosphorylated polypeptide (pp)38 were previously identified in the quail cell line QTP32 expressing pp38 under the control of an inducible promoter. We developed QT35-derived cell lines expressing these splice variants or full length pp38 with the splice acceptor sites mutated to further elucidate the role of pp38. Only induction of full length pp38 resulted in an increase in mitochondrial succinate dehydrogenase activity compared to non-induced cells. Transcript copy numbers of cytochrome C oxidase subunit I and ATP synthase were reduced in induced cells. The ATP content of isolated mitochondria from induced cells was greatly reduced compared to those of non-induced cells. Mitochondrial and pp38 staining suggests that there is no direct interaction between pp38 and the mitochondria. Mitochondrial transcripts were also reduced in DF-1 cells expressing full length pp38 and in MDV-infected chick kidney cells indicating that this effect occurs independent of other viral genes and after in vitro infection with MDV.
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PMID:Marek's disease virus phosphorylated polypeptide pp38 alters transcription rates of mitochondrial electron transport and oxidative phosphorylation genes. 1947 43

Previously, we demonstrated that hypoxic pulmonary vasoconstriction (HPV) of intra-acinar arteries (IAA) requires mitochondrial complex II (= succinate dehydrogenase, SDH) activity (citeauthor ch41:paddenberg2006, Respir Res, 7:93, citeyear ch41:paddenberg2006). Interestingly, SDH subunits A and B have recently been described as components of a multiprotein mitochondrial ATP-sensitive potassium channel (mitoK(ATP)), together with mitochondrial ATP-binding cassette protein-1, adenine nucleotide translocator (ANT), ATP synthase, and phosphate carrier (citeauthor ch41:ardehali2004, Proc Natl Acad Sci USA, 101(32):11880-5, citeyear ch41:ardehali2004). Hence, we tested the hypothesis that such an SDH-containing mitoK(ATP) is involved in HPV. For this purpose, the impact of modulators of mitoK(ATP) on HPV of IAA was studied videomorphometrically in precision cut murine lung slices. Inhibitors of mitoK(ATP) (glibenclamide, 5-hydroxydecanoate) completely suppressed HPV, mitoK(ATP) activators (pinacidil, diazoxide) even induced vasodilatation, and ANT inhibitors (bongkrekic acid, atractyloside) attenuated HPV. This pharmacological profile differs clearly from that described for mitoK(ATP). Accordingly, co-immunoprecipitation experiments provided no evidence for association of complex II subunits SDH-A, -B and -C with ANT, ATP synthase or cytochrome c oxidase in murine heart mitochondria. Hence, it is likely that the inhibitory effects on HPV that we observed in our experiments result from modulation of several mitochondrial protein complexes independently involved in the signalling cascade such as ROS-producing complex II and ANT-regulated mitochondrial permeability transition pore.
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PMID:Impact of modulators of mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) on hypoxic pulmonary vasoconstriction. 1953

Hyperosmotic stress triggers a great variety of adaptive responses in eukaryotic cells that affect many different physiological functions. Here we investigate the role of the mitochondria during osmostress adaptation in budding yeast. Mitochondrial function is generally required for proper salt and osmotic stress adaptation because mutants with defects in many different mitochondrial components show hypersensitivity to increased NaCl and KCl concentrations. Mitochondrial protein abundance rapidly increases upon osmoshock in a selective manner, because it affects Calvin cycle enzymes (Sdh2 and Cit1) and components of the electron transport chain (Cox6) but not the ATP synthase complex (Atp5). Transcription of the SDH2, CIT1, and COX6 genes is severalfold induced within the first minutes of osmotic shock, dependent to various degree on the Hog1 and Snf1 protein kinases. Mitochondrial succinate dehydrogenase enzyme activity is stimulated upon osmostress in a Snf1-dependent manner. The osmosensitivity of mitochondrial mutants is not caused by impaired stress-activated transcription or by a general depletion of the cellular ATP pool during osmostress. We finally show that the growth defect of mitochondrial mutants in high salt medium can be partially rescued by supplementation of glutathione. Additionally, mitochondrial defects cause the hyperaccumulation of reactive oxygen species during salt stress. Our results indicate that the antioxidant function of the mitochondria might play an important role in adaptation to hyperosmotic stress.
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PMID:Mitochondrial function is an inducible determinant of osmotic stress adaptation in yeast. 1972 Aug 30


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