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PubMed1977

[Tissue specific uncoupler of mitochondrial oxidative phosphorylation].

The influence of endogenous uncoupling agent from the rat liver on oxidative phosphorylation of the liver, kidney, heart, lungs, and brain mitochondria was studied; the tissue-specificity of its action was demonstrated. The selective action of the uncoupler on the mitochondrial membrane is more obviously expressed within the range of pH 6.9--6.3 approaching such of the hepatocyte cytoplasm. The tissue-specificity was independent of the original state of mitochondria and could be eliminated only by heat injury of the oxidative phosphorylation. The activity of the tissue-specific uncoupling factor failed to diminish when the ribosomes and microsomes were removed by centrifugation. Addition of bovine albumin to the incubation medium had no influence of the value of the tissue-specific uncoupling. Participation of the uncoupler in the intratissue proliferation control is discussed.

Animals↗
PubMed1986

The efficiencies of the component steps of oxidative phosphorylation. I. A simple steady state theory.

Most earlier theoretical work on oxidative phosphorylation has emphasized the application of the formalism of nonequilibrium thermodynamics to the overall process. The resultant mathematical development and interpretation of some experimental data is complicated somewhat by the necessity of treating a system which is incompletely coupled (degree of coupling, q less than 1). Here a simple alternative approach is proposed which can be applied to many studies in the field. In this approach the overall process is broken up into sequential steps so that the product of the efficiencies of the steps is equal to the efficiency of the overall process. Steps of interest for which the degree of coupling may be quite close to unity can be "isolated" by this procedure. This approach results in a simple mathematical formalism emphasizing the power use (or energy use) at each step of the energy transduction process. The efficiencies of the steps of the process can be experimentally evaluated as is shown in the accompanying paper (B.D. Jensen, K. K. Gunter, and T. E. Gunter, 1986, Arch. Biochem. Biophys. 248, 305-323) where measurements are performed as dictated by the assumptions of the current theory. This alternative approach simplifies the analysis of changes induced in the process of oxidative phosphorylation as a result of agents added to the system or of changes in conditions. The locus (or loci) of such changes becomes rapidly apparent if the data is treated as suggested. Furthermore, the mathematical formalism lends itself both to the development of expressions and new experimental approaches which minimize the effects of a decrease in a value of q below unity and also to optimal statistical treatment of the data. As a concrete example of the use of this approach we reinvestigate the question of the equivalence of use of energy from the pH gradient and of the membrane potential in phosphorylation.

Adenosine Triphosphate↗
PubMed1998

Mitochondrial oxidative phosphorylation thermodynamic efficiencies reflect physiological organ roles.

Mitochondria cannot maximize energy production, efficiency, and the cellular ATP phosphorylation potential all at the same time. The theoretical and observed determinations of coupling of oxidative phosphorylation in mitochondria from rat liver, heart, and brain were compared using classical and nonequilibrium thermodynamic measures. Additionally, the optimal thermodynamic efficiency and flow ratios were determined for control of the two energy-converting complexes of the respiratory chain: complex I (NADH), which reflects the integrated cellular pathway, and complex II (FADH2), the predominantly tricarboxylic acid (TCA) cycle pathway. For all three organs, the cellular respiratory pathway was more tightly coupled than the TCA pathway and resulted in a greater optimal efficiency. Liver mitochondria are the most thermodynamically efficient at ATP production using oxidative phosphorylation. Heart and brain mitochondrial systems utilize more oxygen, but can produce ATP at a faster rate than liver systems. Per the theory of economic degrees of coupling, isolated rat liver mitochondrial systems are designed for the economic production of ATP for use in cellular processes. In the brain, the mitochondrial TCA cycle pathway promotes the maximal maintenance of the cellular energy state for cellular viability, whereas in the heart the TCA cycle pathway maximizes the production of ATP. The coupling of oxidative phosphorylation not only can be expected to change with substrate availability but may also reflect an ontogenetic response of mitochondria to fit specific organ roles in the rat.

Animals↗
PubMed1988

[Regulation of oxidative phosphorylation, K+ ions transport and the volume of mitochondrial matrix by cytoplasmic glycopeptide and Ca2+ ions].

A thermostable low molecular weight glycopeptide containing syalic acids, which uncouples mitochondrial oxidative phosphorylation, has been detected, isolated and purified from rat liver cytoplasm. In the presence of the glycopeptide, oxidative phosphorylation in rat liver mitochondria is uncoupled by low physiological concentrations of Ca2+, which otherwise do not have any appreciable effect on the mitochondria. Oxidative phosphorylation uncoupling by the glycopeptide is accompanied by an increase of the mitochondrial volume. This process has a limited amplitude and is regulated by changes in Ca2+ concentration in the extramitochondrial space. The glycopeptide has been shown to induce K+ transport across the inner mitochondrial membrane, this effect is enhanced by Ca2+.

Animals↗
PubMed2026

PPRC1 is a prognostic biomarker and key regulator of mitochondrial oxidative phosphorylation in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) remains an incurable haematological malignancy, underscoring the need for novel prognostic biomarkers and therapeutic targets. This study aimed to investigate the clinical and biological significance of peroxisome proliferator-activated receptor gamma coactivator-related protein 1 (PPRC1) in MM. METHODS: Expression and clinical data were obtained from public databases and an independent local cohort. Kaplan-Meier and Cox regression analyses were performed to evaluate prognostic value. Differential expression analysis, pathway enrichment analysis and single-cell RNA-seq data analysis were used to explore biological functions. PPRC1 was silenced in MM cell lines using siRNA to assess its effects on cell survival and oxidative phosphorylation. RESULTS: PPRC1 was significantly upregulated in MM and was associated with advanced disease stage and poor overall survival. Multivariate Cox analysis identified PPRC1 as an independent prognostic factor. A nomogram incorporating PPRC1 and revised-ISS improved survival prediction. Functional analyses revealed that PPRC1 was positively correlated with oxidative phosphorylation and oncogenic signalling pathways. A potential connection between PPRC1 expression and immune cell infiltration was observed. PPRC1 knockdown inhibited cell proliferation, induced cell cycle arrest and apoptosis and impaired oxidative phosphorylation in MM. CONCLUSIONS: PPRC1 acts as a prognostic biomarker and metabolic regulator in MM by sustaining mitochondrial oxidative phosphorylation. These findings highlight PPRC1 as a potential therapeutic target in MM.

Humans↗
PubMed1992

Substrate regulation of mitochondrial oxidative phosphorylation in hypercapnic rabbit muscle.

Endurance muscle performance is highly dependent on ATP production from mitochondrial oxidative phosphorylation. To study the role of the mitochondrial oxidative enzymes in muscle fatigue, we analyzed the relationship between the concentrations of substrates associated with ATP synthesis and the muscle performance of electrically stimulated rabbit muscle under CO2-induced acidosis. Two different conditions of pacing-induced muscle performance were produced in the gastrocnemius and soleus muscle groups in anesthetized rabbits by stimulating the sciatic nerve submaximally at two frequencies. Phosphorus nuclear magnetic resonance was used to measure ATP, phosphocreatine, and Pi and to provide data for a calculation of intracellular pH and free ADP. To induce acidosis, the animal was ventilated with 20% CO2. The administration of CO2 effectively reduced the intracellular pH from 6.9 to 6.7 and reduced the isometric tension-time integral (TTI) to below half the value measured in normocapnia at the low pacing frequency. A twofold increase in the pacing frequency resulted in a doubling of the TTI in normocapnia and a tripling of TTI in hypercapnia. The increases in TTI corresponded with increases in free ADP and Pi concentrations. Under the various conditions, all free ADP values were near the in vitro Michaelis-Menten constant (Km) of ADP. The Michaelis-Menten relationship of the oxidative phosphorylative enzymes was applied to the change in substrate concentrations with respect to TTI. From this relationship we observed that the in vivo Km of free ADP was 26 microM, which is close to the in nitro Km, and that Km and maximal reaction velocity did not change under hypercapnia and increased pacing frequency.(ABSTRACT TRUNCATED AT 250 WORDS)

Acidosis↗
PubMed1980

Oxidative phosphorylation coupled with nitrate respiration. IV. Replacement of soluble fraction from Escherichia coli, Pseudomonas aeruginosa and Mycobacterium avium.

The optimal pH range was from 7.0 to 7.5 in oxidative phosphorylation coupled to nitrate reduction. A cell-free extract of Escherichia coli showed weak myokinase activity. Oxidative phosphorylation coupled to nitrate reduction occurred with fractions of cell-free extracts of Mycobacterium avium. Soluble and particulate fractions separated from the cell-free extract of the organism were necessary for oxidative phosphorylation coupled to nitrate reduction. Each soluble fraction could be replaced by that obtained from another organism, e.g. Escherichia coli, Pseudomonas aeruginosa, and Mycobacterium avium. This suggests the existence of coupling factors common to these soluble fractions, and the possibility that the coupling factors are ATPase and components of the ATP-Pi exchange reaction. The P/NO3- ratio depended more on soluble fractions than on particulate fractions. Both phosphorylation and nitrate reduction activity were reduced by washing particulate fractions of Escherichia coli with 0.1 M KCl, while the P/NO3- ratio slightly increased.

Adenine Nucleotides↗
PubMed2000

Ca(2+) activation of heart mitochondrial oxidative phosphorylation: role of the F(0)/F(1)-ATPase.

Ca(2+) has been postulated as a cytosolic second messenger in the regulation of cardiac oxidative phosphorylation. This hypothesis draws support from the well-known effects of Ca(2+) on muscle activity, which is stimulated in parallel with the Ca(2+)-sensitive dehydrogenases (CaDH). The effects of Ca(2+) on oxidative phosphorylation were further investigated in isolated porcine heart mitochondria at the level of metabolic driving force (NADH or Deltapsi) and ATP production rates (flow). The resulting force-flow (F-F) relationships permitted the analysis of Ca(2+) effects on several putative control points within oxidative phosphorylation, simultaneously. The F-F relationships resulting from additions of carbon substrates alone provided a model of pure CaDH activation. Comparing this curve with variable Ca(2+) concentration ([Ca(2+)]) effects revealed an approximate twofold higher ATP production rate than could be explained by a simple increase in NADH or Deltapsi via CaDH activation. The half-maximal effect of Ca(2+ )at state 3 was 157 nM and was completely inhibited by ruthenium red (1 microM), indicating matrix dependence of the Ca(2+) effect. Arsenate was used as a probe to differentiate between F(0)/F(1)-ATPase and adenylate translocase activity by a futile recycling of ADP-arsenate within the matrix, catalyzed by the F(0)/F(1)-ATPase. Ca(2+) increased the ADP arsenylation rate more than twofold, suggesting a direct effect on the F(0)/F(1)-ATPase. These results suggest that Ca(2+) activates cardiac aerobic respiration at the level of both the CaDH and F(0)/F(1)-ATPase. This type of parallel control of both intermediary metabolism and ATP synthesis may provide a mechanism of altering ATP production rates with minimal changes in the high-energy intermediates as observed in vivo.

Adenosine Triphosphate↗
PubMed2006

Gender- and region-specific expression of insulin receptor protein in mouse brain: effect of mild inhibition of oxidative phosphorylation.

Insulin receptors (IR) and inhibition of oxidative metabolism have been suggested to partake in the pathophysiological cascade of neurodegenerative disorders. The goal of this study was to investigate gender- and region-specificity of insulin receptor protein expression in mouse brain subsequent to a mild hypoxic episode. Tissue was prepared from untreated male and female mice and animals pretreated in vivo with 20 mg/kg body weight i.p. 3-nitroproprionic acid (3-np; an inhibitor of succinic dehydrogenase) 1 hr prior to tissue preparation. IR expression in control animals was alike in males and females during proestrus and estrus but reduced during diestrus. On pretreatment, IR protein expression decrease in hippocampus in males but remained alike in other regions and females. In summary, IR protein expression is regionally different in males and females, gender-dependent, and modulated during the stages of the estrus cycle in females. Contrary to expectations it is not modified on mild inhibition of oxidative phosphorylation in any region in females and altered in hippocampus solely in males. The latter effect, however, warrants further scrutiny concerning participation in pathophysiological cascades affecting the hippocampus such as in Alzheimer's disease.

Alzheimer Disease↗
PubMed2002

Cardiolipin: a proton trap for oxidative phosphorylation.

The role of specific lipid structures in biological membranes has been elusive. There are hundreds of them in nature. Why has nature made them? How do they aid in the functioning of membrane proteins? Genetics with its 'knock out' organisms declares that functions persist in the absence of any particular lipid. Nonetheless some lipids, such as cardiolipin (CL), are associated with particular functions in the cell. It may merely expand the variety of culture conditions (pH, temperature, etc.) under which the wild-type organism survives. This article explores a unique role of CL as a proton trap within membranes that conduct oxidative phosphorylation and therefore the synthesis of ATP. CL's pK(2) (above 8.0) provides a role for it as a headgroup proton trap for oxidative phosphorylation. It suggests why CL is found in membranes that pump protons. The high pK(2) also indicates that the headgroup has but one negative charge in the neutral pH range. Data on the binding of CL to all of the oxidative phosphorylation proteins suggest that the CL may aggregate the oxidative phosphorylation proteins into a patch while it restricts pumped protons within its headgroup domain - supplying protons to the ATP synthase with minimal changes in the bulk phase pH.

Cardiolipins↗
PubMed1991

Fatty acid circuit as a physiological mechanism of uncoupling of oxidative phosphorylation.

Free fatty acids, natural uncouplers of oxidative phosphorylation, are shown to differ from artificial ones in that they fail to increase conductance of phospholipid bilayers which are permeable for the protonated form of fatty acids but impermeable for their anionic form. Recent studies have revealed that uncoupling by fatty acids in mitochondria is mediated by the ATP/ADP antiporter and, in brown fat, by thermogenin which is structurally very similar to the antiporter. It is suggested that both the ATP/ADP antiporter and thermogenin facilitate translocation of the fatty anions through the mitochondrial membrane.

Adipose Tissue, Brown↗
PubMed2006

Critical role of 5'-AMP-activated protein kinase in the stimulation of glucose transport in response to inhibition of oxidative phosphorylation.

5'-AMP-activated protein kinase (AMPK) functions as an energy sensor to provide metabolic adaptation under conditions of ATP depletion, such as hypoxia and inhibition of oxidative phosphorylation. Whether activation of AMPK is critical for stimulation of glucose transport in response to inhibition of oxidative phosphorylation is unknown. Here we found that treatment of Glut1-expressing Clone 9 cells with sodium azide (5 mM for 2 h) or the AMPK activator 5'-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR, 2 mM for 2 h) stimulated the rate of glucose transport by two- to fourfold. Use of small interference RNA (siRNA) directed against AMPKalpha(1) or AMPKalpha(1) + AMPKalpha(2) (total AMPKalpha) resulted in a significant inhibition of the glucose transport response and the content of phosphorylated AMPKalpha(1) + phosphorylated AMPKalpha(2) (total p-AMPKalpha) and phosphorylated acetyl-CoA carboxylase (p-ACC) in response to azide. Transfection with siRNA directed against AMPKalpha(2) did not affect the glucose transport response. The efficacy of transfection with siRNAs in reducing AMPK content was confirmed by Western blotting. Incubation of cells with compound C, an inhibitor of AMPK, abrogated the glucose transport response and abolished the increase in total p-AMPK in azide-treated or hypoxia-exposed cells. Simultaneous exposure to azide and AICAR did not augment the rate of transport in response to AICAR alone. There was no evidence of coimmunoprecipitation of total p-AMPKalpha with Glut1. However, LKB1 was associated with total p-AMPKalpha. We conclude that activation of AMPK plays both a sufficient and a necessary role in the stimulation of glucose transport in response to inhibition of oxidative phosphorylation.

AMP-Activated Protein Kinase Kinases↗
PubMed1987

The role of adenine nucleotide translocators in regulation of oxidative phosphorylation in heart mitochondria.

The regulative role of adenine nucleotide translocators (ANTs) in oxidative phosphorylation has been estimated by the titration of respiration of isolated rabbit heart mitochondria with carboxyatractyloside in the presence of a non-rate limiting creatine phosphokinase ADP-regenerating system. It has been established that the respiration rate is not controlled by ANTs in the two extreme states, state 3 and state 4. On the other hand, at an intermediate respiration rate (30-70% of the state 3 respiration, which roughly corresponds to that under physiological conditions) the ANT control coefficient had a value of 0.62-0.75. Thus, ANTs seem to play a key role in the regulation of oxidative phosphorylation.

Animals↗
PubMed1983

Dependence of mitochondrial oxidative phosphorylation on activity of the adenine nucleotide translocase.

The coupled reactions of electron transport and ATP synthesis for the first two sites of mitochondrial oxidative phosphorylation have been previously reported to be near equilibrium in isolated respiring pigeon heart (Erecińska, M., Veech, R. L., and Wilson, D. F. (1974) Arch. Biochem. Biophys. 160, 412-421) and rat liver mitochondria (Forman, N. G., and Wilson, D. F. (1982) J. Biol. Chem. 257, 12908-12915). Measurements are presented in this paper which demonstrate that the same relationship exists for both forward and reverse electron transport in rat heart mitochondria. This conclusion implies that adenine nucleotide translocation, a partial reaction of the system, is also near equilibrium, contrasting with proposals that the translocase is rate-limiting for oxidative phosphorylation. To resolve this controversy, the respiratory rates of suspensions of isolated rat liver and rat heart mitochondria were controlled by varying either the added [ATP]/[ADP][Pi] ratios ratios or [ADP] (by varying hexokinase in a regenerating system). Titrations with carboxyatractyloside, a high affinity inhibitor of the translocase which is noncompetitive with ADP, were carried out to assess the dependence of the respiratory rate on translocase activity. Plots of respiratory rate versus [carboxyatractyloside] were all strongly sigmoidal. In liver mitochondria, 40%-70% and in heart mitochondria 66% of the sites could be blocked with carboxyatractyloside before a 10% decrease in the respiratory rate was observed. Further analysis showed that liver and heart mitochondria have translocase/cytochrome a ratios of 1.52 and 3.20, respectively, and that at 23 degrees C the maximal turnover numbers for the translocases were 65 s-1 and 23 s-1. In all states of controlled respiration (no added inhibitor), a substantial excess of translocase activity was present, suggesting that the translocase was not normally rate-limiting in oxidative phosphorylation.

Animals↗
PubMed1994

Impairment of mitochondrial oxidative phosphorylation in the brain of aged mice.

To elucidate the role of mitochondrial oxidative phosphorylation in neuronal aging, we have studied the activity of the respiratory complexes in the brain of young, adult and old mice. In synaptic mitochondria, we found a significant decrease in complexes IV (29%, P < 0.001) and V (21%, P < 0.01) in old as compared with adult mice. Nonsynaptic mitochondria also showed a senescent decrease in complexes I (15%, P < 0.01), II + III (34%, P < 0.01) and IV (17%, P < 0.01) activities. These findings suggest a dysfunction in mitochondrial oxidative phosphorylation in brain aging.

Aerobiosis↗
PubMed1981

Non-equilibrium thermodynamics of oxidative phosphorylation by inverted inner membrane vesicles of rat liver mitochondria.

The relationship of the phosphate potential (delta GP) to the free energy released by the oxidation of NADH (redox potential or delta GR) was studied in suspensions of inverted inner membrane vesicles prepared from rat liver mitochondria. At delta GR values less negative than -52.2 kcal/mol, delta GP was a linear function of delta GR during oxidative phosphorylation at static head. At more negative delta GR, delta GP no longer increased but remained, more or less, at a constant value. At all values of delta GR, delta GP increased as Pi decreased. At high Pi, ATP/ADP was relatively independent of Pi, but at low Pi there was a strong interdependence of ATP/ADP and Pi. The experimental data were analyzed in terms of the theory of non-equilibrium thermodynamics. The degree of coupling, q, averaged 0.8 as estimated from the dependence of respiratory rate on delta GP. From measurements of -delta GR/delta GP at static head and from the estimates of q, an average value of four was calculated for Z, the phenomenological stoichiometry. The results support a 4-proton model of chemiosmotic coupling in which proton stoichiometries are 4H+/site, 3H+/ATPase, and 1H+/translocation of ATP for ADP and Pi. The results further indicate that the site by site reactions of oxidative phosphorylation operate close to thermodynamic equilibrium. This implies that ATP/site ratios are proportional to the redox potentials across each site at static head. Based on the oxidation-reduction potentials of NADH, ubiquinone, and cytochrome c, it follows that the ideal ATP/site ratios of mitochondrial oxidative phosphorylation are 1, 1/2, and 1 1/2, respectively, for sites 1, 2, and 3.

Adenosine Diphosphate↗
PubMed1989

Pentachlorobutadienyl-L-cysteine uncouples oxidative phosphorylation by dissipating the proton gradient.

A very early event in the toxicity of pentachlorobutadienyl-L-cysteine (PCBC) to rabbit renal proximal tubules is uncoupling of oxidative phosphorylation (R.G. Schnellmann, E. A. Lock, and L. J. Mandel (1986), Toxicologist 6, 176; (1987), Toxicol. Appl. Pharmacol. 90, 521). The mechanism of PCBC uncoupling of mitochondrial oxidative phosphorylation has been investigated using isolated rabbit renal cortical mitochondria (RCM). PCBC increased state 4 respiration of RCM respiring on pyruvate/malate or succinate in a concentration (10-100 microM)- and time (1-5 min)-dependent manner. PCBC also increased state 4 respiration in the presence of oligomycin, an inhibitor of F0F1-ATPase. The effect of PCBC on mitochondrial proton permeability was determined by measuring passive mitochondrial swelling. After a 2-min exposure to PCBC, RCM swelled when placed in NH4Cl or NaCl, but not KCl or sucrose. The protonophore carbonyl cyanide p-trifluoromethoxyphenyl hydrazone (FCCP) (1 microM) produced similar effects. After 5 min, RCM swelled when placed in NH4Cl, NaCl, or KCl, but not in sucrose. Aminooxyacetic acid, an inhibitor of cysteine conjugate beta-lyase, blocked the effects of PCBC on respiration, indicating that PCBC can be metabolized by RCM to produce RCM toxicity. These results show that PCBC initially uncouples oxidative phosphorylation by dissipating the proton gradient. Subsequently, additional ion permeabilities occur. These results are in complete agreement with previous observations in rabbit renal proximal tubule suspensions.

Animals↗