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V V Lemeshko

Publications and source records attributed to V V Lemeshko.

At least 19 recordsLinked to original sources
PubMed2003

The voltage-dependent anion channel as a biological transistor: theoretical considerations.

The voltage-dependent anion channel (VDAC) is a porin of the mitochondrial outer membrane with a bell-shaped permeability-voltage characteristic. This porin restricts the flow of negatively charged metabolites at certain non-zero voltages, and thus might regulate their flux across the mitochondrial outer membrane. Here, we have developed a mathematical model illustrating the possibility of interaction between two steady-state fluxes of negatively charged metabolites circulating across the VDAC in a membrane. The fluxes interact by contributing to generation of the membrane electrical potential with subsequent closure of the VDAC. The model predicts that the VDAC might function as a single-molecule biological transistor and amplifier, because according to the obtained calculations a small change in the flux of one pair of different negatively charged metabolites causes a significant modulation of a more powerful flux of another pair of negatively charged metabolites circulating across the same membrane with the VDAC. Such transistor-like behavior of the VDAC in the mitochondrial outer membrane might be an important principle of the cell energy metabolism regulation under some physiological conditions.

Animals↗
PubMed2001

Failure of exogenous NADH and cytochrome c to support energy-dependent swelling of mitochondria.

The possibility of direct oxidation of external NADH in rat liver mitochondria and of the inner membrane potential generation in this process is still not clear. In the present work, the energy-dependent swelling of mitochondria in the medium containing valinomycin and potassium acetate was measured as one of the main criteria of the proton-motive force generation by complex III, complex IV, and both complexes III and IV of the respiratory chain. Mitochondria swelling induced by external NADH oxidation was compared with that induced by succinate or ferrocyanide oxidation, or by electron transport from succinate to ferricyanide. Mitochondria swelling, nearly equal to that promoted by ferrocyanide oxidation, was observed under external NADH oxidation, but only after the outer mitochondrial membrane was ruptured as a result of the swelling-contraction cycle, caused by succinate oxidation and its subsequent inhibition. In this case, significantly accelerated intermembrane electron transport and well-detected inner membrane potential generation, in addition to mitochondria swelling, were also observed. Presented results suggest that exogenous NADH and cytochrome c do not support the inner membrane potential generation in intact rat liver mitochondria, because the external NADH-cytochrome c reductase system, oriented in the outer mitochondrial membrane toward the cytoplasm, is inaccessible for endogenous cytochrome c reduction; as well, the inner membrane cytochrome c oxidase is inaccessible for exogenous cytochrome c oxidation.

Animals↗
PubMed2000

Mg(2+) induces intermembrane electron transport by cytochrome c desorption in mitochondria with the ruptured outer membrane.

The mechanism of external NADH oxidation in rat liver mitochondria is not clear yet, but it evidently includes the intermembrane electron transport (IMET). We showed that Mg(2+) significantly stimulated IMET insensitive to rotenone-antimycin A-myxothiazol in mitochondria with the hypotonically damaged outer membrane, even in the absence of exogenous cytochrome c. This effect was more specific than simply ionic strength increase. Direct evidence for cytochrome c desorption from mitochondrial membranes under 4 mM Mg(2+) influence was obtained to explain the stimulatory effect of Mg(2+) on external NADH oxidation that was coupled to the inner membrane potential generation. Obtained data suggest that cytochrome b(5) is normally oriented towards the cytosol in the outer membrane, and can be accessible for endogenous cytochrome c reduction only through the outer membrane rupture or permeabilization, to activate external NADH oxidation.

Animals↗
PubMed2000

Metabolically derived potential on the outer membrane of mitochondria: a computational model.

The outer mitochondrial membrane (OMM) is permeable to various small substances because of the presence of a voltage-dependent anion channel (VDAC). The voltage dependence of VDAC's permeability is puzzling, because the existence of membrane potential on the OMM has never been shown. We propose that steady-state metabolically derived potential (MDP) may be generated on the OMM as the result of the difference in its permeability restriction for various charged metabolites. To demonstrate the possibility of MDP generation, two models were considered: a liposomal model and a simplified cell model with a creatine kinase energy channeling system. Quantitative computational analysis of the simplified cell model shows that a MDP of up to -5 mV, in addition to the Donnan potential, may be generated at high workloads, even if the OMM is highly permeable to small inorganic ions, including potassium. Calculations show that MDP and DeltapH, generated on the OMM, depend on the cytoplasmic pH and energy demand rate. Computational modeling suggests that MDP may be important for cell energy metabolism regulation in multiple ways, including VDAC's permeability modulation and the effect of electrodynamic compartmentation. The osmotic pressure difference between the mitochondrial intermembrane space and the cytoplasm, as related to the electrodynamic compartmentation effects, might explain the morphological changes in mitochondria under intense workloads.

Animals↗
PubMed1993

Hypotonic fragility of outer membrane and activation of external pathway of NADH oxidation in rat liver mitochondria are increased with age.

Great importance is attached to structural and functional deterioration of mitochondria as a reason for ageing of an organism; the attention of many scientists has been concentrated on such questions as age changes in the system of oxidative phosphorylation, damage of mitochondrial DNA by free radicals generated in the respiratory chain and inclusion of some fragments of mitochondrial DNA into the nuclear genome. Mitochondrial high amplitude swelling in a cell under some extreme conditions can possibly play a very important role in mechanisms of deterioration of energy transformation function, in activation of lipid peroxidation and mitochondrial DNA damage as a result of outer membrane disruption and release of enzymes from the intermembrane space (e.g. superoxide dismutase amd adenylate kinase). In this work the age changes of the hypotonic fragility of the outer membrane of rat liver mitochondria and the activation of the external, rotenone-insensitive pathway of NADH oxidation have been examined. It is shown that the obligatory condition for activation of rotenone-insensitive NADH oxidation is a break in the outer membrane and that the rate of NADH oxidation substantially increases in the presence of physiological concentrations of Mg2+ which cause a multiple increase in the affinity of the inner membrane to cytochrome c. Research on the rate of rotenone-insensitive NADH oxidation with respect to the osmotic pressure, the ionic strength of the medium, the presence of Mg2+ ions and cytochrome c in the medium has demonstrated a considerable increase in the hypotonic fragility of the outer membrane of liver mitochondria with age in male rats. In female rats the age changes were insignificant. It is supposed that the damage to the outer membrane of mitochondria in cells can serve as one of the possible explanations of both decrease in the reliability of an aged organism under extreme conditions and sex differences of life-span.

Aging↗
PubMed1992

Decrease of phosphorylating oxidation and increase of heat producing NADH oxidation in rat liver mitochondria during life-span prolongation of rats by calorie-restricted diet.

The influence of calorie-restricted diet, initiated at weaning, on some of the oxidative processes in liver homogenates and isolated mitochondria of 2-, 3-, 4-, 24-, 35- and 45-month-old male Wistar rats was studied in comparison with control ad libitum-fed 1-2 day-old rats and 0.5-, 1-, 2-, 3-, 4- and 24-month-old rats. It was shown that a calorie-restricted diet (at 37% of the ad libitum calorific level) did not change the rate of succinate oxidation coupled with oxidative phosphorylation in homogenates, but resulted in a decrease of succinate, glutamate plus malate and beta-hydroxybutyrate oxidation and cytochrome c-oxidase activity in isolated mitochondria without any uncoupling of oxidative phosphorylation or change in cytochrome content in the mitochondria. On the other hand, a significant increase in mitochondrial rotenone-insensitive NADH oxidation and a higher liver mass/body mass ratio in rats under the calorie-restricted diet was established. It may be considered that the activation of a heat-producing mechanism is a very important physiological function in such a condition.

Aging↗
PubMed1991

[Age-related differences in the effect of osmotic pressure on liver mitochondrial respiration in rats].

The subject under investigation is the influence of osmotic pressure of incubation medium (25-500 mM of sucrose) upon the respiration and the respiration control (RC) of mitochondria of the liver of rats aged 1, 3, 12 and 24 months when oxidizing succinate. In a medium with 0.3 M of sucrose the respiration rate under condition 3 (V3) and RC increased from the age of 1 to 12 months and decreased by 24 months. In a medium with 0.15 M of sucrose the age differences have not been observed. In a uncoupling state the osmotic dependence of the respiration of mitochondria of 1- and 12-month-old rats did not vary. It is assumed that with age there is a change in the rate of structural coupling of the carrier of adenine nucleotides with H(+)-ATP synthetase complex and (or) the viscosity of the matrix.

Aging↗
PubMed1987

Ion permeability induction by the SH cross-linking reagents in rat liver mitochondria is inhibited by the free radical scavenger, butylhydroxytoluene.

The hydrophobic, potentially SH cross-linking reagent, phenylarsine oxide (PhAsO), was found to induce K+ and Ca2+ effluxes from mitochondria and to accelerate the respiration rate in state 4. The hydrophobic monofunctional electrophilic agent, N-ethylmaleimide, does not exhibit this effect but prevents the action of PhAsO. The polar potentially SH cross-linking regents (arsenite, diamide) induce ion fluxes only in the presence of Pi. Ion fluxes induced by the SH reagents are inhibited by butylhydroxytoluene (an inhibitor of free radical reactions), and N,N'-dicyclohexylcarbodiimide, not by oligomycin. It is inferred that the induction of ion fluxes in mitochondria caused by cross-linking of two juxtaposed SH groups is related to the development of free radical reactions.

Adenosine Triphosphatases↗
PubMed1987

[Damage to the Ca2+-transport function and the lipid component of the sarcoplasmic reticulum membrane in total ischemia of the rat myocardium].

The Ca2+-transporting activity, lipoperoxide chemiluminescence and phospholipid spectrum of sarcoplasmic reticular membranes were studied in ischemic rats. It was shown that a substantial reduction in Ca2+ uptake rate by the sarcoplasmic reticulum occurred within the first 30 minutes and correlated with the increase in chemiluminescence intensity and accumulation of lysophosphatidylcholine. It has been suggested that free radical lipid peroxidation and phospholipase activation are directly related to the reduction of Ca2+-transporting rate by sarcoplasmic reticulum in myocardial ischemia.

Animals↗
PubMed1985

[Enzymes utilizing hydroperoxides and O ./2 in the myocardium of rats of different ages].

Superoxide dismutase activity of myocardial cytosol increases with rat age (1, 3, 12, 24 months) whereas catalase activity is unchanged. Glutathione peroxidase activity with H2O2, cumene and t-butyl hydroperoxides as substrates increases more than 1.5-fold over the period from 1 to 12 months. The high activity of these enzymes is maintained in 24-month-old rats.

Aging↗
PubMed1982

[ATP-synthetase activity, respiration and cytochromes of rat heart mitochondria in aging and hyperthyroidism].

The ATP-synthetase activity, the rate of oxygen uptake under different metabolic conditions, the tightness of coupling of respiration to oxidative phosphorylation and the cytochrome contents in heart mitochondria of rats from different age groups were studied under normal conditions and in hyperthyroidism. It was found that heart mitochondria of aged animals did not practically differ in terms of their functional activity from those of the young animals. Administration of thyroxin to the animals from all age groups produced no significant effects on the state of mitochondria, increasing the rate of ATP synthesis on alpha-glycerophosphate, which was especially well-pronounced in aged animals, and the cytochrome content in 1-month-old rats.

ATP Synthetase Complexes↗
PubMed1982

[Effect of freezing-thawing rates on the functional state and ionic permeability of rat liver mitochondria].

The effects of various rats of freezing-thawing reactions on the functional state and ionic permeability of rat liver mitochondria were studied. The degree of mitochondrial damage during the freezing -- thawing process depended on the rate of thawing rather than on that of freezing. The mitochondria which were slowly or rapidly frozen down to --196 degrees and subsequently slowly thawed revealed a higher membrane permeability for K+ Na+ and H+ and a more than 2-fold increase of the ATPase activity and the maximal rate of NADH oxidation via the antimycin-insensitive pathway in the presence of cytochrome c. This was concomitant with a complete inhibition of the ATP-synthetase activity and a marked inhibition of the respiratory chain function due to the efflux of cytochrome c from the inner mitochondrial membrane. After freezing and rapid thawing the functional activity of mitochondria changed insignificantly. A comparison of different cryoeffects demonstrated that the minimal damaging effects were exerted by rapid freezing -- rapid thawing, when the mitochondria partly restored their ability for oxidative phosphorylation.

ATP Synthetase Complexes↗
PubMed1982

[Lipid peroxidation in rat liver mitochondria in aging and in hyperthyroidism].

The rate of lipid peroxidation (LPO) in rat liver mitochondria induced by the Fe++ + ascorbate system was considerably reduced in 1--12-month-old rats, remained unchanged thereafter up to the 24th postnatal month and was decreased in hyperthyroid rats aged 1- and 3 months. The rate of NADPH-dependent LPO was also sharply decreased up to the 12th month of age, showing a further rise in 24-month-old animals, i. e. thus remained lower than in 1- and 3-month-old rats; under hyperthyroidism the LPO rate was increased in more highly 12-month-old animals. A reverse correlation between the level of reducibility of matrix pyridine nucleotides and the rate of enzymatic LPO in mitochondria was established. A physiological role of LPO is postulated.

Aging↗
PubMed1981

[Lipid peroxidation in the postnuclear and microsomal fractions of rat liver homogenates upon aging].

The rate of lipid peroxidation in the postnuclear fraction of rat liver homogenate determined by malonic dialdehyde appearance decreases upon ageing. This is due to a decrease in the enzymatic lipid peroxidation in microsomes and to an increase in the NADPH-dependent (antioxidant) effect of the soluble fraction of rat liver cells. The latter effect is mediated by thiols and is presumably caused by the increase in the glutathione peroxidase activity upon ageing.

Animals↗