Computational modeling analysis of mitochondrial superoxide production under varying substrate conditions and upon inhibition of different segments of the electron transport chain.

A computational mechanistic model of superoxide (O2•-) formation in the mitochondrial electron transport chain (ETC) was developed to facilitate the quantitative analysis of factors controlling mitochondrial O2•- production and assist in the interpretation of experimental studies. The model takes into account all individual electron transfer reactions in Complexes I and III. The model accounts for multiple, often seemingly contradictory observations on the effects of ΔΨ and ΔpH, and for the effects of multiple substrate and inhibitor conditions, including differential effects of Complex III inhibitors antimycin A, myxothiazol and stigmatellin. Simulation results confirm that, in addition to O2•- formation in Complex III and at the flavin site of Complex I, the quinone binding site of Complex I is an additional superoxide generating site that accounts for experimental observations on O2•- production during reverse electron transfer. However, our simulation results predict that, when cytochrome c oxidase is inhibited during oxidation of succinate, ROS production at this site is eliminated and almost all superoxide in Complex I is generated by reduced FMN, even when the redox pressure for reverse electron transfer from succinate is strong. In addition, the model indicates that conflicting literature data on the kinetics of electron transfer in Complex III involving the iron-sulfur protein-cytochrome bL complex can be resolved in favor of a dissociation of the protein only after electron transfer to cytochrome bH. The model predictions can be helpful in understanding factors driving mitochondrial superoxide formation in intact cells and tissues

Phenomenological Description of a Giant Temperature Hysteresis of the Ultrasound Velocity and the Internal Friction in Lanthanum Manganite

We propose an explanation for the experimentally observed [JETP Lett. 74, 115 (2001)] giant temperature hysteresis of the ultrasound velocity and the internal friction in single crystals of lanthanum manganite (La0.8Sr0.2MnO3). The effect is interpreted within the framework of a phenomenological model based on the notion of two coexisting sublattices of the oxygen octahedra performing cooperative tilting-rotational oscillations in bistable potential fields.Comment: 4 pages, 4 figure

Computational Modeling Analysis of Generation of Reactive Oxygen Species by Mitochondrial Assembled and Disintegrated Complex II.

Reactive oxygen species (ROS) function as critical mediators in a broad range of cellular signaling processes. The mitochondrial electron transport chain is one of the major contributors to ROS formation in most cells. Increasing evidence indicates that the respiratory Complex II (CII) can be the predominant ROS generator under certain conditions. A computational, mechanistic model of electron transfer and ROS formation in CII was developed in the present study to facilitate quantitative analysis of mitochondrial ROS production. The model was calibrated by fitting the computer simulated results to experimental data obtained on submitochondrial particles (SMP) prepared from bovine and rat heart mitochondria upon inhibition of the ubiquinone (Q)-binding site by atpenin A5 (AA5) and Complex III by myxothiazol, respectively. The model predicts that only reduced flavin adenine dinucleotide (FADH2) in the unoccupied dicarboxylate state and flavin semiquinone radical (FADH•) feature the experimentally observed bell-shaped dependence of the rate of ROS production on the succinate concentration upon inhibition of respiratory Complex III (CIII) or Q-binding site of CII, i.e., suppression of succinate-Q reductase (SQR) activity. The other redox centers of CII such as Fe-S clusters and Q-binding site have a hyperbolic dependence of ROS formation on the succinate concentration with very small maximal rate under any condition and cannot be considered as substantial ROS generators in CII. Computer simulation results show that CII disintegration (which results in dissociation of the hydrophilic SDHA/SDHB subunits from the inner membrane to the mitochondrial matrix) causes crucial changes in the kinetics of ROS production by CII that are qualitatively and quantitatively close to changes in the kinetics of ROS production by assembled CII upon inhibition of CIII or Q-binding site of CII. Thus, the main conclusions from the present computational modeling study are the following: (i) the impairment of the SQR activity of CII resulting from inhibition of CIII or Q-binding site of CII and (ii) CII disintegration causes a transition in the succinate-dependence of ROS production from a small-amplitude sigmoid (hyperbolic) shape, determined by Q-binding site or [3Fe-4S] cluster to a high-amplitude bell-shaped kinetics with a shift to small subsaturated concentrations of succinate, determined by the flavin site. © Copyright © 2020 Markevich, Markevich and Hoek

Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades

Mitogen-activated protein kinase (MAPK) cascades can operate as bistable switches residing in either of two different stable states. MAPK cascades are often embedded in positive feedback loops, which are considered to be a prerequisite for bistable behavior. Here we demonstrate that in the absence of any imposed feedback regulation, bistability and hysteresis can arise solely from a distributive kinetic mechanism of the two-site MAPK phosphorylation and dephosphorylation. Importantly, the reported kinetic properties of the kinase (MEK) and phosphatase (MKP3) of extracellular signal–regulated kinase (ERK) fulfill the essential requirements for generating a bistable switch at a single MAPK cascade level. Likewise, a cycle where multisite phosphorylations are performed by different kinases, but dephosphorylation reactions are catalyzed by the same phosphatase, can also exhibit bistability and hysteresis. Hence, bistability induced by multisite covalent modification may be a widespread mechanism of the control of protein activity

Some features of reproduction and egg development of <i>Stichaeus grigorjewi</i> from Peter the Great Bay

Reproduction of long shanny Stichaeus grigorjewi is observed in natural conditions and its eggs embryogenesis is investigated in details in aquarium. The embryos and larvae of S. grigorjewi differ from other species by strong development of midbrain that assumes good eyesight forming. Duration of egg development and morphology of embryos and larvae coincide with earlier description made in Hokkaido, Japan, except of body ventral row of 10 melanophores described for S. grigorjewi larvae for the first time. The embryogenesis accelerates sharply under heightened water temperature

Termination Reaction in the Anionic Polymerization of Methacrylonitrile

The anionic polymerization of methacrylonitrile initiated by triethylphosphine in dimethylformamide was studied. Experimental evidence for two mechanisms of termination reaction was obtained. By addition of water or alcohol in polymerizing system the rate of polymerization and molecular weight of polymethacrylon1itrile decrease, which proves the termination reaction to be bimolecular and proceed by interaction of the active carbanion with water or alcohol. The rate constant for termination of free anions with water was determined, k~,0 = 2.2 x 102 dm3 moP s-1• The termination reaction could not be excluded by purification and prolonged drying of all components of the system, which indicates that the second mechanism of termination is operative as well. Conductivity measurements gave evidence for a monomolecular spontaneous reaction leading to deactivation of the anion