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PubMed1977

Mutants of Bacillus megaterium resistant to uncouplers of oxidative phosphorylation.

Mutants of Bacillus megaterium displaying malate-stimulated ATP synthesis resistant to uncouplers of oxidative phosphorylation were isolated and partially characterized. ATP synthesis in such mutants was resistant to carbonyl cyanide m-chlorophenyl hydrazone as well as to other uncouplers including 2,4-dinitrophenol, pentachlorophenol, and sodium azide. ATP synthesis in the wild type and in resistant mutants was sensitive to N,N'-dicyclohexylcarbodiimide, tributyltin, valinomycin plus potassium, and potassium cyanide. Active transport of glycine and glutamine which are sensitive to uncouplers in the wild type was also uncoupler-sensitive in the mutants.

Adenosine Triphosphate↗
PubMed1991

Mitochondrial oxidative phosphorylation defects in Parkinson's disease.

Parkinson's disease has been associated with defects in oxidative phosphorylation (Oxphos). We analyzed mitochondria isolated from muscle biopsies of 6 patients with Parkinson's disease for deficiencies in Oxphos enzymes and for mutations in the mitochondrial DNA. Oxphos enzyme assays were compared to the 5 to 95% confidence intervals from 16 control subjects. Four patients had complex I defects, whereas 1 patient had a complex IV defect. A genetic basis for Parkinson's disease was suggested by the presence of affected relatives of 2 patients with Parkinson's disease. Known pathological mitochondrial DNA mutations (insertion-deletions or point mutations) were not found. We conclude that Parkinson's disease is a systemic disorder of Oxphos, probably of a complex genetic etiology. Premature cell death in the nigrostriatal dopamine pathway could be due to energetic impairment and accentuated free radical generation caused by an Oxphos defect.

Adult↗
PubMed1998

Uncouplers of mitochondrial oxidative phosphorylation are not substrates of the erythrocyte glutathione-S-conjugate pump.

Uncouplers of mitochondrial oxidative phosphorylation, dinitrophenol (DNP) and carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP), were found to stimulate Mg(2+)-ATPase activity of human erythrocyte membranes in a manner competitive with respect to 2,4-dinitrophenyl-S-glutathione (DNP-SG) which suggested that these compounds may also be substrates of the glutathione-S-conjugate pump. We confirm that the stimulation of erythrocyte membrane ATPase activity by DNP and by another uncoupler, carbonyl cyanide m-chlorophenylhydrazone (CCCP), is competitive with respect to DNP-SG. However, we found no evidence for active transport of DNP and CCCP out of erythrocytes and demonstrate that they inhibit the low-affinity component of DNP-SG transport noncompetitively while stimulating the high-affinity DNP-SG transport (mediated by multidrug resistance-associated protein, MRP1). Implications of these findings may indicate the electrogenic nature of MRP1-mediated transport of glutathione-S conjugates and stimulation of aminophospholipid translocase (flippase) rather than the glutathione-S-conjugate pump by the uncouplers.

ATP-Binding Cassette Transporters↗
PubMed1968

Inhibition of membrane transport in Streptococcus faecalis by uncouplers of oxidative phosphorylation and its relationship to proton conduction.

We studied the effect of compounds that uncouple oxidative phosphorylation on membrane function in Streptoccocus faecalis, an organism which relies upon glycolysis for the generation of metabolic energy. At low concentrations (ranging from 10(-7) to 10(-4)m), tetrachlorosalicylanilide, tetramethyldipicrylamine, carbonylcyanide m-chlorophenylhydrazone, pentachlorophenol, and dicoumarol strongly inhibited energy-dependent transport of rubidium, phosphate, and certain amino acids. However, these compounds had little effect on the generation of adenosine triphosphate via glycolysis or on its utilization for the synthesis of macromolecules. They also did not seriously inhibit uptake of those monosaccharides and amino acids which do not require concurrent metabolism. It is proposed that the uncouplers interfere with the utilization of metabolic energy for membrane transport. The uncouplers accelerated the translocation of protons across the cytoplasmic membrane. It appears that a proton-impermeable membrane is required for transport, perhaps, because a proton gradient is involved in the coupling of metabolic energy to the translocation of substrates across the membrane.

Adenosine Triphosphate↗
PubMed1999

Dynamic adaptation of cardiac oxidative phosphorylation is not mediated by simple feedback control.

The classic idea about regulation of cardiac oxidative phosphorylation (OxPhos) was that breakdown products of ATP (ADP and P(i)) diffuse freely to the mitochondria to stimulate OxPhos. On the basis of this metabolic feedback control system, the response time of OxPhos (t(mito)) is predicted to be inversely proportional to the mitochondrial aerobic capacity (MAC). We determined t(mito) during steps in heart rate in isolated perfused rabbit hearts (n = 16) before and after reducing MAC with nonsaturating doses of oligomycin. The reduction of MAC was quantified in mitochondria isolated from each perfused heart, dividing oligomycin-sensitive, ADP-stimulated state 3 respiration by oligomycin-insensitive uncoupled respiration. The t(mito) to heart rate steps from 60 to 70 and 80 beats/min was 5. 6 +/- 0.6 and 7.2 +/- 0.8 s (means +/- SE) and increased an estimated 34 and 40% for a 50% decrease in MAC (P < 0.05), respectively, which is much less than the 100% predicted by the feedback hypothesis. For steps to 100 or 120 beats/min, t(mito) was 8.3 +/- 0.5 and 11.2 +/- 0.6 s and was not reduced with decreases in MAC (P > 0.05). We conclude that immediate feedback control by quickly diffusing ADP and P(i) cannot explain the dynamic regulation of cardiac OxPhos. Because calcium entry into the mitochondria also cannot explain the first fast phase of OxPhos activation, we propose that delay of the energy-related signal in the cytoplasm dominates the response time of OxPhos.

Adaptation, Physiological↗
PubMed1975

Pseudomonas aeruginosa lipopolysaccharide: an uncoupler of mitochondrial oxidative phosphorylation.

The addition of Pseudomonas aeruginosa KCIIR LPS to respiring mitochondria stimulated the rate of substrate oxidation, reduced the respiratory control ratio, stimulated oxygen uptake in state 4, and released the inhibition imposed upon state 3 by atractyloside. It was concluded that LPS acted as an uncoupler of oxidative phosphorylation and that it produced effects similar to those observed with the classical uncoupler 2,4-dinitrophenol.

Adenosine Diphosphate↗
PubMed1980

The effects of acidosis on canine hepatic and renal oxidative phosphorylation.

The intracellular effects of acidosis remain poorly defined. To examine the effects of acidosis on oxidative phosphorylation, liver biopsies and weight nephrectomies were performed on 10 adult German shepherd dogs. The mitochondria were isolated from each tissue and their respiratory activity was studied by the polarographic technique with the pH of the reaction media varied from 5.5 to 8.0. Glutamate and succinate substrates were employed. Results showed a dramatic reduction in the efficiency of oxygen utilization by mitochondria with glutamate as the reaction medium became more acidic. The efficiency of succinate oxidation was significantly (P less than 0.01) preserved. These findings were confirmed by both the respiratory control indices and by ADP:O ratios. Acidosis appears to result in severe inhibition of NAD-linked energy substrate oxidation.

Acidosis↗
PubMed1967

Salicylanilides: a new group of active uncouplers of oxidative phosphorylation.

Investigations using housefly mitochondria revealed several salicylanilide derivatives as the most effective uncoupling agents of oxidative phosphorylation reported so far. Even greater inhibition of the associated P(i)-adenosine triphosphate exchange was shown with these compounds in both housefly and rat-liver mitochondria, and close similarity was observed between the two types of organelles.

Adenosine Triphosphatases↗
PubMed1988

QSAR studies of hydrazone uncouplers of oxidative phosphorylation.

Semiempirical molecular orbital calculations have been performed on a series of hydrazone uncouplers of mitochondrial oxidative phosphorylation which show insecticidal activity. Regression analysis yielded significant correlations between uncoupling activity, insecticidal potency and such physicochemical or theoretically-derived parameters as lipophilicity, pKa and atom charges.

Adenosine Diphosphate↗
PubMed2004

Mutant mitochondrial elongation factor G1 and combined oxidative phosphorylation deficiency.

Although most components of the mitochondrial translation apparatus are encoded by nuclear genes, all known molecular defects associated with impaired mitochondrial translation are due to mutations in mitochondrial DNA. We investigated two siblings with a severe defect in mitochondrial translation, reduced levels of oxidative phosphorylation complexes containing mitochondrial DNA (mtDNA)-encoded subunits, and progressive hepatoencephalopathy. We mapped the defective gene to a region on chromosome 3q containing elongation factor G1 (EFG1), which encodes a mitochondrial translation factor. Sequencing of EFG1 revealed a mutation affecting a conserved residue of the guanosine triphosphate (GTP)-binding domain. These results define a new class of gene defects underlying disorders of oxidative phosphorylation.

Chromosomes, Human, Pair 3↗
PubMed2006

Multiple oxidative phosphorylation deficiencies in severe childhood multi-system disorders due to polymerase gamma (POLG1) mutations.

Failure to thrive, feeding difficulties, variable forms of infantile epilepsy or psychomotor developmental delay and hypotonia were the most frequent clinical disease presentations in eight children with combined oxidative phosphorylation enzyme complex deficiencies carrying mutations in the polymerase gamma (POLG1) gene. Five out of eight patients developed severe liver dysfunction during the course of the disease. Three of these patients fulfilled the disease criteria for Alpers syndrome. Most children showed deficiencies of respiratory chain enzyme complexes I and III, in combination with complex II, complex IV and/or PDHc in muscle, whereas in fibroblasts normal enzyme activities were measured. All children carried homozygous or compound heterozygous mutations in the POLG1 gene, including two novel mutations in association with mtDNA depletion. Conclusion We suggest performing POLG1 mutation analysis in children with combined oxidative phosphorylation deficiencies in muscle, even if the clinical picture is not Alpers syndrome.

DNA Mutational Analysis↗
PubMed1993

Inhibition of mitochondrial oxidative phosphorylation and its electron transport pathway by a polycation in vitro.

Effect of the polycation on oxidative phosphorylation in the rat liver mitochondria has been studied. Both oxygen uptake and coupled phosphorylation were progressively inhibited by increasing concentration of the polycation, as observed with NAD-linked substrates, succinate and ascorbate+TMPD which activates the terminal part of the respiratory chain. NADH oxidase, NADH dehydrogenase and cytochrome oxidase were strongly inhibited by the polycation, 80-90% of the activity being lost at an inhibitor concentration of 100 microM. Succinate oxidase and succinate dehydrogenase were inhibited 60-66% at 100 microM concentration of the polycation. The polycation inhibited the uncoupler 2,4-dinitrophenol stimulated ATPase activity both in presence and absence of Mg2+ ions. The polycation also inhibited salt-induced volume change.

Animals↗
PubMed1991

Why is inorganic phosphate necessary for uncoupling of oxidative phosphorylation by Cd2+ in rat liver mitochondria?

The phosphate (Pi)-dependent uncoupling action of Cd2+ in oxidative phosphorylation in rat liver mitochondria was studied mainly in terms of Pi transport. Cd2+ at 2 microM caused full uncoupling in the presence of 10 mM Pi, but no uncoupling in the absence of Pi. Cd2+ released state 4 respiration after a certain lag-time, and then the respiration increased progressively with time. After its addition, Cd2+ was taken up by mitochondria in a similar period to the lag time before respiratory release. KIH-201, a potent and specific inhibitor of Pi transport via the Pi/H+ symporter, abolished the uncoupling completely. Cd2+ caused dissipation of the electric transmembrane potential (delta psi) and swelling of mitochondria in a Pi-dependent manner. Uncoupling by Cd2+ was found to take place in parallel with the uptake of Pi into mitochondria via the Pi/H+ symporter, suggesting that the uncoupling was due to acceleration of H+ influx through the Pi/H+ symporter activated by Cd2+.

Animals↗
PubMed1993

The lipophilic weak base (Z)-5-methyl-2-[2-(1-naphthyl)ethenyl]-4-piperidinopyridine (AU-1421) is a potent protonophore type cationic uncoupler of oxidative phosphorylation in mitochondria.

The lipophilic weak base AU-1421 acts as a simple protonophoric uncoupler of oxidative phosphorylation in rat liver mitochondria judging from the following observations. In the absence of any carrier lipophilic anions or P(i), AU-1421 stimulated the rate of state 4 respiration maximally about 7-fold at a concentration of 30 nmol/mg mitochondrial protein. At the same maximum effective concentration, it also inhibited ATP synthesis, released oligomycin-inhibited state 3 respiration, dissipated the proton motive force in the energized state, and activated latent H(+)-ATPase. AU-1421 also allowed proton conduction in both mitochondrial membranes and liposomes. These actions of AU-1421 resemble those of the typical anionic uncoupler SF6847. A marked difference between the two was, however, that ATPase activation by AU-1421 was not suppressed at higher concentrations of AU-1421, whereas ATPase activated by SF6847 was suppressed on increase of the SF6847 concentration. The finding that this simple protonophoric cation acts as an uncoupler at a micromolar concentration is significant, because all true (i.e., protonophore type) uncouplers known so far are anionic not cationic. Thus, AU-1421 is a unique uncoupler of the protonophore type.

Adenosine Triphosphate↗
PubMed1975

Differentiation between mutants of Escherichia coli K defective in oxidative phosphorylation.

Hybrid membrane particles from two mutants of Escherichia coli K12, Bv4 and K11, defective in oxidative phosphorylation, have been prepared, in which ATP-driven membrane energization is restored. A soluble factor of mutant K11 was found to have properties similar to parental crude coupling factor, ATPase (EC 3.6.1.3). Membrane particles of this mutant could not be reconstituted by parental coupling factor. Either parental coupling factor, or the soluble factor of mutant K11 could reconstitute both respiration-driven and ATP-driven energization to membrane particles of mutant Bv14 or to parental particles depleted of ATPase. Mutant Bv4 was found to be devoid of coupoing factor activity, while retaining the ability to hydrolyze ATP. Both mutants possess an ATPase with an altered binding to the membrane. Mutant K11 is impaired in respiration-driven amino acid transport, in contrast to mutant Bv4. The three major subunits of parental Escherichia coli ATPase have been isolated and antibodies have been prepared against these subunits. Antibodies against the largest subunit (alpha component) or against the intact catalytic subunits (alpha + beta components) inhibit both ATP-Pi exchange in the parent organism as well as ATP hydrolytic activity in parent and mutants. Antibodies against the two other subunits (beta or gamma components) also inhibit these two reactions, but were found to be less effective. Mutant N144, which lacks ATPase activity, shows no precipitin lines with anti-alpha, anti-beta, anti-gamma, or anti (alpha + beta) preparations. In contrast, mutants Bv4 and K11, exhibit cross-reactivity with all of the antisera.

Acridines↗
PubMedDate not supplied

[The respiration and oxidative phosphorylation of the brain mitochondria in rats with different types of behavior].

Respiration and oxidative phosphorylation of brain mitochondria were studied in outbred rats with different types of behaviour in open-field test and in forced swimming test. It was found that in rats with "active" type of behaviour (with high locomotor activity and low level of depressiveness) the brain mitochondria have at succinate oxidation a higher rate of respiration in active metabolic state and in presence of uncoupler 2,4-DNP, and a higher rate of ADP phosphorylation than in rats with "passive" type of behaviour (with low locomotor activity and high and moderate levels of depressiveness). Thus rats with active type of behaviour have a higher succinate oxidase activity than rats with passive type of behaviour. It is supposed that revealed differences in brain energy metabolism may affect the dominance of certain type of behaviour.

Animals↗
PubMed2001

Late-onset corticohippocampal neurodepletion attributable to catastrophic failure of oxidative phosphorylation in MILON mice.

We generated mitochondrial late-onset neurodegeneration (MILON) mice with postnatal disruption of oxidative phosphorylation in forebrain neurons. They develop normally and display no overt behavioral disturbances or histological changes during the first 5 months of life. The MILON mice display reduced levels of mitochondrial DNA and mitochondrial RNA from 2 and 4 months of age, respectively, and severely respiratory chain-deficient neurons from 4 months of age. Surprisingly, these respiratory chain-deficient neurons are viable for at least 1 month without showing signs of neurodegeneration or major induction of defenses against oxidative stress. Prolonged neuronal respiratory chain deficiency is thus required for the induction of neurodegeneration. Before developing neurological symptoms, MILON mice show increased vulnerability to excitotoxic stress. We observed a markedly enhanced sensitivity to excitotoxic challenge, manifest as an abundance of terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) reactive cells after kainic acid injection, in 4-month-old MILON mice, showing that respiratory chain-deficient neurons are more vulnerable to stress. At approximately 5-5.5 months of age, MILON mice start to show signs of disease, followed by death shortly thereafter. The debut of overt disease in MILON mice coincides with onset of rapidly progressive neurodegeneration and massive cell death in hippocampus and neocortex. This profound neurodegenerative process is manifested as axonal degeneration, gliosis, and abundant TUNEL-positive nuclei. The MILON mouse model provides a novel and powerful tool for additional studies of the role for respiratory chain deficiency in neurodegeneration and aging.

Animals↗