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At least 325 records · Page 18Linked to original sources
PubMed2002

An in vitro model of Parkinson's disease: linking mitochondrial impairment to altered alpha-synuclein metabolism and oxidative damage.

Chronic systemic complex I inhibition caused by rotenone exposure induces features of Parkinson's disease (PD) in rats, including selective nigrostriatal dopaminergic degeneration and formation of ubiquitin- and alpha-synuclein-positive inclusions (Betarbet et al., 2000). To determine underlying mechanisms of rotenone-induced cell death, we developed a chronic in vitro model based on treating human neuroblastoma cells with 5 nm rotenone for 1-4 weeks. For up to 4 weeks, cells grown in the presence of rotenone had normal morphology and growth kinetics, but at this time point, approximately 5% of cells began to undergo apoptosis. Short-term rotenone treatment (1 week) elevated soluble alpha-synuclein protein levels without changing message levels, suggesting that alpha-synuclein degradation was retarded. Chronic rotenone exposure (4 weeks) increased levels of SDS-insoluble alpha-synuclein and ubiquitin. After a latency of >2 weeks, rotenone-treated cells showed evidence of oxidative stress, including loss of glutathione and increased oxidative DNA and protein damage. Chronic rotenone treatment (4 weeks) caused a slight elevation in basal apoptosis and markedly sensitized cells to further oxidative challenge. In response to H2O2, there was cytochrome c release from mitochondria, caspase-3 activation, and apoptosis, all of which occurred earlier and to a much greater extent in rotenone-treated cells; caspase inhibition provided substantial protection. These studies indicate that chronic low-grade complex I inhibition caused by rotenone exposure induces accumulation and aggregation of alpha-synuclein and ubiquitin, progressive oxidative damage, and caspase-dependent death, mechanisms that may be central to PD pathogenesis.

Animals↗
PubMed1982

Activation of site I redox-driven H+ pump by exogenous quinones in intact mitochondria.

The site I redox-driven H+ pump has been activated by the addition of exogenous quinones to antimycin A-KCN-inhibited mitochondria. The rate of quinone reduction and the degree of rotenone sensitivity increase in the order, duroquinone less than ubiquinone0 less than ubiquinone1. Apparent Km, Vmax, and degree of sigmoidicity during e- transfer in the absence and presence of rotenone have been determined for each quinone. The data support the view that the NADH dehydrogenase possesses two redox sites, one accounting for the rotenone-sensitive reduction and another accounting for the rotenone-insensitive reduction. The degree of activation of the redox H+ pump, which reflects the rotenone-sensitive e- transfer, depends, for each quinone, on the relative Km, Vmax, and sigmoidicity of the rotenone-sensitive and insensitive processes. The redox H+ pump activation is highest with ubiquinone1, where the rotenone-sensitive reaction has a lower Km than that of the rotenone-insensitive reaction, and lowest with duroquinone where the rotenone-insensitive reaction has a high Vmax and no sigmoidicity with respect to that of the rotenone-sensitive reaction. Using ubiquinone1 the stoichiometry of the site I redox-driven H+ pump has been determined on either the flow or the force ratios. The flow ratios approached values of 4 H+/2 e- under conditions close to stationary state for H+ pumping and to zero for H+ electrochemical gradient. The force ratio also approached values close to 4 H+/2 e- under static head conditions.

Adenosine Triphosphatases↗
PubMed2004

Distinct mechanisms of neurodegeneration induced by chronic complex I inhibition in dopaminergic and non-dopaminergic cells.

Chronic mitochondrial dysfunction, in particular of complex I, has been strongly implicated in the dopaminergic neurodegeneration in Parkinson's disease. To elucidate the mechanisms of chronic complex I disruption-induced neurodegeneration, we induced differentiation of immortalized midbrain dopaminergic (MN9D) and non-dopaminergic (MN9X) neuronal cells, to maintain them in culture without significant cell proliferation and compared their survivals following chronic exposure to nanomolar rotenone, an irreversible complex I inhibitor. Rotenone killed more dopaminergic MN9D cells than non-dopaminergic MN9X cells. Oxidative stress played an important role in rotenone-induced neurodegeneration of MN9X cells, but not MN9D cells: rotenone oxidatively modified proteins more in MN9X cells than in MN9D cells and antioxidants decreased rotenone toxicity only in MN9X cells. MN9X cells were also more sensitive to exogenous oxidants than MN9D cells. In contrast, disruption of bioenergetics played a more important role in MN9D cells: rotenone decreased mitochondrial membrane protential and ATP levels in MN9D cells more than in MN9X cells. Supplementation of cellular energy with a ketone body, D-beta-hydroxybutyrate, decreased rotenone toxicity in MN9D cells, but not in MN9X cells. MN9D cells were also more susceptible to disruption of oxidative phosphorylation or glycolysis than MN9X cells. These findings indicate that, during chronic rotenone exposure, MN9D cells die primarily through mitochondrial energy disruption, whereas MN9X cells die primarily via oxidative stress. Thus, intrinsic properties of individual cell types play important roles in determining the predominant mechanism of complex I inhibition-induced neurodegeneration.

Animals↗
PubMed1982

Properties of mitochondria as a function of the growth stages of Neurospora crassa.

The oxidative and phosphorylative properties of mitochondria isolated from Neurospora crassa were investigated as a function of growth stage. The rates of oxidation of exogenous NADH and NADPH varied independently of each other, thus ruling out the existence of only one unspecific dehydrogenase. Two different pathways were involved in the oxidation of NAD-linked substrates, as indicated by changes in the rate of oxygen uptake, the sensitivity to rotenone, and the efficiency of phosphorylation. One pathway was sensitive to rotenone and involved three energy-coupling sites, whereas the other was resistant to rotenone and bypassed complex I. Our results indicated that the activity of complex I of the respiratory chain increased markedly in the late exponential phase of growth, remained high in the stationary phase, and then decreased when conidiae were formed. In contrast, the activity of the rotenone-resistant bypass was maximal in the early exponential phase. With malate (plus glutamate) as a substrate, the sensitivity to rotenone and the ADP/O ratios were always lower than those observed with other NAD-linked substrates, suggesting a possible cooperation between malate dehydrogenase and the rotenone-resistant pathway. The rate of oxygen uptake measured in the presence of rotenone was significantly increased by the addition of exogenous NAD+, suggesting that added NAD+ could interact with the rotenone-resistant bypass.

Kinetics↗