Normal Rat Liver Mitochondria Research Articles

Synergistic effects of avicins and hydroperoxides on mitochondria: a possible mechanism for the selective killing of cancer cells

Avicins D and G are a class of plant saponins with pro-apoptotic activity in cancer cells, which is due in part to the direct perturbation of mitochondria (Haridas et al., PNAS USA, 2001). In this work, we studied the influence of avicins on the energy metabolism in normal rat liver mitochondria. Mitochondria, when treated with avicins, underwent a significant decrease in oxygen consumption in metabolic state 3 and in uncoupled state. The respiration was completely restored by addition of exogenous cytochrome c. Avicins also markedly increased the rotenone-insensitive oxidation of external NADH in the presence of exogenous cytochrome c, without induction of high amplitude swelling of mitochondria, thus confirming that the earlier effect of avicins is due to a permeabilization of the outer mitochondrial membrane to cytochrome c. On the other hand, avicins debilitate the enzymatic NAD(P)H-GSH-dependent antioxidant system of mitochondria due to a decrease of the inner membrane potential generation. As a result, avicins significantly increased a sensitivity of mitochondria to hydroperoxides, causing the acceleration of hydroperoxide-induced oxidation of endogenous NAD(P)H, the inner membrane potential drop and mitochondrial swelling. These data allow to explain relatively high selectivity of avicins in the killing of cancer cells, which have been shown to produce hydroperoxides with a very high rate.

Do Mitochondria make Nitric Oxide? No?

Several papers have claimed that mitochondria contain nitric oxide synthase (NOS) and make nitric oxide (NO•) in amounts sufficient to affect mitochondrial respiration. However, we found that the addition of l-arginine or the NOS inhibitor l-NMMA to intact rat liver mitochondria did not have any effect on the respiratory rate in both State 3 and State 4. We did not detect mitochondrial NO• production by the oxymyoglobin oxidation assay, or electrochemically using an NO• electrode. An apparent NO• production detected by the Griess assay was identified as an artifact. NO• generated by eNOS added to the mitochondria could easily be detected, although succinate-supplemented mitochondria appeared to consume NO•.Our data show that NO• production by normal rat liver mitochondria cannot be detected in our laboratory, even though the levels of production claimed in the literature should easily have been measured by the techniques used. The implications for the putative mitochondrial NOS are discussed.

Iron-induced peroxidative injury to isolated rat hepatic mitochondria

Peroxidative injury to the mitochondrial inner membrane with resultant defects in oxidative metabolism may be partially responsible for hepatocellular injury in iron overload. We examined the effects of iron-induced lipid peroxidation in vitro on hepatic mitochondrial morphology and function and determined if various inhibitors of free-radical-mediated injury could be protective. Normal rat liver mitochondria were prepared by differential centrifugation and were incubated with 1, 2, and 3 μM Fe 2+, NADPH, and with and without oxygen radical scavengers, iron chelators, and antioxidants. There was a direct linear relationship between the concentration of added iron and the degree of lipid peroxidation as measured by malondialdehyde (MDA) production ( r =.85). With 3 μM Fe 2+ there was a decrease in the respiratory control ratio (RCR) for all four substrates tested; this decrease in RCR was due to a decrease in the state 3 respiratory rate for all substrates, with no changes in the state 4 respiratory rate for glutamate, β-hydroxybutyrate, or succinate. Oxygen radical scavengers failed to prevent iron-induced lipid peroxidation or to protect against associated mitochondrial dysfunction. Iron chelators and antioxidants prevented MDA formation and mitochondrial function was maintained. Iron-induced lipid peroxidation in vitro produces an irreversible inhibitory defect in mitochondrial electron transport that may be specific at complex IV (cytochrome oxidase).

Stoichiometry of H + ejection coupled to electron transport through site 2 in ascites tumor mitochondria

The stoichiometry of H + ejection coupled to electron flow from succinate to ferricyanide in the electron transport chain of mitochondria from Ehrlich ascites tumor and AS30-D hepatoma cells was determined. Values close to 4.0 for the H + 2e − ejection ratio were found in both cell lines, with either Ca 2+ or K + (+ valinomycin) as charge-compensating permeant cation. The 4 H + ejected were compensated by outward movement of two negative charges to reduce 2 Fe(CN)6 3− to 2 Fe(CN)6 4−, and the uptake of two positive charges in the form of the permeant cation. Experiments on (a) omission of rotenone (b) the effect of antimycin A and (c) depletion of endogenous NAD(P)-linked substrates showed that no significant endogenous electron flow or H + ejection occurred, thus eliminating possible overestimation of the H +/2e − ratio from endogenous substrates. These data on mitochondria from two tumor cell lines are fully consistent with earlier measurements of the H +/O stoichiometry for succinate and NADH oxidation in tumor mitochondria and with the H + 2e − stoichiometry for site 2 in normal rat liver mitochondria.

The phosphorylation potentials generated by respiring Ehrlich ascites tumor mitochondria

The extra- and intramitochondrial phosphorylation potentials (Δ G p(out) and Δ G p(in), respectively) generated by respiring Ehrlich ascites tumor mitochondria were determined, using succinate, pyruvate + malate, ascorbate + N,N,N′,N′-tetramethyl- p-phenylenediamine, and ascorbate + ferrocyanide as substrate systems. Values of Δ G p(out) exceeding 15 kcal mol −1 (62.8 kJ mol −1) in post-ADP state 4 respiration were found with succinate as substrate, in agreement with data on normal rat liver mitochondria. ΔG p(out) values exceeding 15 kcal mol −1 (62.8 kJ mol −1) were also observed with ascorbate + TMPD or ascorbate + ferrocyanide as substrates. Slightly lower values of Δ G p(out) were found with the NAD-linked substrates pyruvate + malate. The intramitochondrial Δ G p(in) developed by respiring Ehrlich ascites tumor mitochondria respiring on succinate approached 12 kcal mol −1 (50.2 kJ mol −1), in agreement with reported values on rat liver mitochondria. The prior accumulation of Ca 2+ and phosphate by the Ehrlich cell mitochondria did not lower the extramitochondrial Δ G p(out) developed after a subsequent addition of ADP. Although the rate of oxidative phosphorylation of Ehrlich ascites tumor cells is reduced by intramitochondrial Ca 2+ and phosphate ( Villalobo and Lehninger (1980) J. Biol. Chem., 255, 2457–2464 ) they are still capable of generating ATP in the suspending medium against a high thermodynamic gradient, as expressed by the [ATP]/[ADP][ P i]mass action ratio.

Effect of lead on glycine cleavage activity in rat liver mitochondria

Change of glycine cleavage activity in liver mitochondria of lead-intoxicated rats was studied in this paper. The following results were obtained: (1) The activity in hepatic mitochondria of rats was decreased by a single administration of lead (4 mg/100 g body weight); (2) in vitro the activity in the normal rat liver mitochondria was markedly inhibited by addition of lead acetate (4mM).

DNA biosynthesis in rat liver mitochondria: Inhibition by sulfhydryl compounds and stimulation by cytoplasmic proteins

The sulfhydryl compounds, 2-mercaptoethanol, dithiothreitol, cysteine. and glutathione inhibit the incorporation of [ 3H]dTTP or [ 3H]dATP into mitochondrial DNA by rat liver mitochondria in vitro. The lack of inhibition by non-SH-containing analogs indicates that the SH group is responsible for the inhibition. The inhibition does not result from an effect of the sulfhydryl compounds on precursor permeability, ATP formation, or respiration, or the action of the thiol on the outer mitochondrial membrane. An intact inner membrane is not required for the action of the inhibitor. Furthermore, SH compounds do not appear to exert their effect by activation of a mitochondrial nuclease, chemical breakdown of high molecular-weight mitochondrial DNA or dissociation of membrane-bound DNA from the inner mitochondrial membrane. Incorporation of labeled precursor into DNA by mitochondrial DNA polymerase, when removed from the inner mitochondrial membrane, is not inhibited by SH compounds. Cytoplasmic extracts prepared from rat and mouse tumors and 22-h regenerating rat liver contain a protein(s) not detectable in normal rat liver which can reverse the inhibition by SH compounds of the synthesis of mitochondrial DNA in rat liver mitochondria in vitro. More importantly, when the stimulatory protein(s) is partially purified by affinity chromatography on DNA-cellulose, it is possible to demonstrate that this protein(s) also stimulates the synthesis of mitochondrial DNA by normal rat liver mitochondria in vitro in the absence of the sulfhydryl inhibitor.

Effect of Growth Hormone on Mitochondrial Protein Synthesis

Abstract l-[U-14C]Leucine incorporation into the trichloroacetic acid-precipitable fraction of mitochondria after incubation with succinate as energy source was significantly higher with normal rat liver mitochondria than with hypophysectomized rat liver mitochondria. The incorporation was sensitive to inhibition by chloramphenicol, terramycin, dinitrophenol, and NaCN, but not to RNase and cycloheximide. The differences in the rate of incorporation between the two types of mitochondria were not abolished when the endogenous energy source from succinate was replaced by an external ATP-generating mixture or when cold trichloroacetic acid precipitate was extracted with hot 5% trichloroacetic acid or when high concentrations of unlabeled leucine (up to 200 mm) were added. Uptake of l-[U-14C]leucine, in the absence of incorporation, was higher with hypophysectomized rat liver mitochondria than with normal rat liver mitochondria. However, when mitochondria were washed extensively after incubation there was no significant difference in the uptake. Growth hormone treatment of hypophysectomized rats for 5 days significantly increased both in vivo and in vitro incorporation of leucine. The in vitro stimulating effect of growth hormone became apparent as early as 15 min and was significant 30 min after a single intravenous injection of the hormone. These results suggest that growth hormone has a significant effect on liver mitochondrial protein synthesis.

Properties of density gradient-separated liver mitochondria from triiodothyronine-treated rats.

SummaryTwo populations of liver mitochondria from T3-treated rats, which were separated on sucrose density gradients, and normal rat liver mitochondria were studied. The more dense mitochondrial band from T3-treated rats consistently had the highest in vivo rate of 32P-orthophosphate incorporation into phospholipids and was significantly different from 32P incorporation into the phospholipids of the less dense mitochondrial band at 60 min. No differences in the in vivo rate of 14C-l-leucine incorporation into mitochondrial protein or in the major mitochondrial fatty acids were found among the bands studied. Significant differences in phospholipid:protein ratios were found between the two mitochondrial bands of the T3-treated group. The density differences of the mitochondrial bands might be explained by alterations in the phospholipid:protein ratios since changes in these ratios correlate with mitochondrial densities.The authors thank Dr. Donald Greiff for the use of his ultracentrifuge, and Drs. Roberto ...

Reversible Inhibition of Adenine Nucleotide Translocation by Long Chain Fatty Acyl Coenzyme A Esters in Liver Mitochondria of Diabetic and Hibernating Animals

The sluggish respiratory response to ADP in liver mitochondria of alloxan diabetic rats and hibernating ground squirrels was overcome by addition of uncouplers of oxidative phosphorylation, suggesting that poor penetration of ADP prevented maximum oxygen consumption. The in vivo depression of adenine nucleotide translocation through the inner mitochondrial membrane was confirmed directly by measurements of [14C]ADP translocase and 32Pi-ATP exchange reactions. The inhibition of adenine nucleotide penetration was considered to be a consequence of increased hepatic lipid content, particularly long chain acyl-CoA esters, which occur in diabetes and hibernation. Demonstrated changes in the pattern of mitochondrial long chain fatty acids may be responsible for the altered spectral characteristics of the cytochromes observed in these animals. The inhibition of adenine nucleotide translocation could be reproduced in vitro with normal rat liver mitochondria by production of, or upon addition of certain esters of long chain fatty acids. Simultaneous addition of pyruvate or α-ketoglutarate with the free fatty acid prevented formation of the acyl-CoA ester and inhibition of translocation. Selective reversal of the inhibition by carnitine provided strong evidence implicating the acyl-CoA ester rather than the free fatty acid as the inhibitory agent. From these results, it is postulated that certain long chain acyl-CoA esters, acting as natural effectors of adenine nucleotide translocation, can perform a physiological role in the regulation of mitochondrial metabolism.

Stimulation of mitochondrial protein synthesis and oxygen consumption by thyroxine in vitro without deiodination to triiodothyronine.

Abstract The abilities of triiodothyronine (T 3 ) and thyroxine (T 4 ) to stimulate protein synthesis and oxygen consumption and to alter ADP/O and respiratory control ratios in normal rat liver mitochondria in vitro have been investigated together with determinations of the extent of conversion of T 4 to T 3 . There was no significant differences in the ability of either hormone to stimulate protein synthesis or oxygen consumption. ADP/O and respiratory control ratios were approximately equally depressed by T 4 and T 3 in concentrations (10 and 50 μM) which increased mitochondrial protein synthesis and oxygen consumption. T 4 was not appreciably deiodinated to T 3 , indicating that the hormones are of equal potency in producing these effects in normal mitochondria in vitro .

The relationship of mitochondrial swelling to thyroxine-stimulated mitochondrial protein synthesis.

The effects of thyroid hormones and other swelling agents upon mitochondrial volume and upon uptake and incorporation of leucine by normal rat liver mitochondria have been studied in vitro in the medium usually employed for protein synthesis. The lowest concentration of T4 (10 μM) which consistently caused swelling also stimulated amino acid incorporation; both increased as the concentration of T4 was increased to 50 μM. High levels of T4 (ξ100 μM) caused further swelling but inhibited incorporation.The ability of analogues of T4 to stimulate incorporation paralleled their ability toproduce swelling. Inhibition of protein synthesis by chloramphenicol did not alter T4-induced swelling. Of other agents tested, Pi and Fe+ caused swelling without affecting incorporation. Other cations (Ca+, Zn+, Cu+, Ag+ and Hg+) and steroid hormones (progesterone and deoxycorticosterone acetate) markedly inhibited incorporation while causing variable degrees of swelling. The fatty acids (myristic and palmitic acid) also inhi...

Effect of the Ethyl Ester and Sodium Salt of -p-Chlorophenoxyisobutyric Acid on Cholesterol Oxidation by Rat Liver Mitochondria,

SummaryMitochondrial preparations from livers of rats fed 0.3% ethyl α-p-chlorophenoxyisobutyrate (CPIB) show an increased capacity to oxidize cholesterol-26-14C to 14CO2. When oxidation is calculated per milligram of mitochondrial nitrogen, oxidation of cholesterol by mitochondria from CPIB-fed rats is the same as that observed in normal rat liver mitochondria. In the absence of the boiled supernatant cofactor (cytosol) the mitochondria from CPIB-treated rats show a significantly higher capacity for cholesterol oxidation than do normal mitochondrial preparations. Mitochondria prepared from livers of rats fed sodium α-p-chlorophenoxyisobutyrate also oxidize more cholesterol than do control preparations. Fasting of the rats for 18 hr prior to mitochondrial preparation does not affect the extent of oxidation either in the presence or absence of cytosol. Mitochondrial preparations from CPIB-fed mice also oxidize more cholesterol than do controls. Studies of mitochondrial acid phosphatase and β-glucuronidase ...

Oxidative phosphorylation and adenosine triphosphatase activity in the liver mitochondria of rats administered with phenylhydrazine and hydrolyzed glucose cycloacetoacetate.

The effect of phenylhydrazine and hydroiyzed product of glucose cycloacetoacetate (GCAh) administration on the activity of adenosine triphosphatase (ATPase) in rat-liver mitochondria has been investigated. The results are discussed in relation to the efficiency of mitochondrial oxidative phosphorylation. Phenylhydrazine was found to increase the ATPase activity both in vitro and in vivo. However, preincubation or treatment with hydrolyzed glucose cycloacetoacetate resulted in an appreciable depression of this phenylhydrazine-enhanced enzyme activity. The liver mitochondria from phenylhydrazine-administered rats showed very little difference in milligrams of total protein, but the homogenates had a high protein content as compared to the preparations from normal rats and rats administered with hydrolyzed glucose cycloacetoacetate. With citrate as the substrate, normal rat-liver mitochondria exhibited a P/O ratio of 3.0. With the same substrate, the liver mitochondria from phenylhydrazine-administered rats lowered the oxygen uptake and ATP formation, thereby resulting in a decreased P/O ratio of 2.4, whereas administration of hydrolyzed glucose cycloacetoacetate prior to phenylhydrazine resulted in a partial restoration in oxygen uptake and ATP formation, and thus yielded a P/O ratio of 2.8.

Incorporation of 32P i into mitochondrial and nuclear DNA in regenerating liver

32P i incorporation into the liver DNA of normal and hepatectomized rats was studied. Four h after injection of 32P 1 into normal rats the mitochondrial DNA had a specific activity 6 times as great as did nuclear DNA. Twelve h after hepatectomy a 4-h incorporation of 32P i showed that the specific activity of mitochondrial DNA was 18 times as great as that of nuclear DNA and accounted for 50% of the 32P i incorporated into the total liver DNA. At 24 h post hepatectomy the rate of nuclear synthesis of DNA reached a maximum and the specific activities of nuclear and mitochondrial DNA were then equal after a 4-h incorporation. When normal rats were injected with 32P i and sacrificed at times between 1 and 14 days after injection it was found that the specific activity of the mitochondrial DNA did not change appreciably during that period. In hepatectomized animals, both nuclear and mitochondrial DNA reached a maximum specific activity 2 days after injection and then both decayed at the same rate. The results indicate that mitochondrial DNA, like nuclear DNA, is metabolically stable and that DNA synthesis in normal ratliver mitochondria is a continuous process. The base ratios of mitochondrial and nuclear DNA were slightly but consistently different. A metabolically active contaminant associated with purified mitochondrial DNA after enzymatic digestion to mononucleotides was identified as AMP.

The influence of thyroid hormones on normal rat-liver mitochondria I. Changes associated with the inhibition of phosphorylation by thyroxine added to untreated mitochondria

1. 1. A study of the uncoupling of oxidative phosphorylation by thyroxine in the presence of MgCl 2 has demonstrated that the reduced phosphorylation efficiency was associated with an inhibition of the terminal phosphate-transferring reactions and a slowing of the rate of substrate oxidation. These initial effects were followed by a loosening of respiratory control. No pretreatment of the mitochondria was necessary in order to observe the effects although it was essential that the thyroxine be added to the incubation medium after the mitochondria. 2. 2. Thyroxine did not induce mitochondrial swelling under the conditions required for phosphorylation. However, contrary to the observations of other investigators, thyroxine did induce mitochondrial swelling in the presence of adenosine 5′-triphosphate and MgCl 2. At high levels of adenosine 5′-triphosphate the swelling was followed by an increase in the adenosine-5′-triphosphatase activity of the mitochondria.

Mechanism of Aminonucleoside-Induced Nephrosis in the Rat. IV. Hepatic Mitochondrial Oxidative Phosphorylation.

Summary1. Phosphorylation associated with the oxidation of succinate is significantly higher in aminonucleoside-nephrotic rat liver mitochondria than in normal rat liver mitochondria. This alteration is induced as early as the 4th day during a 10-day period of induction of the disease with aminonucleo-side. 2. Phosphorylation associated with the oxidation of a-ketoglutarate, malate, fuma-rate, and β-hydroxybutyrate is not significantly altered in liver mitochondria of the aminonucleoside-nephrotic rat. 3. Phosphorylation associated with the oxidation of succinate is also increased in normal rat liver mitochondria incubated directly with aminonucleoside. In similar experiments conducted with rat liver submitochondrial phosphorylating complexes, however, aminonucleoside inhibits oxidative phosphorylation.We are indebted to Dr. J. M. Ruegsegger, Lederle Medical Research Section, American Cyanamid Co., for aminonucleoside used in this study.

Biochemical actions of thyroid hormones.

ArticlesBiochemical Actions of Thyroid HormonesFrederic L. HochFrederic L. HochPublished Online:01 Oct 1962https://doi.org/10.1152/physrev.1962.42.4.605MoreSectionsPDF (11 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByCombination treatment with captopril and the thyroid hormone analogue 3,5-diiodothyropropionic acid. 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Changes associated with the inhibition of phosphorylation by thyroxine added to untreated mitochondriaBiochimica et Biophysica Acta (BBA) - General Subjects, Vol. 97, No. 1Comparative uptake of dl-lysine-H3 by normal and regenerative hypoglossal nerve cells in euthyroid, hypothyroid and hyperthyroid male ratsExperimental Neurology, Vol. 10, No. 3Stimulation of amino acid incorporation into protein by isolated mitochondria from rats treated with thyroid hormonesBiochimica et Biophysica Acta (BBA) - Specialized Section on Nucleic Acids and Related Subjects, Vol. 72 More from this issue > Volume 42Issue 4October 1962Pages 605-673 https://doi.org/10.1152/physrev.1962.42.4.605PubMed13954890History Published online 1 October 1962 Published in print 1 October 1962 Metrics

Oxidative phosphorylation in the livers of normal and malnourished human infants.

1. Respiration, oxidative phosphorylation and the uptake of phosphate into phosphatidic acid have been measured in samples of liver obtained by biopsy from malnourished and recovered human infants. All measurements were made on homogenates. 2. Respiration was well maintained in the malnourished liver, but phosphorylation was slightly reduced, and P uptake into phosphatidic acid greatly reduced. Ageing by pre-incubation caused a much greater reduction of phosphorylation in homogenates from malnourished than from normal livers. Albumin had some protective effect. 3. In the malnourished infants the livers were usually fatty. All the changes observed were more severe in the more fatty livers. 4. Homogenates from malnourished fatty livers were capable of inhibiting phosphorylation by normal rat liver mitochondria. This and other evidence suggests that the reduction in phosphorylation in the malnourished livers may result from the uncoupling action of free fatty acids or some other lipid derivative. 5. The question is discussed whether there may be changes of mitochondrial function in the malnourished livers, independent of fatty infiltration.

Effect of hydrocortisone on mitochondrial membrane permeability.

HYDROCORTISONE has been found to inhibit severely oxidative metabolism in vitro by normal rat liver mitochondria. Concentrations of 5 × 10−4 M and greater inhibit the oxidation of octanoate, L-glutamate and all tricarboxylic acid cycle intermediates except succinate. Similar patterns of inhibition have been reported for other steroids1–6.