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PubMed2005

Sleep disturbances in the rotenone animal model of Parkinson disease.

Parkinson disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) and the presence of intracytoplasmatic inclusions known as Lewy bodies. Chronic administration of rotenone (RT) produces Parkinson's-like symptoms in rats. Because PD patients have disrupted sleep patterns, we determined if chronic RT administration produces similar changes in rat sleep. RT was administered for 28 days to rats. Basal and vehicle (VH) rats received saline or dimethyl sulfoxide and polyethylene glycol (1:1), respectively. VH infusion induced a progressive decrease in non-rapid eye movement sleep (NREMS) during the 4-week period of VH infusion and REMS was reduced in the third and fourth week of VH infusion. VH infusion did not induce dopaminergic cell degeneration. Rats receiving RT infusion also showed decreased NREMS during the treatment. REMS was dramatically reduced on day 7 although subsequently on days 13 and 20 REMS was similar to basal values. After 4 weeks of RT infusion, time in REMS was decreased again. In RT-treated rats, progressive dopaminergic cell degeneration occurred in the SNc. After 4 weeks of daily injections of L-dopa in RT-infused rats, NREMS values remained similar to those values obtained after RT alone. L-dopa therapy did, however, induce a recovery of REMS in weeks 3 and 4 of RT infusion. Dopaminergic cell damage persisted in the L-dopa-RT-infused rats. We conclude that the RT-PD rat model is associated with large long-term sleep disruption, however, the vehicle, DMSO/PEG had as large an effect as RT on sleep, thus changes in sleep cannot be ascribed to loss of dopaminergic cells. Such results question the validity of the RT-PD rat model.

Animals↗
PubMed1998

Rotenone-insensitive internal NADH-quinone oxidoreductase of Saccharomyces cerevisiae mitochondria: the enzyme expressed in Escherichia coli acts as a member of the respiratory chain in the host cells.

The NDI1 gene encodes the internal rotenone-insensitive NADH-quinone oxidoreductase localized in the inner mitochondrial membranes of Saccharomyces cerevisiae. The T7 tag-fused mature NDI1 was overexpressed in Escherichia coli. The overexpressed NDI1 was exclusively found in the membrane fraction. The NDI1-overexpressed membranes showed significantly increased activities of NADH oxidase and NADH-ubiquinone-1 (UQ1) reductase when compared with the control membranes. Flavone, which is a specific inhibitor of the S. cerevisiae NDI1, inhibited almost completely NADH oxidase and NADH-UQ1 reductase activities of NDI1-overexpressed membranes but scarcely inhibited these activities of the control membranes. In addition, the NADH oxidase activity of the NDI1-overexpressed membranes was also inhibited by KCN as well as the control membranes. These results indicate that the overexpressed NDI1 worked as a member of the respiratory chain in the host cells, even though E. coli membranes are different from S. cerevisiae inner mitochondrial membranes in terms of quinones and lipid composition.

Cloning, Molecular↗
PubMed1999

Rotenone and pyruvate prevent the tert-butylhydroperoxide-induced necrosis of U937 cells and allow them to proliferate.

Exposure of U937 cells to tert-butylhydroperoxide (tB-OOH) led to cyclosporin A-sensitive mitochondrial membrane permeability transition and necrosis. Pyruvate and rotenone, which increase mitochondrial NADH via different mechanisms, prevented these responses and the cells which received these treatments proliferated with kinetics similar to those observed in untreated cells. In contrast with these results, cells rescued by cyclosporin A were unable to proliferate. Thus, mitochondrial NADH plays a pivotal role in preventing upstream events which result in the onset of mitochondrial membrane permeability transition and death in cells exposed to tB-OOH. These events appear to be critical for recovery of the ability of the cells to proliferate.

Apoptosis↗
PubMed2003

Alpha-synuclein expression in HEK293 cells enhances the mitochondrial sensitivity to rotenone.

Mitochondrial dysfunction has been implicated in the aetiology of sporadic Parkinson's disease but its role in the disease mechanism is not clear. We have investigated the short term effect of G209A mutant or wild-type alpha-synuclein expression upon mitochondrial function using stable inducible cell models. Mitochondrial respiratory chain activities and membrane potential were normal suggesting that increased wild-type or mutant alpha-synuclein expression did not directly affect these parameters. However, both wild-type and mutant G209A alpha-synuclein expression enhanced the fall in mitochondrial membrane potential induced by the complex I inhibitor rotenone. This suggests an indirect interaction between alpha-synuclein expression and mitochondrial function which could render the mitochondria more vulnerable to inhibition by potential endogenous or exogenous factors found in dopaminergic neurones.

Cell Line↗
PubMed2003

The rotenone model of Parkinson's disease: genes, environment and mitochondria.

Parkinson's disease (PD) is occasionally caused by single gene mutations or by single toxic exposures, but most cases of PD are probably caused by some combination of genetic susceptibility and environmental exposure. Using rotenone as a prototype for an environmental toxicant, we argue here that genetic and environmental causes of PD converge on common pathogenic mechanisms. If so, protective strategies devised for one type of PD may be broadly useful for other forms of the disease.

Environmental Exposure↗
PubMed2006

Identification of rotenone-induced modifications in alpha-synuclein using affinity pull-down and tandem mass spectrometry.

Parkinson's disease is a movement disorder that results from a loss of dopaminergic neurons in the substantia nigra. The disease is characterized by mitochondrial dysfunction, oxidative stress, and the presence of "Lewy body" inclusions enriched with aggregated forms of alpha-synuclein, a presynaptic protein. Although alpha-synuclein is modified at various sites in Lewy bodies, it is unclear how sequence-specific posttranslational modifications modulate the aggregation of the protein in oxidatively stressed neurons. To begin to address this problem, we developed an affinity pull-down/mass spectrometry method to characterize the primary structure of histidine-tagged alpha-synuclein isolated from catecholaminergic neurons. Using this method, we mapped posttranslational modifications of alpha-synuclein from untreated neurons and neurons exposed to rotenone, an inhibitor of mitochondrial complex I. Various posttranslational modifications suggestive of oxidative damage or repair were identified in a region comprising a 20-residue stretch in the C-terminal part of the protein. The results indicate that alpha-synuclein is subject to discrete posttranslational modifications in neurons with impaired mitochondrial function. Our affinity pull-down/mass spectrometry method is a useful tool to examine how specific modifications of alpha-synuclein contribute to neurologic disorders such as Parkinson's disease.

Amino Acid Sequence↗
PubMed2006

Rotenone-like action of the branched-chain phytanic acid induces oxidative stress in mitochondria.

Phytanic acid (Phyt) increase is associated with the hereditary neurodegenerative Refsum disease. To elucidate the still unclear toxicity of Phyt, mitochondria from brain and heart of adult rats were exposed to free Phyt. Phyt at low micromolar concentrations (maximally: 100 nmol/mg of protein) enhances superoxide (O(2)(.))(2) generation. Phyt induces O(2)(.) in state 3 (phosphorylating), as well as in state 4 (resting). Phyt stimulates O(2)(.) generation when the respiratory chain is fed with electrons derived from oxidation of glutamate/malate, pyruvate/malate, or succinate in the presence of rotenone. With succinate alone, Phyt suppresses O(2)(.) generation caused by reverse electron transport from succinate to complex I. The enhanced O(2)(.) generation by Phyt in state 4 is in contrast to the mild uncoupling concept. In this concept uncoupling by nonesterified fatty acids should abolish O(2)(.) generation. Stimulation of O(2)(.) generation by Phyt is paralleled by inhibition of the electron transport within the respiratory chain or electron leakage from the respiratory chain. The interference of Phyt with the electron transport was demonstrated by inhibition of state 3- and p-trifluoromethoxyphenylhydrazone (FCCP)-dependent respiration, inactivation of the NADH-ubiquinone oxidoreductase complex in permeabilized mitochondria, decrease in reduction of the synthetic electron acceptor 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide in state 4, and increase of the mitochondrial NAD(P)H level in FCCP-uncoupled mitochondria. Thus, we suggest that complex I is the main site of Phyt-stimulated O(2)(.) generation. Furthermore, inactivation of aconitase and oxidation of the mitochondrial glutathione pool show that enhanced O(2)(.) generation with chronic exposure to Phyt causes oxidative damage.

Aconitate Hydratase↗
PubMed2005

The results of five coded compounds: genistein, metaproterenol, rotenone, p-anisidine and resorcinol tested in the pH 6.7 Syrian hamster embryo cell morphological transformation assay.

The pH 6.7 Syrian hamster embryo (SHE) cell morphological transformation assay is a short-term in vitro test that has been used to predict rodent carcinogenicity. Previous reports have indicated that the SHE assay has an overall concordance of approximately 80% with the 2 year rodent bioassay. We selected five compounds, genistein, metaproterenol, rotenone, p-anisidine and resorcinol, that had extensive genotoxicity and carcinogenicity data and tested them in the standard 7 day exposure SHE assay. Somewhat surprisingly, the SHE assay misclassified the actual rodent carcinogenicity of four out of the five test compounds. It is difficult to explain these findings as the actual mechanisms of SHE cell morphological transformation are currently unknown. However, it is obvious that in these studies there was no simple correlation between in vitro genotoxicity, morphological transformation in SHE cells and rodent carcinogenicity. Clearly, further research is required to accurately assess the role of the SHE assay in the carcinogenic risk assessment of new chemical entities.

Aniline Compounds↗
PubMed2003

Two caspase-mediated apoptotic pathways induced by rotenone toxicity in cortical neuronal cells.

Our results presented here suggest that cortical neurons degenerate via two caspase-mediated apoptotic pathways when challenged with 0.5 microM rotenone. Although these two pathways can be attributed to the loss of mitochondrial integrity, the triggers for these pathways are likely due to two separate subsequent events (the release of cytochrome c and the emergence of mitochondrial permeability transition [MPT]). Despite some reports suggesting that the release of cytochrome c is a consequence of MPT, the results of our time course experiments suggest otherwise. In fact, we observed that the release of cytochrome c occurred much earlier than MPT; hence, the former is unlikely to be a consequence of the latter. In addition, we observed that the presence of an MPT inhibitor did not attenuate the activation of caspase-3, and that caspase-1-mediated cell death did not exhibit nuclear condensation and DNA fragmentation. Taken together, these results suggest that there are two routes by which cortical neurons degenerate during ischemic injury or in neurodegenerative diseases.

Animals↗
PubMed2003

Rotenone alpha-oxime.

The structure determination of the title compound, rotenone alpha-oxime [systematic name: 1,2,12,12a-tetrahydro-8,9-dimethoxy-2-(1-methylethenyl)-[1]benzopyrano[3,4-b]furo[2,3-h][1]benzopyran-6(6H)-one oxime], C(23)H(23)NO(6), confirms that the molecule has an approximately V-shaped structure. One of the rings has a typical cyclohexene-like monoplanar conformation and the central ring adopts a 1,2-diplanar conformation.

Crystallography, X-Ray↗
PubMed1988

Purification and characterization of a rotenone-insensitive NADH:Q6 oxidoreductase from mitochondria of Saccharomyces cerevisiae.

A mitochondrial NADH:Q6 oxidoreductase has been isolated from cells of Saccharomyces cerevisiae by a simple method involving extraction of the enzyme from the mitochondrial membrane with Triton X-100, followed by chromatography on DEAE-cellulose and blue Sepharose CL-6B. By this procedure a 2000-fold purification is achieved with respect to whole cells or a 150-fold purification with respect to the mitochondrion. The purified NADH dehydrogenase consists of a single subunit with molecular mass of 53 kDa as indicated by SDS/polyacrylamide gel electrophoresis. The enzyme contains FAD, non-covalently linked, as the sole prosthetic group with Em,7.6 = -370 mV and no iron-sulphur clusters. The enzyme is specific for NADH with apparent Km = 31 microM and was found to be inhibited by flavone (I50 = 95 microM), but not by rotenone or piericidin. The purified enzyme can use ubiquinone-2, -6 or -10, menaquinone, dichloroindophenol or ferricyanide as electron acceptors, but at different rates. The greatest turnover of NADH was obtained with ubiquinone-2 as acceptor (2500 s-1). With the natural ubiquinone-6 this value was 500 s-1. The NADH:Q2 oxidoreductase activity shows a maximum at pH 6.2, the NADH:Q6 oxidoreductase activity is constant between pH 4.5-9.0. The amount of enzyme in the cell is subject to glucose repression; it increases slightly when cells, grown on glucose or lactate, enter the stationary phase. The experiments performed so far suggest that the enzyme purified in this study is the external NADH:Q6 oxidoreductase, bound to the mitochondrial inner membrane and that it is involved in the oxidation of cytosolic NADH. The relation of this enzyme with respect to various other NADH dehydrogenases from yeast and plant mitochondria is discussed.

Centrifugation, Density Gradient↗
PubMed1991

Isolation and inactivation of the nuclear gene encoding the rotenone-insensitive internal NADH: ubiquinone oxidoreductase of mitochondria from Saccharomyces cerevisiae.

We have recently described the isolation of a mitochondrial rotenone-insensitive NADH:ubiquinone oxidoreductase from Saccharomyces cerevisiae [de Vries, S. & Grivell, L. A. (1988) Eur. J. Biochem. 176, 377-384]. We now report the isolation of the nuclear gene encoding this single-subunit enzyme. Null mutants have been constructed by means of one-step gene disruption. Oxygen-uptake experiments, performed with mitochondria isolated from the mutant cells, showed that this NADH dehydrogenase catalyzes the oxidation of NADH generated inside the mitochondrion. Inactivation of this NADH dehydrogenase does not affect growth on glucose and ethanol, but growth on lactate, pyruvate and acetate is impaired or absent. This phenotype is discussed in terms of the interplay between different metabolic pathways in yeast.

Amino Acid Sequence↗
PubMed1992

Primary structure and import pathway of the rotenone-insensitive NADH-ubiquinone oxidoreductase of mitochondria from Saccharomyces cerevisiae.

The gene encoding the yeast mitochondrial rotenone-insensitive internal NADH: ubiquinone-6 oxidoreductase has been sequenced. The DNA sequence indicates the presence of an open reading frame of 1539 bp predicted to encode a protein of 513 amino acid residues (57.2 kDa). The NADH dehydrogenase is synthesized as a precursor protein containing a signal sequence of 26 residues. In vitro import experiments show that the precursor NADH dehydrogenase is cleaved to the mature size by the matrix processing peptidase. Both cleavage and translocation across the mitochondrial membrane(s) are dependent on the membrane potential component of the proton-motive force. Comparison of the protein sequence of the yeast NADH dehydrogenase with the data bank indicates that the enzyme from yeast is homologous to the NADH dehydrogenase of Escherichia coli (22.2% identical residues). Both NADH dehydrogenases contain in the central part of the protein a sequence predicted to fold into a beta alpha beta structure involved in the binding of NADH or FAD(H2). Various aspects of the protein structure are discussed.

Amino Acid Sequence↗
PubMed2005

Rotenone-induced caspase 9/3-independent and -dependent cell death in undifferentiated and differentiated human neural stem cells.

We used human neural stem cells (hNSCs) and their differentiated cultures as a model system to evaluate the mechanism(s) involved in rotenone (RO)- and camptothecin (CA)-induced cytotoxicity. Results from ultrastructural damage and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining indicated that RO-induced cytotoxicity resembled CA-induced apoptosis more than H(2)O(2)-induced necrosis. However, unlike CA-induced, caspase 9/3-dependent apoptosis, there was no increased activity in caspase 9, caspase 3 or poly (ADP-ribose) polymerase (PARP) cleavage in RO-induced cytotoxicity, in spite of time-dependent release of cytochrome c and apoptosis-inducing factor (AIF) following mitochondrial membrane depolarization and a significant increase in reactive oxygen species generation. Equal doses of RO and CA used in hNSCs induced caspase 9/3-dependent apoptosis in differentiated cultures. Time-dependent ATP depletion occurred earlier and to a greater extent in RO-treated hNSCs than in CA-treated hNSCs, or differentiated cultures treated with RO or CA. In conclusion, these results represent a unique ultrastructural and molecular characterization of RO- and CA-induced cytotoxicity in hNSCs and their differentiated cultures. Intracellular ATP levels may play an important role in determining whether neural progenitors or their differentiated cells follow a caspase 9/3-dependent or -independent pathway in response to acute insults from neuronal toxicants.

Adenosine Triphosphate↗
PubMed2006

Susceptibility to rotenone is increased in neurons from parkin null mice and is reduced by minocycline.

Parkinson's disease is a neurodegenerative disorder which is in most cases of unknown etiology. Mutations of the Park-2 gene are the most frequent cause of familial parkinsonism and parkin knockout (PK-KO) mice have abnormalities that resemble the clinical syndrome. We investigated the interaction of genetic and environmental factors, treating midbrain neuronal cultures from PK-KO and wild-type (WT) mice with rotenone (ROT). ROT (0.025-0.1 microm) produced a dose-dependent selective reduction of tyrosine hydroxylase-immunoreactive cells and of other neurons, as shown by the immunoreactivity to microtubule-associated protein 2 in PK-KO cultures, suggesting that the toxic effect of ROT involved dopamine and other types of neurons. Neuronal death was mainly apoptotic and suppressible by the caspase inhibitor t-butoxycarbonyl-Asp(OMe)-fluoromethyl ketone (Boc-D-FMK). PK-KO cultures were more susceptible to apoptosis induced by low doses of ROT than those from WT. ROT increased the proportion of astroglia and microglia more in PK-KO than in WT cultures. Indomethacin, a cyclo-oxygenase inhibitor, worsened the effects of ROT on tyrosine hydroxylase cells, apoptosis and astroglial (glial fibrillary acidic protein) cells. N-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase, increased ROT-induced apoptosis but did not change tyrosine hydroxylase-immunoreactive or glial fibrillary acidic protein area. Neither indomethacin nor N-nitro-L-arginine methyl ester had any effect on the reduction by ROT of the mitochondrial potential as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. Microglial NADPH oxidase inhibition, however, protected against ROT. The roles of p38 MAPK and extracellular signal-regulated kinase signaling pathways were tested by treatment with SB20358 and PD98059, respectively. These compounds were inactive in ROT-naive cultures but PD98059 slightly increased cellular necrosis, as measured by lactate dehydrogenase levels, caused by ROT, without changing mitochondrial activity. SB20358 increased the mitochondrial failure and lactate dehydrogenase elevation induced by ROT. Minocycline, an inhibitor of microglia, prevented the dropout of tyrosine hydroxylase and apoptosis by ROT; the addition of microglia from PK-KO to WT neuronal cultures increased the sensitivity of dopaminergic neurons to ROT. PK-KO mice were more susceptible than WT to ROT and the combined effects of Park-2 suppression and ROT reproduced the cellular events observed in Parkinson's disease. These events were prevented by minocycline.

Animals↗
PubMed1984

Inhibition of myocardial rotenone-insensitive NADH cytochrome c reductase by amphiphilic compounds.

Because myocardial ischemia is correlated with both an elevation of intracellular levels of amphiphilic lipid metabolites and a decrease in the rotenone-insensitive NADH cytochrome c reductase (RINCR), we investigated the effects in vitro of some amphiphilic lipid metabolites and synthetic detergents on the activity of RINCR-enriched subfractions of microsomes from isolated cardiac myocytes. RINCR activity was unaffected in vitro by the addition of lysophosphatidylethanolamine (up to 0.5 mM) but was inhibited (maximum 63%) by lysophosphatidylcholine (8 microM). Palmitoyl carnitine (up to 2 mM) was ineffective, but the coenzyme A thioesters of palmitate, stearate, oleate, and arachidonate were inhibitory at concentrations (less than 3 microM) below their critical micellar concentrations. Arachidonyl CoA was approximately one order of magnitude more inhibitory than the other long-chain acyl CoA thioesters. Kinetic analyses revealed the effect of arachidonyl CoA on RINCR activity to be exclusively an alteration of the Vmax with no change in the Km for cytochrome c. The inhibition of myocytic RINCR activity by long-chain acyl CoA may be unrelated to the bulk-phase detergency of this lipid amphiphile since the effects were observed at concentrations below the critical micellar concentration, and other lipid amphiphiles had no effect on RINCR activity. Inhibition of microsomal RINCR activity may result from localized disruption of the membrane microenvironment of the enzyme complex by penetration or dissolution of long-chain acyl CoA into the membrane. The pronounced sensitivity of myocytic RINCR activity to long-chain acyl CoA suggests a relationship between the decreased RINCR activity and the increased levels of this class of lipid metabolites observed in the ischemic myocardium.

Acyl Coenzyme A↗
PubMed1977

The inhibitory effect of papaverine on respiration-dependent contracture of guinea pig taenia coli in high-K medium. III. The differential effect of papaverine and rotenone on DT diaphorase.

The differential effects of papaverine (Pap) and rotenone (Rot) were studied on the highly respiration-dependent contracture of guinea pig taenia coli in 40 mM potassium (40-K) medium, on isolated DT diaphorase activity and on mitochondrial respiration. The inhibition of guinea pig taenia coli to the 40-K induced tension by Rot (5 x 10(-7)M) was fully reversed by the addition of a water soluble vitamin K3 (VK3) derivative or menadione sodium bisulfite (MSB). A low concentration (10(-7)--10(-6)M) of Pap which had no effect on the 40-K induced tension inhibited the VK3 restored tension from the Rot suppression, corresponding to a Pap inhibition of the isolated DT diaphorase. Inhibition of the effective concentration of Pap to the 40-K induced tension development was never reversed by addition of VK3 or MSB. In taenia coli, both MSB and VK3 established a bypass of the Rot sensitive site on the mitochondrial respiratory chain by means of the DT diaphorase system. The difference in washout-efficacy between Pap and Rot on the inhibition of 40-K induced tension was ascribed to a difference in their mitochondrial binding properties.

Animals↗
PubMed1993

Mitosis of rotenone-induced endoreduplication in Chinese hamster cells.

Endoreduplication was induced by rotenone with an extremely high frequency (approximately 90% of all the metaphases) in cultured Chinese hamster cells. Endoreduplicated cells were fixed without colchicine or hypotonic treatment, and chromosomal configurations were examined in various mitotic stages. The two sister chromosomes of each diplochromosome at late prophase were widely separated except the centromeric region, but they became gradually paired along the total length as the cell cycle progressed to metaphase. The anaphase cells underwent multipolar division, resulting in three or four aneuploid daughter cells. Indirect immunofluorescence staining using anti-beta tubulin antibody revealed tripolar or tetrapolar spindles and unusual equatorial plates.

Animals↗