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Mitochondrial Complex I (mitochondrial + complex_i)
Selected AbstractsIn Vivo Labeling of Mitochondrial Complex I (NADH:UbiquinoneOxidoreductase) in Rat Brain Using [3H]DihydrorotenoneJOURNAL OF NEUROCHEMISTRY, Issue 6 2000Deepa J. Talpade Abstract: Defects in mitochondrial energy metabolism have beenimplicated in several neurodegenerative disorders. Defective complex I(NADH:ubiquinone oxidoreductase) activity plays a key role in Leber'shereditary optic neuropathy and, possibly, Parkinson's disease, but there isno way to assess this enzyme in the living brain. We previously described anin vitro quantitative autoradiographic assay using[3H]dihydrorotenone ([3H]DHR) binding to complex I. Wehave now developed an in vivo autoradiographic assay for complex I using[3H]DHR binding after intravenous administration. In vivo[3H]DHR binding was regionally heterogeneous, and brain uptake wasrapid. Binding was enriched in neurons compared with glia, and white matterhad the lowest levels of binding. In vivo [3H]DHR binding wasmarkedly reduced by local and systemic infusion of rotenone and was enhancedby local NADH administration. There was an excellent correlation betweenregional levels of in vivo [3H]DHR binding and the in vitroactivities of complex II (succinate dehydrogenase) and complex IV (cytochromeoxidase), suggesting that the stoichiometry of these components of theelectron transport chain is relatively constant across brain regions. Theability to assay complex I in vivo should provide a valuable tool toinvestigate the status of this mitochondrial enzyme in the living brain andsuggests potential imaging techniques for complex I in humans. [source] Design syntheses and mitochondrial complex I inhibitory activity of novel acetogenin mimicsFEBS JOURNAL, Issue 9 2000Kaoru Kuwabara Some natural acetogenins are the most potent inhibitors of mitochondrial complex I. These compounds are characterized by two functional units [i.e. hydroxylated tetrahydrofuran (THF) and ,,,-unsaturated ,-lactone ring moieties] separated by a long alkyl spacer. To elucidate which structural factors of acetogenins, including their active conformation, are crucial for the potent inhibitory activity we synthesized a novel bis-acetogenin and its analogues possessing two ,-lactone rings connected to bis-THF rings by flexible alkyl spacers. The inhibitory potency of the bis-acetogenin with bovine heart mitochondrial complex I was identical to that of bullatacin, one of the most potent natural acetogenins. This result indicated that one molecule of the bis-acetogenin does not work as two reactive inhibitors, suggesting that a ,-lactone and the THF ring moieties act in a cooperative manner on the enzyme. In support of this, either of the two ring moieties synthesized individually showed no or very weak inhibitory effects. Moreover, combined use of the two ring moieties at various molar ratios exhibited no synergistic enhancement of the inhibitory potency. These observations indicate that both functional units work efficiently only when they are directly linked by a flexible alkyl spacer. Therefore, some specific conformation of the spacer must be important for optimal positioning of the two units in the enzyme. Furthermore, the ,,,-unsaturated ,-lactone, the 4-OH group in the spacer region, the long alkyl tail attached to the THF unit and the stereochemistry surrounding the hydroxylated bis-THF rings were not crucial for the activity, although these are the most common structural features of natural acetogenins. The present study provided useful guiding principles not only for simplification of complicated acetogenin structure, but also for further wide structural modifications of these molecules. [source] Two modes of mitochondrial dysfunction lead independently to lifespan extension in Caenorhabditis elegansAGING CELL, Issue 3 2010Wen Yang Summary In Caenorhabditis elegans, longevity is increased by a partial loss-of-function mutation in the mitochondrial complex III subunit gene isp-1. Longevity is also increased by RNAi against the expression of a variety of mitochondrial respiratory chain genes, including isp-1, but it is unknown whether the isp-1(qm150) mutation and the RNAi treatments trigger the same underlying mechanisms of longevity. We have identified nuo-6(qm200), a mutation in a conserved subunit of mitochondrial complex I (NUDFB4). The mutation reduces the function of complex I and, like isp-1(qm150), results in low oxygen consumption, slow growth, slow behavior, and increased lifespan. We have compared the phenotypes of nuo-6(qm200) to those of nuo-6(RNAi) and found them to be distinct in crucial ways, including patterns of growth and fertility, behavioral rates, oxygen consumption, ATP levels, autophagy, and resistance to paraquat, as well as expression of superoxide dismutases, mitochondrial heat-shock proteins, and other gene expression markers. RNAi treatments appear to generate a stress and autophagy response, while the genomic mutation alters electron transport and reactive oxygen species metabolism. For many phenotypes, we also compared isp-1(qm150) to isp-1(RNAi) and found the same pattern of differences. Most importantly, we found that, while the lifespan of nuo-6, isp-1 double mutants is not greater than that of the single mutants, the lifespan increase induced by nuo-6(RNAi) is fully additive to that induced by isp-1(qm150), and the increase induced by isp-1(RNAi) is fully additive to that induced by nuo-6(qm200). Our results demonstrate that distinct and separable aspects of mitochondrial biology affect lifespan independently. [source] Oxidative modification of mitochondrial proteins and cell death in Parkinson's diseaseJOURNAL OF NEUROCHEMISTRY, Issue 2002W. Maruyama Oxidative stress is one of the cell death mechanisms in neurodegenerative disorders, such as Parkinson's disease (PD) and Alzheimer's disease. Most of reactive oxygen species (ROS) generate in mitochondria through oxidative phosphorylation, and a part of them are not scavenged by antioxidative system and react with bioactive molecules. Recently, alpha-synuclein containing nitrotyrosine, a marker for oxidative modification by peroxynitrite, was identified in Lewy body. In addition, inhibitors of mitochondrial respiratory chain were reported to induce formation of Lewy body-like inclusion in vivo and in vitro. In this paper it was examined whether ROS and reactive nitrogen species (RNS) generated in mitochondria oxidize mitochondrial respiratory enzymes and induce the formation of inclusion body and cell death in PD. Human neuroblastoma SH-SY5Y cells were treated with a peroxynitrite donor, SIN-1, or an inhibitor of complex I, rotenone. After the treatment, proteins modified with toxic aldehydes, 4-hydroxynonenal and acrolein, and containing nitrotyrosine were analyzed by immunoblotting. Particularly in mitochondrial fraction, the oxidized protein was characterized by two-dimensional immunoblotting. Most of the oxidized proteins were detected in subunits proteins of complex I. These results indicate that mitochondrial complex I is a main target of oxidative stress in dopamine neurons and its dysfunction may be involved in the death mechanism in neurodegenerative disorders. [source] Hexokinase II gene transfer protects against neurodegeneration in the rotenone and MPTP mouse models of Parkinson's disease,JOURNAL OF NEUROSCIENCE RESEARCH, Issue 9 2010Juan Carlos Corona Abstract A typical feature of Parkinson's disease is the progressive loss of dopaminergic neurons in the substantia nigra, in which inhibition of mitochondrial complex I activity may play an important role. Rotenone or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) inhibit the mitochondrial complex I and they cause the death of substantia nigra dopaminergic neurons, thereby providing acute murine models of Parkinson's disease. We have found that increasing mitochondrial hexokinase II activity can prevent cell death in neuronal cultures treated with rotenone. As a result, we have studied the effects of hexokinase II gene transfer in vivo using a herpes simplex virus type 1 (HSV-1) amplicon vector. The placHK2 amplicon vector was injected into substantia nigra of mice that were subsequently administered rotenone or MPTP. Overexpression of hexokinase II prevented both rotenone and MPTP-induced dopaminergic neuronal cell death, as well as reducing the associated motor defects. Our results provide the first proof-of-principle that hexokinase II protects against dopaminergic neurodegeneration in vivo, emphasizing the role of this enzyme in promoting neuronal survival. Thus, the increase of hexokinase II expression by gene transfer or other means represents a promising approach to treat Parkinson's and other neurodegenerative diseases. © 2010 Wiley-Liss, Inc. [source] Herbicidal action of 2-hydroxy-3-alkyl-1,4-naphthoquinonesPEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 3 2002Philip J Jewess Abstract The main mode of herbicidal activity of 2-hydroxy-3-alkyl-1,4-naphthoquinones is shown to be inhibition of photosystem II (PSII). The herbicidal and in vitro activities have been measured and correlated with their (Log)octanol/water partition coefficients (Log Ko/w). The length of the 3- n -alkyl substituent for optimal activity differed between herbicidal and in vitro activity. The maximum in vitro activity was given by the nonyl to dodecyl homologues (Log Ko/w between 6.54 and 8.12), whereas herbicidal activity peaked with the n -hexyl compound (Log Ko/w,=,4.95). The effect of chain branching was also investigated using isomeric pentyl analogues substituted at position 3. All exhibited similar levels of in vitro activities but herbicidal activities differed, albeit moderately, with the exception of one analogue that was much less phytotoxic. Other modes of action were also investigated using two representative compounds. They did not show any activity on photosystem I or mitochondrial complex I, or generate toxic oxygen radicals by redox cycling reactions. Only moderate activity was found against mitochondrial complex III from plants, in contrast to much higher corresponding activity using an insect enzyme. © 2002 Society of Chemical Industry [source] Infrared Radiation Influence on Molt and Regeneration of Neohelice granulata Dana, 1851 (Grapsidae, Sesarminae)PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 5 2009Vinícius Cunha Gonzalez This paper analyzes the influence of infrared radiation (IR) on regeneration, after autotomy of limb buds of Neohelice granulata and consequently the time molt. Eyestalks were ablated to synchronize the start of molt. Afterward, animals were autotomized of five pereopods and divided into control and irradiated groups. The irradiated group was treated for 30 min daily until molt. Limb buds from five animals of days 4, 16 and 20 were collected and histological sections were made from them. These sections were photographed and chitin and epithelium content measured. Another group was made, and after 15 days limb buds were extracted to analyze mitochondrial enzymatic activity from complex I and II. The irradiated group showed a significant reduction in molt time (19.38 ± 1.22 days) compared with the control group (32.69 ± 1.57 days) and also a significant increase in mitochondrial complex I (388.9 ± 27.94%) and II (175.63 ± 7.66%) in the irradiated group when compared with the control group (100 ± 17.90; 100 ± 7.82, respectively). However, these effects were not acompanied by histological alterations in relation to chitin and epithelium. This way, it was possible to demonstrate that IR increases complex I and II activity, reduces the time molt and consequently increases the appendage regeneration rate. [source] | |||||||||||||