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PubMed1976

Inhibition by triphenyltin chloride of a tightly-bound membrane component involved in photophosphorylation.

At very low concentrations (less than 1 muM) triphenyltin chloride inhibits ATP formation and coupled electron transport in isolated spinach chloroplasts. Basal (-Pi) and uncoupled electron transport are not affected by triphenyltin. The membrane-bount ATP in equilibrium Pi exchange and Mg2+-dependent ATPase activities of chloroplasts are also completely sensitive to triphenyltin, although the Ca2+-dependent and Mg2+-dependent ATPase activities of the isolated coupling factor protein are insensitive to triphenyltin. The light-driven proton pump in chloroplasts is stimulated (up to 60%) by low levels of triphenyltin. Indeed, the amount of triphenyltin necessary to inhibit ATP formation or stimulate proton uptake is dependent upon the amount of chloroplasts present in the reaction mixture, with an apparent stoichiometry of 2-2.5 triphenyltin molecules/100 chlorophyll molecules at 50% inhibition of ATP formation and half-maximal stimulation of proton uptake. Chloroplasts partially stripped of coupling factor by an EDTA was are no longer able to accumulate protons in the light. However, low levels of triphenyltin can effectively restore this ability. The amount of triphenyltin required for the restoration of net proton uptake is also dependent upon the amount of chloroplasts, with a stoichiometry of 4-5 triphenyltin molecules/100 chlorophyll molecules at 50% reconstitution. On the basis of this and other evidence it is concluded that triphenyltin chloride inhibits phosphorylation, ATP + Pi exchange and membrane-bound ATPase activities in chloroplasts by specifically blocking the transport of protons through a membrane-bound carrier or channel located in a hydrophobic region of the membrane at or near the functional binding site for the coupling factor.

Adenosine Triphosphatases↗
PubMed1979

The uncoupled regulation of fibronectin and collagen synthesis in Rous sarcoma virus transformed avian tendon cells.

We have investigated the regulation of fibronectin and procollagen synthesis in normal and Rous sarcoma virus transformed primary avian tendon cells. These two proteins interact at the cell periphery and both are reportedly lost upon transformation. We thus examined whether their synthesis was coordinately regulated in Rous sarcoma virus-infected cells. It was found that while the synthesis of both pro alpha 1 and pro alpha 2 peptides was reduced upon transformation, the synthesis of fibronectin was not altered. Nevertheless, long term radiolabeling demonstrated that fibronectin levels were reduced in transformed cells. It is concluded that the reduction in levels of these components at the surface is brought about by different mechanisms; collagen levels being regulated by procollagen synthesis and fibronectin levels by degradation and/or release into the culture medium. The possibility is discussed that fibronectin is lost from the cell periphery of primary avian tendon cells as a consequence of decreased levels of anchoring collagen molecules.

Animals↗
PubMed1979

The metabolism of 4-methyl-2-oxopentanoate in rat pancreatic islets.

1. Radioactively labelled 4-methyl-2-oxopentanoate was taken up by isolated pancreatic islets in a concentration- and pH-dependent manner and led to the intracellular accumulation of labelled amino acid and to a decrease in the intracellular pH. Uptake of 4-methyl-2-oxopentanoate did not appear to be either electrogenic or Na+-dependent. The islet content of 2-oxo acid radioactivity was not affected by either 2-cyano-3-hydroxy-cinnamate (10mM) or pyruvate (10mM), although both these substances inhibited the oxidation of [U-14C]4-methyl-2-oxopentanoate by islet tissue. 2. 4-Methyl-2-oxopentanoate markedly stimulated islet-cell respiration, ketone-body formation and biosynthetic activity. The metabolism of endogenous nutrients by islets appeared to be little affected by the compound. 3. Studies with the 3H- and 14C-labelled substrate revealed that 4-methyl-2-oxopentanoate was incorporated by islets into CO2, water, acetoacetate, L-leucine and to a lesser extent into islet protein and lipid. Carbon atoms C-2, C-3 and C-4 of the acetoacetate produced were derived from the carbon skeleton of the 4-methyl-2-oxopentanoate, but the acetoacetate carboxy group was derived from the incorporation of CO2. These results, and consideration of the relative rates of 14CO2 and acetoacetate formation from 1-14C-labelled as opposed to U-14C-labelled 4-methyl-2-oxopentanoate, led to the conclusion that the pathway of catabolism of this 2-oxo acid in pancreatic islets is identical with that described in other tissues. The amination of 4-methyl-2-oxopentanoate by islets was attributed to the presence of a branched-chain amino acid aminotransferase (EC 2.6.1.42) activity in the tissue. Although glutamate dehydrogenase activity was demonstrated in islet tissue, the reductive amination of 2-oxoacids did not seem to be of importance in the formation of leucine from 4-methyl-2-oxopentanoate. 4. The results of experiments with respiratory inhibitors and uncouplers, and the finding that 14CO2 production and islet respiration were linked in a 1:1 stoicheiometry suggested that 4-methyl-2-oxopentanoate catabolism was coupled to mitochondrial oxidative phosphorylation. The catabolism of 4-methyl-2-oxopentanoate in islet tissue appeared to be regulated at the level of the initial 2-oxo acid dehydrogenase (EC 1.2.1.25) reaction.

Acetoacetates↗
PubMed2026

Ectomesenchymal identity emerges via relief of Twist1 transcript destabilisation.

During vertebrate development, a subset of cranial neural crest cells (CNCCs) termed 'ectomesenchyme' differentiates into cell types canonically associated with the mesoderm (cartilage, bone and muscle). While the molecular decisions that guide CNCCs toward ectomesenchymal identity remain incompletely understood, the transcription factor Twist1 plays a central role. Here, we show that while Twist1 transcripts accumulate in late migratory CNCCs as cells enter the pharyngeal arch environment, a Twist1 enhancer within Hdac9 is active in the neural tube and CNCCs. We reconcile the temporal discrepancy between enhancer activity and transcript accumulation by showing that the Twist1 3' UTR from multiple vertebrate species (but not the non-vertebrate chordate Ciona intestinalis) destabilises transcripts in the ectoderm via a conserved AU-Rich Element. Together, these findings reveal a vertebrate-specific, two-tiered regulatory mechanism that uncouples enhancer activity from transcript accumulation, gating the onset of Twist1 expression and the acquisition of ectomesenchymal identity in vertebrate CNCCs.

Animals↗
PubMed1976

The uptake of choline by rat liver mitochondria.

1. Rat liver mitochondria can accumulate choline against a concentration gradient. Maximally about 30 nmol choline per mg mitochondrial protein are found in the matrix space. 2. The process of choline uptake is biphasic. After a rapid uptake of 1.5-15 nmol per mg protein, a slower uptake occurs if an energy supply is present. In the absence of energy, only the rapid uptake is found. 3. The inhibition of uncoupler-stimulated choline oxidation by cations is the result of an inhibition of choline uptake.

Adenosine Triphosphate↗
PubMed1978

Studies on the mode of action of hygromycin B, an inhibitor of translocation in eukaryotes.

Hygromycin B is an unusual aminoglycoside antibiotic active against both prokaryotic and eukaryotic cells. Hygromycin B at 0.38 mM concentration completely halts yeast cell growth in rich media, presumably by preventing protein synthesis by cytoplasmic ribosomes. Polypeptide synthesis in cell-free extracts from rabbit reticulocytes, wheat germ and yeast is strongly blocked by low concentrations of hygromycin B. The antibiotic inhibits peptide chain elongation by yeast polysomes by preventing elongation factor EF-2-dependent translocation, although it does not affect either the formation of the EF-2-GTP-ribosome complex or the EF-2- and ribosome-dependent GTP hydrolysis which takes place uncoupled from translocation. The inhibition of translocation by hygromycin B might result from the stabilization of peptidyl-tRNA bound to the ribosomal acceptor site, since the stability of [3H]Phe-tRNA-EF-1-poly(U)-ribosome and [3H]Phe-tRNA-poly(U)-ribosome complexes is increased in the presence of hygromycin B. The inhibition of polyphenylalanine synthesis by reticulocyte ribosomes and enzymic translocation of peptidyl-tRNA by yeast polysomes can be reversed by increasing concentrations of EF-2 suggesting a relationship between the binding sites of EF-2 and hygromycin B on the ribosome. Neither non-enzymic translocation, that takes place in the presence of high potassium concentrations, nor the peptide bondforming step are affected by hygromycin B.

Animals↗
PubMed1976

Inhibition of energy-transducing functions of chloroplast membranes by lipophilic iron chelators.

Lipophilic metal chelators inhibit various energy-transducing functions of chloroplasts. The following observations were made 1. Photophosphorylation coupled to any known mode of electron transfer, i.e. whole-chain noncyclic, the partial noncyclic Photosystem I or Photosystem II reactions, or cyclic, is inhibited by several lipophilic chelators, but not by hydrophilic chelators. 2. The light- and dithioerythritol-dependent Mg2+-ATPase was also inhibited by the lipophilic chelators. 3. Electron transport through either partial reaction. Photosystem I or Photosystem II was not inhibited by lipophilic chelators. Whole-chain coupled electron transport was inhibited by bathophenanthroline, and the inhibition was not reversed by uncouplers. The diketone chelators diphenyl propanedione and nonanedione inhibited the coupled, whole-chain electron transport and the inhibition was reversed by uncouplers, a pattern typical of energy transfer inhibitors. The electron transport inhibition site is localized in the region of platoquinone leads to cytochrome f. This inhibition site is consistent with other recent work (Prince et al. (1975) FEBS Lett. 51, 108 and Malkin and Aparicio (1975) Biochem. Biophys. Res. Commun. 63, 1157) showing that a non-heme iron protein is present in chloroplasts having a redox potential near + 290 mV. A likely position for such a component to function in electron transport would be between plastoquinone and cytochrome f. just where our data suggests there to be a functional metalloprotein. 4. Some of the lipophilic chelators induce H+ leakiness in the chloroplast membrane, making interpretation of their phosphorylation inhibition difficult. However, 1-3 mM nonanedione does not induce significant H+ leakiness, while inhibiting ATP formation and the Mg2+-ATPase. Nonanedione, at those concentrations, causes a two- to four-fold increase in the extent of H+ uptake. 5. These results are consistent with, but do not prove, the involvement of a non-heme iron or a metalloprotein in chloroplast energy transduction.

Adenosine Triphosphatases↗
PubMed1977

Tightly bound nucleotides of the energy-transducing ATPase, and their role in oxidative phosphorylation. II. The beef heart mitochondrial system.

1. Beef heart mitochondrial ATPase, in both the membrane-bound and isolated form, contains tightly bound ATP and ADP. Each mol of ATPase contains about 2.2 mol ATP and 1.3 mol ADP. 2. In the absence of ATPase activity, these nucleotides exchange only slowly with nucleotides in solution. The exchange rate is increased during coupled ATPase activity, but not when the ATPase is uncoupled. 3. Oligomycin and dicyclohexylcarbodiimide inhibit exchange of the bound nucleotides, as does the ATPase inhibitor protein, although in each case some residual exchange occurs. Aurovertin, although inhibiting phosphorylation, does not inhibit the exchange. This is discussed in terms of the reversibility of these inhibitors. 4. The stimulation of exchange seen during coupled ATPase activity requires energisation of the ATPase molecule. Using the exchange reaction as a probe of energisation, it is deduced that energy can be transferred between different ATPase molecules. 5. It is proposed that coupled ATPase activity and phosphorylation in submitochondrial particles involve the tight nucleotide binding sites and the (weak) ATPase site, while uncoupled ATPase activity involves only the weak site.

Adenosine Diphosphate↗
PubMed1978

Phospholipid substitution of the purple membrane. The stoichiometry of light-induced proton release by phospholipid-substituted purple membranes.

The method of Warren et al. (1974, Proc. Natl. Acad. Sci. U.S. 71, 622--626) was employed to substitute the polar lipids of the purple membrane of Halobacterium halobium by different phosphatidylcholine species. Substitution at pH 6.5 yields proteolipid complexes in the form of bent open sheets which have a protein to lipid phosphorus ratio similar to the natural membrane, i.e. about 1 : 10 (mol/mol). The extent of substitution increases with the length of the fatty acid chain of the phosphatidylcholine used. The spectral properties of bacteriorhodopsin are only slightly affected by substitution of 95% of the lipid, except that the photocycle is slowed down appreciably. Due to this slow rate the M412 intermediate of the cycle accumulates in the light. Associated with this accumulation is a net light-induced proton release, which proved insensitive to uncoupler. A comparison between the net proton release and the amount of M412 accumulated, studied as a function of pH, shows that no fixed stoichiometry exists between the two processes. Phospholipid substitution by egg phosphatidylcholine at pH 7.5 or by egg phosphatidylethanolamine leads to preparations of purple membrane with 15 or 25 mol of phospholipid per mol of bacteriorhodopsin, respectively. These preparations seem to consist of closed membrane structures. They take up protons in the light in an uncoupler-sensitive way.

Bacteriorhodopsins↗
PubMed1978

Glucose transport in Achlya: characterization and possible regulatory aspects.

The freshwater fungus Achlya transported D-(+)glucose (glucose) and 2-deoxy-D-glucose (deoxyglucose) by an energy-related system. Their transport4 was inhibited by uncouplers of metabolic energy such as 2,4-dinitrophenol, cyanide, azide, and carbonylcyanide-p-chlorophenylhydrazone. Besides inhibiting each other, glucose and deoxyglucose transport was inhibited by D-(+)galactose, D-(+)mannose, and D-(+)xylose. Many other sugars tested failed to inhibit glucose transport implying a certain degree of specificity. Glucose transport was pH (optimum at 6.5) and temperature (optimum at 30-40 degrees C) dependent. Glucose transport was also inhibited by citrate, N6-substituted adenines (cytokinins), and iodine. None of these agents penetrated the cell membrane within the brief (1-3-min) period in which glucose transport was measured. In every case, transport was inhibited within 10 s (the shortest time in which measurements could be made). When cells were osmotically shocked to release a cell-wall membrane phosphorylated proteoglycan (PPG), they became incapable of transporting glucose for several hours until new PPG material was reisolable from the membrane by osmotic-shock treatment. The osmotically shocked cells could not transport glucose or deoxyglucose. No glucose-binding protein was detected in the shock fluid. Practically all of the glucose transported within 1-2 min was recovered as glucose-6-phosphate. No other phosphorylated sugar was detected suggesting that glucose may be phosphorylated in transport. Related studies have shown that citrate removed calcium bound by PPG; N6-substituted adenines were bound by PPG while three polyphosphorylated dinucleosides, HS3, HS2, and HS1, were displaced from it. Iodine formed stable complexes with the HS compounds. All of these agents inhibited glucose transport without entering the cell. It is therefore possible that HS compounds, calcium and PPG may be involved in maintaining the cell membrane in proper form for glucose transport.

Biological Transport, Active↗
PubMed1978

Membrane energization in relation with nitrogen fixation in Azotobacter vinelandii and Rhizobium leguminosarum bacteroids.

Nitrogen fixation in A. vinelandii and R. leguminosarum bacteroides shows identical characteristics with respect to the dependence on membrane energization, the sensitivity to uncouplers, the ATP/ADP-ratio, and the dependences on flavodoxinhydroquinone as electrondonor. Although we have been successful in preparing inside-out vesicles which can be energized, attempts to couple these membranes to N2-ase were still unsuccessful. One of the major problems could be the failure to energize these vesicles directly by ATP. Although subject to polymerisation after addition of MgCl2, it could be shown that the actual mol.wt. of the O2-stable N2-ase complex is about 300,000 in agreement with a 1:1:1 stoichiometry of the three constituent proteins, namely, component I, component II and the 2Fe-2S protein.

Adenosine Diphosphate↗
PubMed2026

Copper and iron engage distinct metabolic programs for cellular survival.

Copper and iron are redox-active micronutrients with tightly coupled homeostasis, yet how copper modulates iron-dependent stress responses remains unclear. Using Saccharomyces cerevisiae under nutrient-limited conditions, we uncoupled proliferative growth from long-term survival to dissect metal-dependent adaptation. Copper selectively preserved survival without affecting growth, whereas iron showed similar effects. Iron chelation impaired growth and suppressed electron transport chain gene expression; copper partially rescued these defects but required iron availability for its pro-survival activity. Despite this interdependence, copper and iron engaged distinct signaling programs. Iron-dependent survival required a Target of Rapamycin complex 1 (TORC1)-permissive state and was attenuated by rapamycin, whereas copper remained active under TORC1 inhibition. In contrast, copper promoted survival through AMP-activated protein kinase (AMPK) and antioxidant pathways, while iron exhibited context-dependent AMPK reliance. Together, these findings reveal that copper and iron support cellular survival through distinct metabolic programs and suggest that the consequences of micronutrient availability are shaped by the underlying nutrient-sensing and metabolic state of the cell. This framework provides insight into how alterations in micronutrient homeostasis and metabolic signaling may influence cellular resilience during aging.

AMPK↗
PubMed1979

The isolation of coupled mitochondria from Physarum polycephalum and their response to Ca2+.

A method for the isolation of coupled mitochondria from the acellular slime mould Physarum polycephalum is described. The mitochondria oxidize respiratory substrates at rates comparable to those of mitochondria from other microorganisms and show similar responses to respiratory inhibitors. ADP/O values approach similar values to those obtained with mitochondria from higher organisms: 3 with NAD-linked substrates, 2 with succinate, and 1 with ascorbate-TMPD. Mitochondria actively take up low concentrations of Ca2+ with stimulation of their respiration. With succinate or pyruvate-malate as substrates respiratory responses are depressed by Ca2+ concentrations in excess of 200 micron in the presence or absence of phosphate. Exogenous NADH is unique in supporting the uptake of large amounts of Ca2+ in the presence of phosphate and in showing an unusual 'uncoupled' response in the absence of phosphate. A sigmoidal relationship occurs between initial velocity of Ca2+ uptake and Ca2+ concentration with a maximum velocity of approx. 15 nmol/s per mg protein and half maximum velocity occurring at approx. 50 micron Ca2+.

Biological Transport, Active↗
PubMed1979

Transient 45Ca uptake and release in isolated rat-liver cells during recovery from deenergized states.

1. Aerobic incubation of isolated rat liver cells--after dilution from the anaerobic stock suspension--transiently brings about a state, during which a reversible calcium uptake can be observed on addition of a respiratory substrate. Uptake varies greatly and can reach more than 50 nmol/mg protein, but declines to zero on prolonged preincubation, especially at higher temperature. Repeated additions of succinate or 3-hydroxybutyrate evoke new calcium transients. If ATP is simultaneously added, if greatly potentiates succinate-initiated reversible uptake. 2. If rotenone is present during the preincubation phase, calcium transients are strongly enhanced. Uptake is blocked by uncouplers and respiratory inhibitors, indicating the involvement of mitochondria. 3. Calcium uptake is not accompanied by increased oxygen consumption. The actual respiration cannot account sufficiently for the energy need of calcium uptake. Participation of cytoplasmic ATP is likely, as inhibitors of adenine nucleotide translocase affect uptake. 4. Lanthanum enhances calcium uptake in contrast to its action on mitochondria. 5. Pulse-labeling experiments indicate that the calcium taken up is removed from a rapidly exchangeable calcium pool by withdrawal into the mitochondria as a deep compartment. 6. Calcium uptake is accelerated either by increasing the phosphate level or by high temperature. It is prolonged by low temperature, high pH or high ATP concentration. Calcium release accelerates with increasing temperature, decreasing pH and a further rise in phosphate concentration. 7. The dependency on phosphate and temperature reveals a delicately poised equilibrium of uptake and release. At ambient temperature, phosphate increases uptake up to a concentration of 0.5 mM. Higher concentrations accelerate both uptake and release. At lower temperature, the accelerating effect on uptake predominates. A temperature shift during incubation results in adaptation of the calcium equilibrium to the new temperature, i.e. release of calcium at high temperature, uptake at low temperature. 8. Oxidizing metabolites inhibit succinate-stimulated calcium uptake and promote release of previously accumulated calcium. An increased sensitivity to phosphate is established. 9. With respect to isolated mitochondria, isolated liver cells appear to be a more realistic model for studying the physiological mechanism of mitochondrial calcium release, since compartmental constraints and regulations are maintained.

Aerobiosis↗
PubMed1978

Oxygen uptake and lactate production by Schistosoma mansoni cercaria, cercarial body and tail, and schistosomule.

1. Oxygen consumption by Schistosoma mansoni cercarial bodies varies, with the batch of organisms, the incubation media and the temperature (27-37 degrees C), from 27.4 +/- 3.4 to 55.0 +/- 4.8 microliters O2/mg larval protein per hr. It is proportional to the concentration of organisms incubated, up to 25,000/ml, as calculated from whole protein. 2. Oxygen uptake by cercariae is inhibited by 5.6 mM glucose in the incubation media, a concentration that stimulates the respiration of cercarial bodies. 3. No significant differences in the oxygen uptake were presented by cercarial bodies with and without glycocalyx or glandular secretions, or devoid of all of them. 4. Inhibitors of the Krebs cycle and the respiratory chain, and uncoupling agents influence the oxygen uptake by cercariae, cercarial bodies and schistosomules to the same extent. 5. The permeability change presented by transformed larvae had no influence on the excretion of lactate by cercarial bodies, which is about 0.3 mumoles/mg protein per hr and remains constant for 5 hr; under nitrogen, this amount increased 70%. Cercariae in anaerobiosis, however, excreted as much as 15 times more lactate than under air. 6. Lactic dehydrogenases of cercariae, cercarial bodies and tails, and schistosomules are of the muscle type and do not change during the transformation.

Animals↗
PubMed1975

Effects of barbiturates on ultrastructure and polymerization of microtubules in vitro.

Barbiturates were examined for in vitro effects on ultrastructure of the frog sciatic system and polymerization of microtubules (MT) in a brain supernatant. Exposure for 5-17 h to 2.0 mM barbiturates caused a considerable loss of MT in ganglionic cell bodies and sciatic axons. This was mostly followed by a proliferation of 10 nm filaments. Under similar conditions treatment with 1 mM NaCN or 0.1 mM 2,4-DNP did not change the number or ultrastructure of MT and filaments. Eight barbiturates, varying in binding ratios to serum albumin and partition coefficients, were tested for effects on polymerization of MT using viscometry. Inhibitory effects were found which correlated with their reported ability to bind to albumin and brain fractions. Dimethylsulphoxide and ethanol were used as solvents for some of the barbiturates. These solvents at 1% had stabilizing effects on MT. The present results are discussed in relation to previous findings of inhibition of rapid axonal transport in vitro in the frog sciatic system by barbiturates.

Animals↗
PubMed1978

Calcium-ion transport by intact Ehrlich ascites-tumour cells. Role of respiratory substrates, Pi and temperature.

1. The interaction of intact Ehrlich ascites-tumour cells with Ca2+ at 37 degrees C consists of Ca2+ uptake followed by efflux from the cells. Under optimum conditions, two or three cycles of uptake and efflux are observed in the first 15 min after Ca2+ addition. 2. The respiratory substrates malate, succinate and ascorbate plus p-phenylenediamine support Ca2+ uptake. Ca2+ uptake at 37 degrees C is sensitive to the respiratory inhibitors rotenone and antimycin A when appropriate substrates are present. Ca2+ uptake and retention are inhibited by the uncoupler S-13. 3. Increasing extracellular Pi (12 to 30 mM) stimulates uncoupler-sensitive Ca2+ uptake, which reaches a maximum extent of 15 nmol/mg of protein when supported by succinate respiration. Ca2+ efflux is partially inhibited at 30 mM-Pi. 4. Optimum Ca2+ uptake occurs in the presence of succinate and Pi, suggesting that availability of substrate and Pi are rate-limiting. K. Ca2+ uptake occurs at 4 degrees C and is sensitive to uncouplers and oligomycin. Ca2+ efflux at this temperature is minimal. These data are consistent with a model in which passive diffusion of Ca2+ through the plasma membrane is followed by active uptake by the mitochondria. Ca2+ uptake is supported by substrates entering respiration at all three energy-coupling sites. Ca2+ efflux appears to be an active process with a high temperature coefficient.

Animals↗
PubMed1979

Evidence for the rapid direct control both in vivo and in vitro of the efficiency of oxidative phosphorylation by 3,5,3'-tri-iodo-L-thyronine in rats.

1. Examination of the distribution of L-tri-iodothyronine among rat liver tissue fractions after its intravenous injection into thyroidectomized rats focused attention on mitochondria at very short times after administration. By 15 min this fraction contained 18.5% of the tissue pool; however, the content had decreased sharply by 60 min and even further over the next 3 h. By contrast, the content in all other fractions was constant or increased over 4 h. About 60% of tissue hormone was bound to soluble protein. 2. Mitochondria isolated from thyroidectomized rats showed P/O ratios that were about 50% of those found in normal controls, with both succinate and pyruvate plus malate as substrates. There was no evidence of uncoupling; the respiratory-control ratio was about 6. 3. Mitochondria isolated 15 min after injection of tri-iodothyronine into thyroidectomized rats showed P/O ratios and respiratory-control ratios that were indistinguishable from those obtained in mitochondria from euthyroid animals. The oxidation rate was, however, not restored. 4. Incubation of homogenates of livers taken from thyroidectomized animals injected with L-tri-iodothyronine before isolation of the mitochondria restored the P/O ratio to normal; by contrast, direct addition of hormone to isolated mitochondria had no effect. The role of extramitochondrial factors in rapid tri-iodothyronine action is discussed. 5. Possible mechanisms by which tri-iodothyronine might rapidly alter phosphorylation efficiency are considered: it is concluded that control of adenine nucleotide translocase is unlikely to be involved. 6. The amounts of adenine nucleotides in liver were measured both after thyroidectomy and 15 min after intravenous tri-iodo-thyronine administration to thyroidectomized animals. The concentrations found are consistent with a decreased phosphorylation efficiency in thyroidectomized animals. Tri-iodothyronine injection resulted in very significant changes in the amounts of ATP, ADP and AMP, and in the [ATP]/[ADP] ratio, consonant with those expected from an increased efficiency of ADP phosphorylation. This suggests that the changes seen in isolated mitochondria may indeed reflect a rapid response of liver in vivo to tri-iodo-thyronine.

Animals↗