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Depolarization of In Situ Mitochondria Due to Hydrogen Peroxide-Induced Oxidative Stress in Nerve Terminals 总被引:8,自引:0,他引:8
Mitochondrial membrane potential (delta psi(m)) was determined in intact isolated nerve terminals using the membrane potential-sensitive probe JC-1. Oxidative stress induced by H2O2 (0.1-1 mM) caused only a minor decrease in delta psi(m). When complex I of the respiratory chain was inhibited by rotenone (2 microM), delta psi(m) was unaltered, but on subsequent addition of H2O2, delta psi(m) started to decrease and collapsed during incubation with 0.5 mM H2O2 for 12 min. The ATP level and [ATP]/[ADP] ratio were greatly reduced in the simultaneous presence of rotenone and H2O2. H2O2 also induced a marked reduction in delta psi(m) when added after oligomycin (10 microM), an inhibitor of F0F1-ATPase. H2O2 (0.1 or 0.5 mM) inhibited alpha-ketoglutarate dehydrogenase and decreased the steady-state NAD(P)H level in nerve terminals. It is concluded that there are at least two factors that determine delta psi(m) in the presence of H2O2: (a) The NADH level reduced owing to inhibition of alpha-ketoglutarate dehydrogenase is insufficient to ensure an optimal rate of respiration, which is reflected in a fall of delta psi(m) when the F0F1-ATPase is not functional. (b) The greatly reduced ATP level in the presence of rotenone and H2O2 prevents maintenance of delta psi(m) by F0F1-ATPase. The results indicate that to maintain delta psi(m) in the nerve terminal during H2O2-induced oxidative stress, both complex I and F0F1-ATPase must be functional. Collapse of delta psi(m) could be a critical event in neuronal injury in ischemia or Parkinson's disease when H2O2 is generated in excess and complex I of the respiratory chain is simultaneously impaired. 相似文献
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Gy. Szabados A. Andó L. Tretter I. Horváth 《Journal of bioenergetics and biomembranes》1987,19(1):21-30
Lipid peroxidation in isolated rat liver mitochondria, mitoplast, and mitochondrial inner membrane fragments was induced either by ferrous ions, or in an NADPH-dependent process by complexing with adenine nucleotides (ADP or ATP) iron. The Fe2+-induced lipid peroxidation is nonenzymic when inner membrane fragments are used, while the differences in the inhibitory effect of Mn2+ ions and the stimulatory effect of the ionophore A-23187 in mitochondria and inner membrane fragments suggest an enzymic mechanism for ferrous ion-induced lipid peroxidation in intact mitochondria. Contrary to this the ADP/Fe/NADPH-dependent lipid peroxidation is an enzymic process both in mitochondria and inner membrane preparations. We have shown that cytochrome P450 is involved in the ADP/Fe/NADPH-induced lipid peroxidation. Succinate, a known inhibitor of NADPH-dependent lipid peroxidation, inhibited the Fe2+-induced process also, and there was no difference in this effect when inner membrane preparations, mitochondria, or mitoplasts were used. 相似文献
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Release of H(2)O(2) in response to Ca(2+) loads (1-100 microM) was investigated using Amplex red fluorescent assay in isolated guinea-pig brain mitochondria respiring on glutamate plus malate or succinate. In mitochondria challenged with Ca(2+) (10 microM), in the absence of adenine nucleotides and inhibitors of the respiratory chain, the rate of H(2)O(2) release, taken as an indication of H(2)O(2) production, was decreased by 21.8+/-1.6% in the presence of NADH-linked substrates and by 86.5+/-1.8% with succinate. Parallel with this, a Ca(2+)-induced loss in NAD(P)H fluorescence, sustained depolarization, decrease in fluorescent light scattering signal and in calcein fluorescence were detected indicating an increased permeability and swelling of mitochondria, which were prevented by ADP (2 mM). In the presence of ADP H(2)O(2) release from mitochondria was decreased, but Ca(2+) no longer influenced the generation of H(2)O(2). We suggest that the decreased H(2)O(2) generation induced by Ca(2+) is related to depolarization and NAD(P)H loss resulting from a non-specific permeability increase of the mitochondrial inner membrane. 相似文献
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Nicholas?H?CarbonettiEmail author R?Michael?Mays Galina?V?Artamonova Roger?D?Plaut Zo??EV?Worthington 《BMC microbiology》2005,5(1):7
Background
Pertussis toxin (PT) is an exotoxin virulence factor produced by Bordetella pertussis, the causative agent of whooping cough. PT consists of an active subunit (S1) that ADP-ribosylates the alpha subunit of several mammalian G proteins, and a B oligomer (S2–S5) that binds glycoconjugate receptors on cells. PT appears to enter cells by endocytosis, and retrograde transport through the Golgi apparatus may be important for its cytotoxicity. A previous study demonstrated that proteolytic processing of S1 occurs after PT enters mammalian cells. We sought to determine whether this proteolytic processing of S1 is necessary for PT cytotoxicity. 相似文献56.
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Initiation of Neuronal Damage by Complex I Deficiency and Oxidative Stress in Parkinson's Disease 总被引:11,自引:0,他引:11
Oxidative stress and partial deficiencies of mitochondrial complex I appear to be key factors in the pathogenesis of Parkinson's disease. They are interconnected; complex I inhibition results in an enhanced production of reactive oxygen species (ROS), which in turn will inhibit complex I. Partial inhibition of complex I in nerve terminals is sufficient for in situ mitochondria to generate more ROS. H2O2 plays a major role in inhibiting complex I as well as a key metabolic enzyme, alpha-ketoglutarate dehydrogenase. The vicious cycle resulting from partial inhibition of complex I and/or an inherently higher ROS production in dopaminergic neurons leads over time to excessive oxidative stress and ATP deficit that eventually will result in cell death in the nigro-striatal pathway. 相似文献
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Induction of activin A is essential for the neuroprotective action of basic fibroblast growth factor in vivo 总被引:14,自引:0,他引:14
Tretter YP Hertel M Munz B ten Bruggencate G Werner S Alzheimer C 《Nature medicine》2000,6(7):812-815
Exogenous application of neurotrophic growth factors has emerged as a new and particularly promising approach not only to promote functional recovery after acute brain injury but also to protect neurons against the immediate effect of the injury. Among the various growth factors and cytokines studied so far, the neuroprotective and neurotrophic profile of basic fibroblast growth factor (bFGF) is the best documented. Using an animal model of acute excitotoxic brain injury, we report here that the neuroprotective action of bFGF, which is now being tested in stroke patients, depends on the induction of activin A, a member of the transforming growth factor-beta superfamily. Our evidence for this previously unknown mechanism of action of bFGF is that bFGF strongly enhanced lesion-associated induction of activin A; in the presence of the activin-neutralizing protein follistatin, bFGF was no longer capable of rescuing neurons from excitotoxic death; and recombinant activin A exerted a neuroprotective effect by itself. Our data indicate that the development of substances influencing activin expression or receptor binding should offer new ways to fight neuronal loss in ischemic and traumatic brain injury. 相似文献
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Babak Moradi Philipp Schnatzer Sébastien Hagmann Nils Rosshirt Tobias Gotterbarm Jan Philippe Kretzer Marc Thomsen Hanns-Martin Lorenz Felix Zeifang Theresa Tretter 《Arthritis research & therapy》2014,16(2):R97