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Studies with four benzoquinones, viz. juglone, embelin, maesaquinone and maesanin, on rat liver mitochondria oxidative phosphorylation have been carried out. Three of the benzoquinones are uncouplers in the order juglone greater than maesoquinone greater than embelin, while maesanin is an inhibitor of electron transport and oxidative phosphorylation.
In order to ascertain whether oxidative phosphorylation in plant mitochondria is sensitive to light, coupled durum wheat (Triticum durum Desf.) mitochondria were irradiated with a low power continuous wave Helium-Neon laser (fluence: 2 Joules/cm2), with measurements made of certain processes related to ATP production. As a result of irradiation, an increase in the rate of ATP synthesis was found, as continuously monitored via luciferine/luciferase, moreover the mitochondrial ATP and ADP endogenous contents were found to increase and decrease, respectively with a 1:1 stoichiometry, as revealed by HPLC measurements. Consistently, an increase in mitochondrial rate of delta psi generation was found as measured by using the fluorescent probe safranine. Thus, this paper gives a first evidence of a novel property of plant mitochondria: the direct light sensitivity of ATP synthesis via oxidative phosphorylation.
An 18-month-old girl with an oxidative phosphorylation defect had neonatal onset of chronic lactic acidosis, lipid storage myopathy, bilateral cataracts, and primary adrenal insufficiency. Chronic lactic acidosis responded to treatment with dichloroacetate. Sequential muscle biopsies demonstrated resolution of the lipid storage myopathy associated with the return to normal muscle free carnitine levels. This case demonstrates a new clinical phenotype associated with a defect in oxidative phosphorylation and the need to consider mitochondrial disorders in the differential diagnosis of primary adrenal insufficiency in childhood.
Electron transfer and oxidative phosphorylation were studied as affected by tinalkyls. It is shown that all of them inhibit effectively respiration of the rat liver mitochondria. The action of bis(tributyl tin)oxide and dibutyl diisooctyl thioglycolate tin on the mitochondria in a state of dissociation is localized in the terminal step of the respiration chain. The other alkyls act in the site located before cytocrome c. The effect of bis (tributyl tin) oxide on both the ADP-activated respiration and DNP-activated ATPase of intact mitochondria is similar to that of oligomycin. These effects might be explained by the presence two electrophilic centres in a molecule of this compound.
1. Progressive alterations in oxidative phosphorylation of liver mitochondria were followed for 14 d in growing chickens fed on either semi-purified low (7%) or high (61%) protein-energy diet. Hepatic mitochondrial oxidative phosphorylation rates were assessed polarographically with pyruvate + malate as substrates. 2. The ADP:O values were reduced significantly 4 d after the feeding of a high-protein-energy diet, when compared with those in chickens fed on a low-protein-energy diet, whereas the state 3 oxidation rates in chickens fed on a high-protein-energy diet from day 6 to 14 were significantly lower than those in low-protein-fed chickens. 3. No changes in sensitivity of mitochondrial ATPase activity to oligomycin, expressed as % of total ATPase activity, were observed among chickens fed for 21 d on diets with various protein concentrations though the FoF1-ATPase activity, expressed per mg protein, tended to decrease in chickens fed on high-protein-energy diet. 4. These results suggest that the reduced ADP:O values for liver mitochondria in the high-protein-fed chickens may not be involved in the degrees of integrity of the FoF1-ATPase.
The oxygen dependence of mitochondrial oxidative phosphorylation measured in isolated cells of cardiac and non-cardiac origin are affected by the metabolic state of the cells. The contribution of oxygen diffusion to the measured P50 value in resting cells is small. In cardiac myocytes, and possibly in the other cells as well, this contribution may become significant near maximal levels of respiration. The influence of cellular energy metabolism on the oxygen dependence of respiration in cardiac myocytes suggests strongly that mitochondrial oxidative phosphorylation in these cells is an oxygen sensor for adjusting coronary vascular tone during normal cardiac function.
Life of higher organisms is essentially dependent on the efficient synthesis of ATP by oxidative phosphorylation in mitochondria. An important and as yet unsolved question of energy metabolism is how are the variable rates of ATP synthesis at maximal work load during exercise or mental work and at rest or during sleep regulated. This article reviews our present knowledge on the structure of bacterial and eukaryotic cytochrome c oxidases and correlates it with recent results on the regulatory functions of nuclear-coded subunits of the eukaryotic enzyme, which are absent from the bacterial enzyme. A new molecular hypothesis on the physiological regulation of oxidative phosphorylation is proposed, assuming a hormonally controlled dynamic equilibrium in vivo between two states of energy metabolism, a relaxed state with low ROS (reactive oxygen species) formation, and an excited state with elevated formation of ROS, which are known to accelerate aging and to cause degenerative diseases and cancer. The hypothesis is based on the allosteric ATP inhibition of cytochrome c oxidase at high intramitochondrial ATP/ADP ratios ("second mechanism of respiratory control"), which is switched on by cAMP-dependent phosphorylation and switched off by calcium-induced dephosphorylation of the enzyme.
The dynamics of primary aliphatic amines (ethylamine, propylamine) effects on the processes of oxidative phosphorylation in rat liver mitochondria was estimated. The inhibiting action of ethylamine and propylamine on the oxidative phosphorylation processes in the rat liver mitochondria was revealed.
The ADP:O values in both cardiac and hepatic mitochondria have significantly decreased with an increase in protein level after 7, 14 and 21 d of feeding (Toyomizu et al. 1992). The present studies were undertaken to clarify tissue-specific effects of dietary protein levels on oxidative phosphorylation in the liver, kidney, skeletal muscles and small intestine and to characterize oxidative metabolism with diverse substrates in the liver. Chicks were fed on semi-purified diets of different protein levels (7, 25, 43 and 61% of metabolizable energy content) for 21 d. The responses of protein levels to oxidative phosphorylation showed tissue-dependency; although liver mitochondria of chickens fed on higher-protein diets exhibited reduced ADP:O values and state 3, neither changes in ADP:O value nor state 3 and state 4 rates were observed in the isolated mitochondria from kidney and skeletal muscles. Small intestinal mucosal mitochondria from chickens fed on a high (61%)-protein-energy diet showed significantly reduced ADP:O value and respiratory control ratio when compared with medium-protein-energy diets (25 and 43%). In liver mitochondria showing the most sensitive dependency to the levels of dietary protein, the ADP:O value decreased with increasing protein levels when pyruvate+malate- or glutamate-requiring complexes I, III and IV of the electron transport chain were used as substrates, but it did not change when succinate-requiring complexes II, III and IV or ascorbate+tetramethyl-p-phenylenediamine requiring complex IV was used. These results imply that impaired oxidative phosphorylation capacities with increasing dietary protein levels may be associated with functional damage to the respiratory chain for electron flow from NAD-linked substrates to the ubiquinone pool.
Secondary deterioration of mitochondrial function has been reported in patients with anorexia and cancer-related malnutrition. Inadequate nutrition, failure to thrive and feeding problems are also common symptoms in children with primary oxidative phosphorylation defects. As a standard intervention protocol we advise an age-appropriate diet and energy intake in our patients diagnosed with a mitochondrial dysfunction. By comparing the results of the first and the second samples from a group of children who underwent repeated muscle biopsies, we observed biochemical improvement in the mitochondrial function in 7 out of 10 patients following dietary advice and intervention. We suggest evaluating the nutritional state by interpretation of the skeletal muscle biochemistry in patients with a suspected oxidative phosphorylation defect. Since an insufficient dietary intake could play a role in secondary mitochondrial dysfunction, nutritional intervention should be performed prior to the biopsy. On the other hand, our data suggest that optimizing the nutritional and energy intake might also improve the utilization of the residual mitochondrial energy-generating capacity in patients with primary oxidative phosphorylation defects.
Three lichen acids-namely, (+)usnic acid, vulpinic acid, and atranorin-were isolated from three lichen species (Usnea articulata, Letharia vulpina, and Parmelia tinctorum, respectively). The effects of these lichen products on mice-liver mitochondrial oxidative functions in various respiratory states and on oxidative phosphorylation were studied polarographically in vitro. The lichen acids exhibited characteristics of the 2,4-dinitrophenol (DNP), a classical uncoupler of oxidative phosphorylation. Thus, they released respiratory control and oligomycin inhibited respiration, hindered ATP synthesis, and enhanced Mg(+2)-ATPase activity. (+)Usnic acid at a concentration of 0.75 microM inhibited ADP/O ratio by 50%, caused maximal stimulation of both state-4 respiration (100%) and ATPase activity (300%). Atranorin was the only lichen acid with no significant effect on ATPase. The uncoupling effect was dose-dependent in all cases. The minimal concentrations required to cause complete uncoupling of oxidative phosphorylation were as follows: (+)usnic acid (1 microM), vulpinic acid, atranorin (5 microM) and DNP (50 microM). It was postulated that the three lichen acids induce uncoupling by acting on the inner mitochondrial membrane through their lipophilic properties and protonophoric activities.
The effect of accumulation of Ca2+ at physiological concentrations (10(-8)-10(-6) M) on the rates of ATP synthesis and hydrolysis in rat liver mitochondria was studied. An addition of 5 x 10(-7) M Ca2+ resulted in the maximal rates of synthesis and hydrolysis of ATP. Decrease in the concentration of Ca2+ to 10-8 M or its increase to 5 x 10(-6) M inhibited oxidative phosphorylation and ATP hydrolysis. It was found that the rate of oxidative phosphorylation correlated with the phosphorylation level of a 3.5-kD peptide in the mitochondrial inner membrane on varying the Ca2+ concentration. The possible regulation of oxidative phosphorylation in mitochondria by Ca2+ is discussed.
Changes in the capacity of mitochondria to carry out oxidative phosphorylation and in the rate of synthesis and incorporation of phospholipids into mitochondria were measured during the germination of conidiospores of Neurospora crassa. The competence of isolated mitochondria to carry out coupled respiration was very low during the first 3 h growth, but it increased rapidly, reaching maximal levels at 5 to 6 h growth. Changes in mitochondrial function were the same in cells grown in 2% sucrose- or 15% glucose-supplemented medium. The rate of synthesis of mitochondrial phospholipids was very low during the first 2 h growth and increased to maximal levels between 3 and 5 h. The rate of synthesis of mitochondrial phospholipids was approximately three times higher in cells grown in 15% glucose than in those grown in 2% sucrose. The maximal rate of synthesis of mitochondrial phospholipids occurred during spore germination and preceded attainment of full competence for oxidative phosphorylation. The lipid-rich condition of the mitochondrial resulting from the high rate of synthesis of phospholipids in glucose-grown cells is postulated to be related to the whorled inclusions observed in thin sections of Neurospora cells.
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Uncouplers of oxidative phosphorylation increased the speed of substrate oxidation and ATP hydrolysis and raised cAMP induced neuron membrane current. Different inhibitors decreased it. Both effects support the hypothesis that a signal of intracellular injected cAMP spreads to the neuron membrane as a mechanical signal. This signal propagated to the membrane along microtubules which according to this hypothesis serve as a sound generator with metabolic heat pumping.
The pH dependence of the binding of weakly acidic uncouplers of oxidative phosphorylation to rat-liver mitochondria and liposomes is mainly determined by the pKa of the uncoupler molecule. The absorption and fluorescene excitation spectra of the anionic form of weakly acidic uncouplers of oxidative phosphorylation are red-shifted upon interaction with liposomal or mitochondrial membranes. The affinity for the liposomes, as deduced from the red shift, is independent of the degree of saturation of the fatty acid chains of different lecithins. The intensity of the spectra at one pH value is strongly dependent upon the surface charge of the liposomes. With positively charged liposomes the results obtained can be almost quantitatively explained with the Gouy-Chapman theory, but with negatively charged ones deviations are observed. At a particular pH, the divalent ion Ca-2+ stongly influences the intensity of the spectra in the presence of negatively charged liposomes, but has no effect with neutral liposomes. With mitochondrial membranes an effect of Ca-2+ similar to that with negatively charged liposomes is observed. Depletion of the phospholipids of the mitochondria and subsequent restoration of the mitochrondrial membrane with lecithin, strongly diminishes this effect, but restoration with negatively charged phospholipids does not influence it. From these observations it is concluded that the anionic form of the uncoupler molecule when bound to mitochondria is located within the partly negatively charged phospholiped moiety of the membrane, with its anionic group pointing to the aqueous solution.
The effect of the concentration of extramitochondrial adenine nucleotides on oxidative phosphorylation was studied in isolated rat liver mitochondria. Mitochondria were incubated with succinate and hexokinase or creatine kinase at constant or varying extramitochondrial adenine nucleotide concentrations ranging over 0.3-5 mM. As parameters of oxidative phosphorylation, rate of respiration, membrane potential as well as intra- and extra-mitochondrial adenine nucleotide concentrations were determined. Below a threshold concentration of extramitochondrial adenine nucleotides of 2 mM, the free Gibb's energy for the adenine nucleotide transport increased but the extramitochondrial ATP/ADP ratio decreased at intermediate rates of respiration with decreasing extramitochondrial adenine nucleotide concentrations. In this range the rate of respiration was dependent on the extramitochondrial ADP concentration. No effect of the extramitochondrial adenine nucleotide concentration on the relationships between the rate of respiration and the membrane potential, the intramitochondrial adenine nucleotide pool and the intramitochondrial ATP/ADP ratio was found. This suggests that the decline of extramitochondrial ATP due to adenine nucleotide degradation and the limitation of adenine nucleotide transport may be of importance in the postischemic phase as nucleotide resynthesis and reorganization of physiological ion distribution are ATP consuming processes.
The oxidative phosphorylation and the activity of polyenzymatic systems in the rat liver mitochondrial membranes were studied upon a 5 day administration to rats of butylcaptax in the dose of 1/10 LD50. It is established that butylcaptax led to significant disturbances in the system of oxidative phosphorylation and in the transfer of electrons in the rat liver mitochondrial respiratory chain.