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:1.6.5.3 (complex I)
8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Iron catalyzed free radical formation and lipid peroxidation are accepted mechanisms of heme protein-induced acute renal failure. However, the source(s) of those free radicals which trigger lipid peroxidation in proximal tubular cells remains unknown. This study tested the potential involvement of mitochondrial electron transport, xanthine oxidase activity, and arachidonic acid metabolism in the heme-induced peroxidative state. The impact of cytosolic Ca2+ loading also was assessed. Rhabdomyolysis was induced in mice by glycerol injection, and two hours later heme-laden proximal tubular segments (PTS) were isolated for study. PTS from normal mice served as controls. During 30 to 60 minute incubations, heme loaded PTS developed progressive cytotoxicity (LDH release) and iron-dependent lipid peroxidation (malondialdehyde, MDA, generation; inhibited by deferoxamine). Site 2 (antimycin A) or site 3 (cyanide, hypoxia) mitochondrial respiratory chain inhibition completely blocked lipid peroxidation, whereas site 1 inhibition (rotenone) doubled its extent (presumably by shunting NADH through NADH dehydrogenase, a free radical generating system). Conversely, these agents did not substantially alter MDA in normal PTS. Normal and heme loaded PTS developed comparable degrees of LDH release during respiratory blockade irrespective of increased or decreased MDA production (indicating that lipid peroxidation was not a critical determinant of cell death). Neither increasing free arachidonic acid (PLA2 treatment) nor adding cyclooxygenase/lipoxygenase/cytochrome p450 inhibitors conferred a consistent protective effect. Altering free Ca2+ status (chelators; ionophore addition) and xanthine oxidase inhibition had no discernible impacts. Despite mitochondrial free radical production, mitochondrial function, as assessed by the ATP/ADP ratio, seemingly remained intact. In conclusion, (1) the terminal mitochondrial respiratory chain is the dominant source of free radicals which trigger PTS lipid peroxidation; (2) iron is a required secondary factor; (3) although mitochondria fuel lipid peroxidation, they do not appear to be critical targets of the heme-induced oxidant attack.
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PMID:Mitochondrial free radical production induces lipid peroxidation during myohemoglobinuria. 864 15

Heart mitochondria can be made to oxidize extramitochondrial NADH via the exogenous NADH dehydrogenase. Oxidation of extramitochondrial NADH was found to be associated with the disappearance of H+ from the suspension medium. Our studies on the possible pathway through which H+ may disappear from the extramitochondrial space were focused on (i) an unspecific transmembranous H+ leakage along the electrochemical H+ gradient following peroxidative membrane alteration, (ii) stimulation of a controlled H+ reconduction through the H+ channel of the ATP synthase, and (iii) stimulation of the Na+/H+ counterporter by Ca2+ release. Our experiments revealed that none of these H+ pathways was involved in the observed alkalinization of the extramitochondrial space during respiration of external NADH. The latter effect was inhibited when oxidation of external NADH via the respiratory chain was blocked and could be turned into the opposite when artificial e- acceptors of the exogenous NADH dehydrogenase were used to reactivate NADH consumption. Stoichiometric analysis of H+ disappearance and O2 consumption revealed that reducing equivalents of external NADH were transferred to oxygen via cytochrome oxidase and H+ from the suspension was used to release water.
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PMID:The effect of the exogenous NADH dehydrogenase of heart mitochondria on the transmembranous proton movement. 866 Jul 6

The catecholaminergic neurotoxin 6-hydroxydopamine causes parkinsonian symptoms in animals and it has been proposed that reactive oxygen species and oxidative stress, enhanced by iron, may play a key role in its toxicity. The present results demonstrate that 6-hydroxydopamine reversibly inhibits complex I (NADH dehydrogenase) of brain mitochondrial respiratory chain in isolated mitochondria. 6-Hydroxydopamine itself, rather than its oxidative products, was responsible for the inhibition. Iron (III) did not enhance inhibition but decreased it by stimulating the nonenzyme oxidation of 6-hydroxydopamine. Inhibition was potentiated to some extent by calcium ion. Desferrioxamine protected complex I activity against the inhibition, but it was not due to its chelator or antioxidative properties. Desferrioxamine was also shown to activate NADH dehydrogenase in the absence of 6-hydroxydopamine. Activation of mitochondrial respiration by desferrioxamine may contribute to the enhanced neuron survival in the presence of desferrioxamine in some neurodegenerative conditions.
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PMID:Nature of inhibition of mitochondrial respiratory complex I by 6-Hydroxydopamine. 878 29

Expression of the human protooncogene bcl-2 protects neural cells from death induced by many forms of stress, including conditions that greatly elevate intracellular Ca2+. Considering that Bcl-2 is partially localized to mitochondrial membranes and that excessive mitochondrial Ca2+ uptake can impair electron transport and oxidative phosphorylation, the present study tested the hypothesis that mitochondria from Bcl-2-expressing cells have a higher capacity for energy-dependent Ca2+ uptake and a greater resistance to Ca(2+)-induced respiratory injury than mitochondria from cells that do not express this protein. The overexpression of bcl-2 enhanced the mitochondrial Ca2+ uptake capacity using either digitonin-permeabilized GT1-7 neural cells or isolated GT1-7 mitochondria by 1.7 and 3.9 fold, respectively, when glutamate and malate were used as respiratory substrates. This difference was less apparent when respiration was driven by the oxidation of succinate in the presence of the respiratory complex I inhibitor rotenone. Mitochondria from Bcl-2 expressors were also much more resistant to inhibition of NADH-dependent respiration caused by sequestration of large Ca2+ loads. The enhanced ability of mitochondria within Bcl-2-expressing cells to sequester large quantities of Ca2+ without undergoing profound respiratory impairment provides a plausible mechanism by which Bcl-2 inhibits certain forms of delayed cell death, including neuronal death associated with ischemia and excitotoxicity.
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PMID:Bcl-2 potentiates the maximal calcium uptake capacity of neural cell mitochondria. 879 Apr 27

Parkinson's disease may be linked to defects in mitochondrial function. Mitochondrially transformed cells (cybrids) were created from Parkinson's disease patients or disease-free controls. Parkinson's disease cybrids had 26% less complex I activity, but maintained comparable basal calcium and energy levels. Parkinson's disease cybrids recovered from a carbachol-induced increase in cytosolic calcium 53% more slowly than controls even with lanthanum and thapsigargin blockade. Inhibition of complex I with the Parkinson's disease-inducing metabolite 1-methyl-4-phenylpyridinium (MPP+) similarly reduced the rate of recovery after carbachol. This MPP(+)-induced reduction in recovery rates was much more pronounced in control cybrids than in Parkinson's disease cybrids. Parkinson's disease cybrids had less carbonyl cyanide m-chlorophenylhydrazone-releasable calcium. Bypassing complex I with succinate partially restored Parkinson's disease cybrid, and MPP+ suppressed control cybrid recovery rates. The subtle alteration in calcium homeostasis of Parkinson's disease cybrids may reflect an increased susceptibility to cell death under circumstances not ordinarily toxic.
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PMID:Altered calcium homeostasis in cells transformed by mitochondria from individuals with Parkinson's disease. 904 69

The mitochondrial permeability pore is subject to regulation by a thiol-dependent voltage sensor (Petronilli, V., Costantini, P., Scorrano, L., Colonna, R., Passamonti, S., and Bernardi, P., J. Biol. Chem. 269, 16638-16642, 1994); thiol oxidation increases the gating potential, which increases the probability of pore opening. Monofunctional sulfhydryl-alkylating agents, by preventing formation of the disulfide, inhibit oxidant-induced changes in the gating potential. According to this paradigm, redox-cycling and arylating quinones should have distinct and opposing effects on the voltage-dependent permeabilization of mitochondrial membranes. Freshly isolated rat liver mitochondria were susceptible to a calcium-dependent permeability transition characterized by osmotic swelling and membrane depolarization, both of which were inhibited by Cyclosporine A. 1,4-Naphthoquinone, 2-methyl-1,4-naphthoquinone (menadione), and 2,3-dimethoxy-1,4-naphthoquinone elicited an increase in gating potential of the permeability pore that was prevented by Cyclosporine A or N-ethylmaleimide and reversed by dithiothreitol. Benzoquinone, on the other hand, inhibited NADH-ubiquinone oxidoreductase. Accordingly, in mitochondria energized with glutamate plus malate benzoquinone caused a direct, calcium-independent depolarization of membrane potential and mitochondrial swelling that were not inhibited by Cyclosporine A. In contrast, benzoquinone did not interfere with succinate-supported mitochondrial bioenergetics. In fact, adding benzoquinone to succinate-energized mitochondria prevented induction of the mitochondrial permeability transition by all three redox-cycling naphthoquinones. We attribute this to the electrophilic, sulfhydryl-arylating reactivity of benzoquinone. The results suggest that differences in the mechanisms by which quinones of varying chemical reactivity interfere with mitochondrial bioenergetics can be explained in terms of the distinct manner in which they react with the thiol-dependent voltage sensor of the mitochondrial permeability pore.
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PMID:Benzoquinone inhibits the voltage-dependent induction of the mitochondrial permeability transition caused by redox-cycling naphthoquinones. 914 50

Alzheimer's disease (AD) is associated with defects in mitochondrial function. Mitochondrial-based disturbances in calcium homeostasis, reactive oxygen species (ROS) generation, and amyloid metabolism have been implicated in the pathophysiology of sporadic AD. The cellular consequences of mitochondrial dysfunction, however, are not known. To examine these consequences, mitochondrially transformed cells (cybrids) were created from AD patients or disease-free controls. Mitochondria from platelets were fused to rho0 cells created by depleting the human neuroblastoma line SH-SY5Y of its mitochondrial DNA (mtDNA). AD cybrids demonstrated a 52% decrease in electron transport chain (ETC) complex IV activity but no difference in complex I activity compared with control cybrids or SH-SY5Y cells. This mitochondrial dysfunction suggests a transferable mtDNA defect associated with AD. ROS generation was elevated in the AD cybrids. AD cybrids also displayed an increased basal cytosolic calcium concentration and enhanced sensitivity to inositol-1,4, 5-triphosphate (InsP3)-mediated release. Furthermore, they recovered more slowly from an elevation in cytosolic calcium induced by the InsP3 agonist carbachol. Mitochondrial calcium buffering plays a major role after this type of perturbation. beta-amyloid (25-35) peptide delayed the initiation of calcium recovery to a carbachol challenge and slowed the recovery rate. Nerve growth factor reduced the carbachol-induced maximum and moderated the recovery kinetics. Succinate increased ETC activity and partially restored the AD cybrid recovery rate. These subtle alterations in calcium homeostasis and ROS generation might lead to increased susceptibility to cell death under circumstances not ordinarily toxic.
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PMID:Calcium homeostasis and reactive oxygen species production in cells transformed by mitochondria from individuals with sporadic Alzheimer's disease. 916 22

Tributyltin (TBT) salts are potent skin irritants both in humans and rodents. Data in the literature indicate mitochondria as target of TBT effects. Here, we investigate the early intracellular molecular events that follow TBT treatment and the relevance of calcium ions and mitochondria in gene-regulatory signaling pathways. Confluent HEL30 cells were treated with increasing doses of TBT (0-5 microM). At different times thereafter, the level of intracellular Ca2+, the cellular oxidative activity, nuclear factor-kappaB (NF-kappaB) activation, and IL-1alpha production were measured. TBT induced a dose-related increase of intracellular Ca2+ that reached the plateau 4 min following treatment. The increase of intracellular Ca2+ was followed by an increase in cellular oxidative activity as measured by DCFH oxidation (15 min) that preceded NF-kappaB activation (30 min) and IL-1alpha production (4 hr). All these events can be almost completely abrogated by BAPTA, an intracellular Ca2+ chelator. Furthermore, the modulation of cellular oxidative activity induced by TBT observed with rotenone, an inhibitor of the electron entry from complex I to ubiquinone, or after prolonged treatment with ethidium bromide, an inhibitor of mitochondrial DNA and RNA synthesis, indicates mitochondria as an important intracellular source of reactive oxygen species. These findings indicate the rise in intracellular Ca2+ as the starting event and indicate the role of mitochondria as the source of second messenger molecules essential for TBT-induced NF-kappaB activation and IL-1alpha production.
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PMID:Role of mitochondria and calcium ions in tributyltin-induced gene regulatory pathways. 922 26

Peroxynitrite anion, the reaction product of superoxide and nitric oxide, is a potent biological oxidant, which inactivates mammalian heart mitochondrial NADH-coenzyme Q reductase (complex I), succinate dehydrogenase (complex II), and ATPase, without affecting cytochrome c oxidase (complex IV). In this paper, we evaluated the effect of peroxynitrite on mitochondrial membrane integrity and permeability under low calcium concentration. Phosphate buffer was used in most of our experiments since Hepes, Tris, mannitol, and sucrose were found to inhibit the oxidative chemistry of peroxynitrite. Peroxynitrite (0.1-1.0 mM) caused a dose-dependent decrease in the ability of mitochondria to build up a membrane potential when N,N,N',N'-tetramethyl-p-phenylenediamine/ascorbate were used as substrate. Elimination of the membrane potential was accompanied by penetration of the osmotic support (KCl/NaCl) into the matrix as judged by the parallel occurrence of mitochondrial swelling. This swelling was partially inhibited by dithiothreitol (DTT) or butylated hydroxytoluene (BHT) and was insensitive to ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid, ADP, and cyclosporin A. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of solubilized membrane proteins indicated that alterations in membrane permeability were associated with the production of protein aggregates due to membrane protein thiol cross-linking. The protective effect of DTT on both mitochondrial swelling and protein polymerization suggests the involvement of disulfide bonds in the membrane permeabilization process. In addition, the increase in thiobarbituric acid-reactive substances and the partial inhibitory effect of BHT indicate the occurrence of lipid peroxidation. These results support the idea that under our experimental conditions peroxynitrite causes mitochondrial structural and functional alterations by Ca2+-independent mechanisms through lipid peroxidation and protein sulfhydryl oxidation.
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PMID:Ca2+-independent permeabilization of the inner mitochondrial membrane by peroxynitrite is mediated by membrane protein thiol cross-linking and lipid peroxidation. 930 96

Excitotoxicity, mitochondrial dysfunction and free radical induced oxidative damage have been implicated in the pathogenesis of several different neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease. Much of the interest in the association of neurodegeneration with mitochondrial dysfunction and oxidative damage emerged from animal studies using mitochondrial toxins. Within mitochondria 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), acts to inhibit NADH-coenzyme Q reductase (complex I) of the electron transport chain. MPTP produces Parkinsonism in humans, primates, and mice. Similarly, lesions produced by the reversible inhibitor of succinate dehydrogenase (complex II), malonate, and the irreversible inhibitor, 3-nitropropionic acid (3-NP), closely resemble the histologic, neurochemical and clinical features of HD in both rats and non-human primates. The interruption of oxidative phosphorylation results in decreased levels of ATP. A consequence is partial neuronal depolarization and secondary activation of voltage-dependent NMDA receptors, which may result in excitotoxic neuronal cell death (secondary excitotoxicity). The increase in intracellular Ca2+ concentration leads to an activation of Ca2+ dependent enzymes, including the constitutive neuronal nitric oxide synthase (cnNOS) which produces NO.. NO. may react with the superoxide anion to from peroxynitrite. We show that systemic administration of 7-nitroindazole (7-NI), a relatively specific inhibitor of cnNOS in vivo. attenuates lesions produced by striatal malonate injections or systemic treatment with 3-NP or MPTP. Furthermore 7-NI attenuated increases in lactate production and hydroxyl radical and 3-nitrotyrosine generation in vivo, which may be a consequence of peroxynitrite formation. Our results suggest that neuronal nitric oxide synthase inhibitors may be useful in the treatment of neurologic diseases in which excitotoxic mechanisms play a role.
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PMID:The role of mitochondrial dysfunction and neuronal nitric oxide in animal models of neurodegenerative diseases. 930 87


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