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When rat liver mitochondria are allowed to cycle Ca(2+) and are incubated in the presence of the pro-oxidant menadione, they undergo swelling, membrane potential (DeltaPsi) collapse, and ion release. These effects, which are inhibited by cyclosporin A (CsA), are fully consistent with the opening of the so-called permeability transition pore. However, when Ca(2+) cycling is abolished by EGTA, the mitochondria remain energized (DeltaPsi collapse and swelling are avoided), but Ca(2+) efflux, promoted by the chelating agent, is stimulated by menadione. This stimulation goes together with the release of Mg(2+), K(+), and adenine nucleotides (AdN) and is inhibited by bongkrekic acid (BKA). The effect of menadione is also characterized by biphasic NAD(P)H oxidation which becomes monophasic in the presence of BKA, CsA, or EGTA and by the oxidation of thiol groups not restrained by the above-mentioned inhibitors. These results suggest that BKA acts indirectly by preserving in the matrix a critical amount of AdN without modifying the monophasic oxidation of pyridine nucleotides by menadione. A critical number of thiol groups also seems to be involved in the phenomenon. Their oxidation most probably causes a conformational change on adenine nucleotide translocase with the opening of the "low-conductance state" of the mitochondrial permeability transition, resulting in ion permeability without DeltaPsi disruption and mitochondrial swelling.
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PMID:Menadione induces a low conductance state of the mitochondrial inner membrane sensitive to bongkrekic acid. 1533 23

1. Herein we study the effects of the mitochondrial complex II inhibitor malonate on its primary target, the mitochondrion. 2. Malonate induces mitochondrial potential collapse, mitochondrial swelling, cytochrome c (Cyt c) release and depletes glutathione (GSH) and nicotinamide adenine dinucleotide coenzyme (NAD(P)H) stores in brain-isolated mitochondria. 3. Although, mitochondrial potential collapse was almost immediate after malonate addition, mitochondrial swelling was not evident before 15 min of drug presence. This latter effect was blocked by cyclosporin A (CSA), Ruthenium Red (RR), magnesium, catalase, GSH and vitamin E. 4. Malonate added to SH-SY5Y cell cultures produced a marked loss of cell viability together with the release of Cyt c and depletion of GSH and NAD(P)H concentrations. All these effects were not apparent in SH-SY5Y cells overexpressing Bcl-xL. 5. When GSH concentrations were lowered with buthionine sulphoximine, cytoprotection afforded by Bcl-xL overexpression was not evident anymore. 6. Taken together, all these data suggest that malonate causes a rapid mitochondrial potential collapse and reactive oxygen species production that overwhelms mitochondrial antioxidant capacity and leads to mitochondrial swelling. Further permeability transition pore opening and the subsequent release of proapoptotic factors such as Cyt c could therefore be, at least in part, responsible for malonate-induced toxicity.
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PMID:Malonate induces cell death via mitochondrial potential collapse and delayed swelling through an ROS-dependent pathway. 1565 18

In adherent and motile neutrophils NAD(P)H concentration, flavoprotein redox potential, and production of reactive oxygen species and nitric oxide, are all periodic and exhibit defined phase relationships to an underlying metabolic oscillation of approximately 20 s. Utilizing fluorescence microscopy, we have shown in real-time, on the single cell level, that the system is sensitive to externally applied periodically pulsed weak magnetic fields matched in frequency to the metabolic oscillation. Depending upon the phase relationship of the magnetic pulses to the metabolic oscillation, the magnetic pulses serve to either increase the amplitude of the NAD(P)H and flavoprotein oscillations, and the rate of production of reactive oxygen species and nitric oxide or, alternatively, collapse the metabolic oscillations and curtail production of reactive oxygen species and nitric oxide. Significantly, we demonstrate that the cells do not directly respond to the magnetic fields, but instead are sensitive to the electric fields which the pulsed magnetic fields induce. These weak electric fields likely tap into an endogenous signaling pathway involving calcium channels in the plasma membrane. We estimate that the threshold which induced electric fields must attain to influence cell metabolism is of the order of 10(-4) V/m.
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PMID:Real-time control of neutrophil metabolism by very weak ultra-low frequency pulsed magnetic fields. 1574 80

Methomyl and Helminthosporium maydis race T toxin block oxidative phosphorylation in mitochondria isolated from maize plants with Texas male sterile cytoplasm (T) but not in mitochondria isolated from those with Normal cytoplasm (N) (Bednarski, Izawa, Scheffer 1977 Plant Physiol 59: 540-545). Moreover, they have been reported to cause specific swelling in T mitochondria (Miller, Koeppe 1971 Science 173: 67-69; Koeppe, Cox, Malone 1978 Science 201: 1227-1229). We could not detect, by direct volume measurements, any change induced by these compounds in the mitochondrial matrix space. We show here that the proton motive force, which in maize mitochondria is composed of a large transmembrane potential and of a low transmembrane pH difference, is absent in T mitochondria incubated in the presence of methomyl or of Helminthosporium maydis race T toxin, while it is unchanged in N mitochondria. Methomyl and Helminthosporium maydis race T toxin induce, independently of the collapse of the proton motive force, a release of the cofactors NAD and coenzyme A from the mitochondrial matrix space. In particular, we show that NAD is transported in maize mitochondria, and that this transport, which is not dependent on the proton motive force, is inhibited by methomyl or Helminthosporium maydis race T toxin.
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PMID:Effects of Methomyl and Helminthosporium maydis Toxin on Matrix Volume, Proton Motive Force, and NAD Accumulation in Maize (Zea mays L.) Mitochondria. 1666 72

Poly(ADP-ribose)polymerase-1 (PARP-1) overactivation is a key event in neurodegeneration but the underlying molecular mechanisms wait to be unequivocally identified. Energy failure, transcriptional derangement and deadly nucleus-mitochondria cross-talk have been proposed as mechanisms responsible for PARP-1 neurotoxicity. In this study, we sought to determine how these mechanisms contributes to PARP-1-dependent neuronal death. We report that the PARP-1 activating agent methyl-nitrosoguanidine (MNNG) caused poly(ADP-ribosyl)ation-dependent death of pure mouse cortical neurons in culture. Upon PARP-1 hyperactivation, NAD and ATP storages only partially decreased, neurons rapidly acquired apoptotic morphology, apoptosis inducing factor and cytochrome c were released from mitochondria and caspase activation occurred. No evidence for p53 activation was found, lactate dehydrogenase release occurred only 18h later, and JNK kinase was constitutively activated and not affected by PARP-1 activation. The PARP-1 inhibitors 6-(5)H-phenanthridinone and N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide (PJ-34) prevented nucleotide depletion and cell death, whereas the transcription inhibitor actinomycin D did not affect PARP-1-dependent neurotoxicity. Together, our findings provide the first evidence that neither energy collapse nor transcriptional changes are involved in PARP-1-dependent apoptotic neuronal death, and support the existence of a poly(ADP-ribose)-mediated death signaling targeting mitochondria.
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PMID:Neither energy collapse nor transcription underlie in vitro neurotoxicity of poly(ADP-ribose) polymerase hyper-activation. 1705

Saccharopine dehydrogenase [N6-(glutaryl-2)-L-lysine:NAD oxidoreductase (L-lysine forming)] catalyzes the final step in the alpha-aminoadipate pathway for lysine biosynthesis. It catalyzes the reversible pyridine nucleotide-dependent oxidative deamination of saccharopine to generate alpha-Kg and lysine using NAD+ as an oxidizing agent. The proton shuttle chemical mechanism is proposed on the basis of the pH dependence of kinetic parameters, dissociation constants for competitive inhibitors, and isotope effects. In the direction of lysine formation, once NAD+ and saccharopine bind, a group with a pKa of 6.2 accepts a proton from the secondary amine of saccharopine as it is oxidized. This protonated general base then does not participate in the reaction again until lysine is formed at the completion of the reaction. A general base with a pKa of 7.2 accepts a proton from H2O as it attacks the Schiff base carbon of saccharopine to form the carbinolamine intermediate. The same residue then serves as a general acid and donates a proton to the carbinolamine nitrogen to give the protonated carbinolamine. Collapse of the carbinolamine is then facilitated by the same group accepting a proton from the carbinolamine hydroxyl to generate alpha-Kg and lysine. The amine nitrogen is then protonated by the group that originally accepted a proton from the secondary amine of saccharopine, and products are released. In the reverse reaction direction, finite primary deuterium kinetic isotope effects were observed for all parameters with the exception of V2/K(NADH), consistent with a steady-state random mechanism and indicative of a contribution from hydride transfer to rate limitation. The pH dependence, as determined from the primary isotope effect on DV2 and D(V2/K(Lys)), suggests that a step other than hydride transfer becomes rate-limiting as the pH is increased. This step is likely protonation/deprotonation of the carbinolamine nitrogen formed as an intermediate in imine hydrolysis. The observed solvent isotope effect indicates that proton transfer also contributes to rate limitation. A concerted proton and hydride transfer is suggested by multiple substrate/solvent isotope effects, as well as a proton transfer in another step, likely hydrolysis of the carbinolamine. In agreement, dome-shaped proton inventories are observed for V2 and V2/K(Lys), suggesting that proton transfer exists in at least two sequential transition states.
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PMID:A proposed proton shuttle mechanism for saccharopine dehydrogenase from Saccharomyces cerevisiae. 1722 9

We studied the mechanism of the cytotoxic activity of BZL101, an aqueous extract from the herb Scutellaria barbata D. Don, which is currently in phase II clinical trial in patients with advanced breast cancer. The phase I trial showed favorable toxicity profile and promising efficacy. We report here that BZL101 induces cell death in breast cancer cells but not in non-transformed mammary epithelial cells. This selective cytotoxicity is based on strong induction by BZL101 of reactive oxygen species (ROS) in tumor cells. As a consequence, BZL101 treated cancer cells develop extensive oxidative DNA damage and succumb to necrotic death. Data from the expression profiling of cells treated with BZL101 are strongly supportive of a death pathway that involves oxidative stress, DNA damage and activation of death-promoting genes. In breast cancer cells oxidative damage induced by BZL101 leads to the hyperactivation of poly (ADP-ribose) polymerase (PARP), followed by a sustained decrease in levels of NAD and depletion of ATP, neither of which are observed in non-transformed cells. The hyperactivation of PARP is instrumental in the necrotic death program induced by BZL101, because inhibition of PARP results in suppression of necrosis and activation of the apoptotic death program. BZL101 treatment leads to the inhibition of glycolysis selectively in tumor cells, evident from the decrease in the enzymatic activities within the glycolytic pathway and the inhibition of lactate production. Because tumor cells frequently rely on glycolysis for energy production, the observed inhibition of glycolysis is likely a key factor in the energetic collapse and necrotic death that occurs selectively in breast cancer cells. The promising selectivity of BZL101 towards cancer cells is based on metabolic differences between highly glycolytic tumor cells and normal cells.
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PMID:Molecular mechanisms underlying selective cytotoxic activity of BZL101, an extract of Scutellaria barbata, towards breast cancer cells. 1830 10

Cyclin-dependent kinases (Cdks) fulfill key functions in many cellular processes, including cell cycle progression and cytoskeletal dynamics. A limited number of Cdk substrates have been identified with few demonstrated to be regulated by Cdk-dependent phosphorylation. We identify on protein expression arrays novel cyclin E-Cdk2 substrates, including SIRT2, a member of the Sirtuin family of NAD(+)-dependent deacetylases that targets alpha-tubulin. We define Ser-331 as the site phosphorylated by cyclin E-Cdk2, cyclin A-Cdk2, and p35-Cdk5 both in vitro and in cells. Importantly, phosphorylation at Ser-331 inhibits the catalytic activity of SIRT2. Gain- and loss-of-function studies demonstrate that SIRT2 interfered with cell adhesion and cell migration. In postmitotic hippocampal neurons, neurite outgrowth and growth cone collapse are inhibited by SIRT2. The effects provoked by SIRT2, but not those of a nonphosphorylatable mutant, are antagonized by Cdk-dependent phosphorylation. Collectively, our findings identify a posttranslational mechanism that controls SIRT2 function, and they provide evidence for a novel regulatory circuitry involving Cdks, SIRT2, and microtubules.
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PMID:The regulation of SIRT2 function by cyclin-dependent kinases affects cell motility. 1833 17

Ebselen (Ebs) and diphenyl diselenide [(PhSe)(2)] readily oxidize thiol groups. Here we studied mitochondrial swelling changes in mitochondrial potential (Deltapsim), NAD(P)H oxidation, reactive oxygen species production, protein aggregate formation, and oxygen consumption as ending points of their in vitro toxicity. Specifically, we tested the hypothesis that organochalchogens toxicity could be associated with mitochondrial dysfunction via oxidation of vicinal thiol groups that are known to be involved in the regulation of mitochondrial permeability (Petronilli et al. J. Biol. Chem., 269; 16638; 1994). Furthermore, we investigated the possible mechanism(s) by which these organochalchogens could disrupt liver mitochondrial function. Ebs and (PhSe)(2) caused mitochondrial depolarization and swelling in a concentration-dependent manner. Furthermore, both organochalchogens caused rapid oxidation of the mitochondrial pyridine nucleotides (NAD(P)H) pool, likely reflecting the consequence and not the cause of increased mitochondrial permeability (Costantini, P., Chernyak, B. V., Petronilli, V., and Bernardi, P. (1996). Modulation of the mitochondrial permeability transition pore (PTP) by pyridine nucleotides and dithiol oxidation at two separate sites. J. Biol. Chem. 271, 6746-6751). The organochalchogens-induced mitochondrial dysfunction was prevented by the reducing agent dithiothreitol (DTT). Ebs- and (PhSe)(2)-induced mitochondrial depolarization and swelling were unchanged by ruthenium red (4microM), butylated hydroxytoluene (2.5microM), or cyclosporine A (1microM). N-ethylmaleimide enhanced the organochalchogens-induced mitochondrial depolarization, without affecting the magnitude of the swelling response. In contrast, iodoacetic acid did not modify the effects of Ebs or (PhSe)(2) on the mitochondria. Additionally, Ebs and (PhSe)(2) decreased the basal 2' 7' dichlorofluorescin diacetate (H(2)-DCFDA) oxidation and oxygen consumption rate in state 3 and increased it during the state 4 of oxidative phosphorylation and induced the formation of protein aggregates, which were prevented by DTT. However, DTT failed to reverse the formation of protein aggregates, when it was added after a preincubation of liver mitochondria with Ebs or (PhSe)(2). Similarly, DTT did not reverse the Ebs- or (PhSe)(2)-induced Deltapsim collapse or swelling, when it was added after a preincubation period of mitochondria with chalcogenides. These results show that Ebs and (PhSe)(2) can effectively induce mitochondrial dysfunction and suggest that effects of these compounds are associated with mitochondrial thiol groups oxidation. The inability of cyclosporine A to reverse the Ebs- and (PhSe)(2)-induced mitochondrial effects suggests that the redox-regulated mitochondrial permeability transition (MPT) pore was mechanistically regulated in a manner that is distinct from the classical MPT pore.
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PMID:Mitochondrial dysfunction induced by different organochalchogens is mediated by thiol oxidation and is not dependent of the classical mitochondrial permeability transition pore opening. 2057 86

Reversible zinc chelation via thiol groups of cysteines leading to modulation of activity in redox regulated proteins forms a basis for switching on-off of various biochemical processes. Silent information regulator 2 (Sir2), a NAD(+) dependent deacetylase, contains a non-catalytic zinc ion coordinated by thiol groups of cysteines. Using Plasmodium falciparum Sir2 (PfSir2), we have examined the effect of zinc removal on the structure and activity of this enzyme. Our studies show that the enzyme with high affinity for zinc exhibits partial collapse of structure upon removal of the metal ion. Zinc reconstitution of apo PfSir2 led to recovery of both structure and activity highlighting the reversibility of the process.
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PMID:Reversible binding of zinc in Plasmodium falciparum Sir2: structure and activity of the apoenzyme. 2060 Dec 20


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