Stimulation of Dopamine Oxidation in Liver Mitochondria by Palmitic

ISSN 1990-7478, Biochemistry (Moscow), Supplement Series A: Membrane and Cell Biology, 2016, Vol. 10, No. 3, pp. 188–194. © Pleiades Publishing, Ltd., 2016. Original Russian Text © V.N. Samartsev, M.V. Dubinin, 2016, published in Biologicheskie Membrany, 2016, Vol. 33, No. 3, pp. 232–240.

ARTICLES

Stimulation of Dopamine Oxidation in Liver Mitochondria by Palmitic Acid in the Presence of ATP and tert-Butylhydroperoxide V. N. Samartsev and M. V. Dubinin Mari State University, pl. Lenina 1, Yoshkar-Ola, 424001 Russia e-mail: [email protected] Received September 22, 2015

Abstract—The effect of palmitic acid on the oxidation of dopamine, i.e., on the monoamine oxidase (MAoxidase) activity, was investigated on deenergized liver mitochondria, upon energization by ATP and also in the presence of an oxidizing agent tert-butylhydroperoxide (TBH). It was found that palmitic acid reduces the value of the apparent Km for dopamine without alteration of the apparent Vmax. This points to stimulation of the mitochondrial MA-oxidase activity by palmitic acid at low concentrations of dopamine. Stimulatory effect of palmitic acid may be related to the ability of amphiphilic compounds to increase the negative charge density on the outer mitochondrial membrane. This leads to an increase in the local concentration of positively charged ions of dopamine in the layer adjacent to the membrane near the active site of monoamine oxidase. ATP eliminates the ability of palmitic acid to stimulate the MA-oxidase activity of mitochondria. This effect of ATP is not observed in the presence of the FOF1-ATP-synthase inhibitor oligomycin. Apparently, in the case of vector transport of H+ from the matrix induced by ATP-hydrolysis, protonation of palmitic acid anions occurs on the outer mitochondrial membrane, followed by the movement of the neutral molecules to the outer and then to the inner monolayer of the inner membrane. It was found that TBH at a concentration of 300 μM has no significant effect on the ATPase activity of mitochondria and in the presence of ATP and palmitic acid reduces the value of the apparent Km for dopamine without alteration of the apparent Vmax. Antioxidant thiourea eliminates this effect of TBH. We propose that the TBH-induced oxidative stress in the case of ATP-energized mitochondria results in the movement of palmitic acid molecules from the inner to the outer membrane. This leads to an increase in the density of negative charges on the surface of this membrane and, therefore, to the stimulation of the dopamine oxidation. Keywords: mitochondria, dopamine, palmitic acid, oxidative stress DOI: 10.1134/S1990747816020094

INTRODUCTION It is generally accepted nowadays that animal mitochondria are one of the major sources of reactive oxygen species (ROS) produced in a cell [1–3]. Hyperproduction of ROS causing oxidative stress leads to the damage of various intracellular structures and ultimately to a cell death [1, 2, 4]. Reduced production of ROS in mitochondria can be achieved by increasing the proton conductivity of the inner membrane (induction of “mild” uncoupling) using uncouplers of oxidative phosphorylation [1, 2, 5]. Long-chain free fatty acids are natural “mild” uncouplers of oxidative phosphorylation, which are able to reduce the generation of ROS in mitochondria [1, 2, 5–7]. In liver mitochondria the metabolite transfer proteins of the inner mitochondrial membrane performing the exchange transport of ADP to ATP (ADP/ATP antiporter) and aspartate to glutamate (aspartate/glutamate antiporter) are involved in the protonophoric uncoupling effect of fatty acids [8–10].

Previously we have shown [9, 10] that in liver mitochondria, in the presence of ADP and aspartate⎯ physiological substrates of ADP/ATP and aspartate/glutamate antiporters⎯uncoupling activity of palmitic acid increases under the oxidative stress caused by endogenous processes associated with an animal aging or induced by oxidizing agent tert-butylhydroperoxide (TBH). It is suggested that intensification of free radical and peroxide reactions leads to an increase in the transport rate of palmitic acid anions from the inner monolayer of the inner membrane to its outer monolayer with the participation of the ADP/ATP and aspartate/glutamate antiporters [9, 10]. It can also be assumed that the increase in the transport rate of fatty acid anions can lead to their accumulation in the outer monolayer of the inner membrane and subsequent transition to the outer membrane. It is known that the addition of unsaturated oleic acid to liver mitochondria leads to the inhibition of glycerol-3-phosphate dehydrogenase and activation of monoamine oxidase localized on the outer surface of

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the inner membrane and on outer membrane respectively [11]. Magnesium ions, calcium ions and other divalent cations increase the activity of this enzyme and eliminate such effects of fatty acids [11–13]. It was suggested that the effects of oleic acid described above can be accounted for by the ability of an amphiphilic compound to increase the negative charge density on the mitochondrial membrane surface [11]. Monoamine oxidase activity can be enhanced by other methods of increasing the density of negative charges on the membrane surface associated with this enzyme, which is considered as an additional argument in favor of this hypothesis [14, 15]. According to the model proposed in [14, 15], an increase in the density of negative charges on the surface of the outer membrane causes an increase in the local concentration of positively charged dopamine ions near the active center of monoamine oxidase as compared to the average bulk concentration. In kinetic measurements this local change in the concentration of dopamine is manifested as a decrease in the apparent Km without alteration of the apparent Vmax [11, 14, 15]. It should be noted that unsaturated oleic acid, unlike the saturated fatty acids, can undergo peroxidation at the double bond, which in turn may affect the state of the membrane lipid bilayer [16]. In this regard, for the study of the influence of negative surface charges on the activity of enzymes associated with membranes, it is reasonable to use saturated fatty acids, and in particular, palmitic acid, as one of the most widespread natural saturated fatty acids [17] that has a sufficiently high degree of hydrophobicity [18]. Recently, we have found that in the case of ATPdependent energization of liver mitochondria, TBH in the presence of palmitic acid inhibits their glycerol-3phosphate oxidase activity formally in the competitive manner [19]. These data were considered as evidence that TBH-induced oxidative stress in the case of ATPenergized mitochondria results in an increase in transport rate of palmitic acid anions from the inner to outer monolayer of the inner membrane, that, in turn, is accompanied by an increase in the density of negative charges on the outer surface of the inner mitochondrial membrane and inhibition of glycerol-3phosphate oxidase activity of liver mitochondria formally in the competitive manner. It can be supposed that under oxidative stress the molecules and (or) anions of palmitic acid will move from the outer monolayer of the inner membrane to the outer membrane. This movement will increase the density of negative charges on the surface of this membrane, and this in turn would increase the local concentration of positively charged ions of dopamine in the layer adjacent to the outer membrane as compared to the average bulk concentration, and consequently lead to a decrease in the apparent Km for the monoamine oxidase (MA-oxidase) activity of mitochondria.

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In this work, effects of palmitic acid on the MAoxidase activity of liver mitochondria were investigated. It was figured out how the activating effect of this saturated fatty acid changed upon energization of mitochondria by the ATP hydrolysis and in the presence of an oxidizing agent TBH. MATERIALS AND METHODS Mitochondria were isolated from the liver of mature white male rats weighing 210–250 g using a standard differential centrifugation technique with subsequent separation of endogenous fatty acids with fatty acid-free bovine serum albumin (BSA), as described in detail previously [8]. The isolation medium contained 250 mM sucrose, 1 mM EGTA, and 5 mM MOPS-Tris (pH 7.4). The mitochondrial protein concentration was determined by the biuret method with bovine serum albumin used as standard. During the experiments, the suspension of mitochondria (70–80 mg mitochondrial protein in 1 mL) was stored on ice. MA-oxidase activity of liver mitochondria was determined by recording the oxygen consumption by the polarographic method [11]. Dopamine at a concentration of 50–400 μM was used as the substrate of oxidation. Mitochondrial respiration was recorded using Clark type oxygen electrode and Record-4 USB original multichannel electrometrical system in a thermostatic closed cuvette at 37°C. The incubation medium contained 250 mM sucrose, 0.5 mM EGTA, 10 mM MOPS-Tris (pH 7.4). Upon determination of the MA-oxidase activity, rotenone (2 μM) was added into the oxygen cell right after the addition of mitochondria (~1.5 mg/mL), dopamine was added 2 min later. The values of the apparent Km and Vmax, characterizing the dependence of the rate of the MA-oxidase activity (v) on the concentration of dopamine ([s]) were determined as the parameters of a linear regression equation:

v = −K m v + V max , [s] by the method of least squares using a personal computer and software package Statistica 6.0. Changes in the mitochondrial inner membrane Δψ was estimated using tetraphenylphosphonium (TPP+)-sensitive electrode, as described in detail previously [19]. In this case, the incubation medium was supplemented with 1.6 μM TPP+. The rate of the oligomycin-sensitive ATP hydrolysis by mitochondria (ATPase activity) was estimated by an increase in the hydrogen ion concentration in the incubation medium using an H+-electrode [19]. Incubation medium was similar to that mentioned above, except that the MOPS concentration was lowered to 3 mM and the pH was adjusted to 7.4 with KOH. MOPS, Tris, palmitic acid, oligomycin, thiourea, and fatty acid-free bovine serum albumin were from Sigma; rotenone and EGTA, from Serva; dopamine,

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ATP, sucrose, and tetraphenylphosphonium chloride, from Fluka; KOH and MgCl2, from Merck. Palmitic acid was dissolved in double-distilled ethanol. RESULTS In this work we used dopamine (existing in the form of a cation at pH 7.4 [11]) as a substrate of liver mitochondrial monoamine oxidase. It was shown that in the presence of rotenone, the dependence of the respiration rate of liver mitochondria on the dopamine concentration (MA-oxidase activity) is linear in double inverse coordinates (Fig. 1) and therefore has a hyperbolic character. Formally, apparent values of Km and Vmax can be used to characterize this dependence [11]. Under the conditions applied, these values are 143 ± 12 μM and 3.20 ± 0.25 nmol O2/min per 1 mg of protein, respectively, and are in agreement with the published data [11]. As follows from the data presented in Fig. 1, palmitic acid at a concentration of 50 μM (33 nmol per 1 mg of mitochondrial protein) stimulates the mitochondrial MA-oxidase activity; the effect is most pronounced at low concentrations of dopamine. In this case, the apparent Km for dopamine is reduced from 143 ± 12 to 42 ± 3 μM (3.4-fold) without alteration of the apparent Vmax. A possible cause of this palmitic acidinduced decrease in the apparent Km for dopamine can be an increase in the number of negative charges on the outer membrane. It is well known that the divalent metal ions, such as magnesium, can shield the negative surface charges on membranes [11, 20]. In our studies, the addition of 5 mM magnesium chloride to the mitochondria largely eliminates the effect of palmitic acid (data not shown). In the absence of exogenous substrates and in the presence rotenone, liver mitochondria are able to absorb a small amount of TPP+ (Fig. 2). However, this may be due to the energy-independent binding of TPP+ to the mitochondrial membranes [21]. Consequently, the inner membrane of the mitochondria has no Δψ or, in other words, the mitochondria are in the deenergized state. It is well known that FOF1-ATPsynthase, which performs vector transport of H+ from the matrix to the intermembrane space during the ATP hydrolysis, may be involved in the generation of Δψ across the inner membrane [1, 22]. In the conditions applied, the addition of 2 mM ATP to the deenergized liver mitochondria causes the generation of Δψ up to the almost maximal level ([19] and Fig. 2a). In this case, a preliminary application of the FOF1-ATP-synthase inhibitor oligomycin prevents the generation of Δψ in the case of the addition of ATP but not of succinate [19]. Palmitic acid, significantly reducing Δψ in the inner membrane of liver mitochondria (Fig. 2b), has no significant effect on the oligomycin-sensitive ATPase activity (Fig. 3).

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[Dopamine]−1, µM−1 Fig. 1. The dependence of the MA-oxidase activity of liver mitochondria (v) on the concentration of dopamine in double inverse coordinates in the absence of additives (1) and in the presence of palmitic acid (2); palmitic acid and ATP (3) or palmitic acid, ATP and oligomycin (4). Experimental conditions and incubation medium composition are described in Materials and Methods. Final concentrations of dopamine in the incubation medium are 50, 100, 200, 300, and 400 μM; of palmitic acid, 50 μM; of ATP, 2 mM; of oligomycin, 3 μg/mL.

As was established in preliminary studies, 2 mM ATP in the absence of palmitic acid has no effect on the MA-oxidase activity of mitochondria (data not shown). In the following experiments we studied the effect of ATP on the MA-oxidase activity of liver mitochondria in the presence of palmitic acid. As is shown in Fig. 1, the addition of 2 mM ATP to mitochondria in the presence of palmitic acid causes an inhibition of the mitochondrial MA-oxidase activity at low concentrations of dopamine. The value of the apparent Km is increased from 42 ± 3 to 118 ± 6 μM without alteration of the apparent Vmax. Such an inhibitory effect of ATP is not observed in the presence of oligomycin (Fig. 1). In this case, the apparent Km is only 48 ± 5 μM. These data suggest that in the presence of palmitic acid, inhibition of the MA-oxidase activity by ATP is due to its hydrolysis involving FOF1-ATP-synthase. Oxidative stress in mitochondria can be modeled using TBH [10, 23–26]. It is known that the incubation of mitochondria with TBH leads to the oxidation of pyridine nucleotides and glutathione and is accompanied by the formation of methyl and other free radicals, as well as an increase in the amount of products of lipid peroxidation⎯diene conjugates [24–26].

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Thiourea antioxidant significantly reduces the prooxidant action of TBH on mitochondria [26]. At the same time, TBH at concentrations up to 200 μM (200 nmol per 1 mg of mitochondrial protein), possessing a pronounced prooxidant effect on mitochondria, has no effect on the respiration and ATP synthesis [26]. As was shown previously [19] and is confirmed in this study (Fig. 2), the addition to liver mitochondria of TBH at a concentration of 300 μM (200 nmol per 1 mg of mitochondrial protein) has no effect on the ATPinduced Δψ generation. Consequently, TBH does not affect the mitochondrial energy machine associated with the vector transport of protons from the matrix to the intermembrane space during the ATP hydrolysis. In the following experiments it was found that TBH has no effect on the MA-oxidase activity of mitochondria in the absence of ATP and palmitic acid (Fig. 4). However, as is seen in Fig. 5, TBH significantly increases the MA-oxidase activity of mitochondria in the presence of palmitic acid and ATP. In this case, the apparent Km for dopamine is reduced from 118 ± 6 to 45 ± 8 μM without changes in the apparent Vmax. Thiourea eliminates this effect of TBH (Fig. 5). In this

case, the apparent Km for dopamine is 114 ± 9 μM. Without ATP and palmitic acid, thiourea has no effect on the MA-oxidase activity of mitochondria (data not shown). DISCUSSION The results obtained indicate that in deenergized liver mitochondria in the absence of magnesium ions palmitic acid reduces the value of the apparent Km for dopamine without alteration of the apparent Vmax. This points to the stimulation of mitochondrial MA-oxidase activity by palmitic acid at low concentrations of dopamine. As mentioned in the Introduction, the unsaturated oleic acid exerts a similar effect [11]. It is proposed that the stimulatory action of oleic acid is not due to a direct effect on the monoamine oxidase but is related with an increase in the density of negative charges on the surface of the outer membrane [11, 14, 15]. Apparently, in the conditions applied in this work, the stimulating effect of palmitic acid on the MA-oxidase activity of liver mitochondria can also be caused by an increase in the density of negative charges on the outer surface of the membrane near the


active site of monoamine oxidase. On the basis of the known model [11, 14, 15], an assumption can be made that the increase in the density of negative charges on the surface of the outer membrane caused by palmitic acid should increase the local concentration of positively charged ions of dopamine in the layer adjacent to the outer membrane as compared to the average bulk concentration, and consequently lead to a decrease in the apparent Km for the MA-oxidase activity of mitochondria. However, we cannot exclude that an increase in the density of negative charges on the outer surface of the membrane caused by palmitic acid may also lead to structural changes in monoamine oxidase resulting in an increase of the enzyme activity. In the presence of palmitic acid ATP causes inhibition of the MA-oxidase activity of liver mitochondria at low concentrations of dopamine. This effect of ATP is due to its hydrolysis involving FOF1-ATP-synthase because it is inhibited by oligomycin. It is known that in the absence of palmitic acid the ATP hydrolysis with the participation of this complex is accompanied by the generation of Δψ [1]. Palmitic acid as an effective protonophore uncoupler of oxidative phosphorylation [1, 2, 5–7] significantly reduces Δψ and has no effect on the oligomycin-sensitive ATPase activity (Figs. 2 and 3). It should be noted that the effect of protonophore uncouplers on the oligomycin-sensitive ATPase activity of mitochondria is biphasic: at low concentrations and in the case of a small decrease in Δψ protonophore uncouplers significantly increase the rate of the ATP hydrolysis, whereas at higher concentrations and a significant drop in Δψ, the rate of the ATP hydrolysis is reduced [27]. Apparently, palmitic acid acts on the ATP hydrolysis in a similar manner. Fatty acids are weak acids. It is well known that under the conditions of mitochondrial energization weak acids pass through the inner membrane of these organelles in the protonated form using pH gradient, then get deprotonated and accumulate in the matrix in the form of anions [1]. Recently we assumed that under the influence of the vector transport of H+ from the matrix to the intermembrane space of mitochondria induced by the ATP hydrolysis the amount of palmitic acid anions in the outer monolayer of the inner membrane of these organelles is significantly reduced [19]. This may be due to protonation of fatty acid anions and subsequent passage of most of their neutral molecules from the outer to the inner monolayer of the inner membrane. It can also be assumed that in these conditions there is a movement of the molecules of fatty acids by the concentration gradient from the outer membrane to the outer monolayer of the inner membrane. This movement is accompanied by a decrease in the density of negative charges on the surface of the outer membrane and is manifested as an increase in the apparent Km for dopamine without alteration of the apparent Vmax in the case of mitochondrial energization by the ATP hydrolysis.

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contact sites [28, 29]. Palmitic acid has a sufficiently high degree of hydrophobicity, and being added to the mitochondrial suspension is localized mainly in the lipid phase of these organelles [18]. Apparently, movement of the molecules of this fatty acid between the outer and inner membranes is carried out mainly in the field of intermembrane contact sites. In the presence of ATP and in the case of the TBHinduced oxidative stress palmitic acid stimulates MAoxidase activity of mitochondria, as well as in the absence of high energy compounds. It was noted in the Introduction that in the conditions of high energy state of mitochondria upon succinate oxidation, the oxidative stress induced by TBH results in an increased uncoupling activity of palmitic acid, and it may be associated with an increase in transport rate of palmitic acid anions from the inner monolayer of the inner membrane to its outer monolayer [10]. Under oxidative stress, the movement of the palmitic acid molecules to the outer membrane will increase the density of negative charges on its surface. Obviously, if this mechanism operating in the case of TBH-induced oxidative stress would also work in the conditions of ATP-dependent mitochondrial energization, then an increase in the number of negative charges on the outer monolayer should increase the local concentra-

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tion of positively charged dopamine ions in the layer adjacent to the membrane near the active center of monoamine oxidase, as compared to the average bulk concentration. This is manifested as a decrease in the apparent Km for dopamine without alteration of the apparent Vmax. It should be noted that one of the active oxygen species – hydrogen peroxide – is generated during the oxidation of dopamine and other biogenic monoamines by mitochondrial monoamine oxidase of various organs and tissues [2, 3, 30]. This may lead to cell death and consequently, dysfunctions of various organs [30]. Ii is obvious that if the accumulation of long-chain fatty acids in cells leads to stimulation of the oxidation of biogenic monoamines, it can be considered as one of the factors enhancing oxidative stress and consequent cell death. The study of this provisional mechanism of the fatty acid effect is the task of further research. ACKNOWLEDGMENTS The work was supported by the Russian Foundation for Basic Research (project no. 14-04-00688) and by the Ministry of Education and Science of the Russian Federation (project no. 1365). REFERENCES 1. Skulachev V.P., Bogachev A.V., Kasparinsky F.O. 2010. Membrannaja bioenergetika (Membrane bioenergetics). Moscow: Moscow University. 2. Zorov D.B., Juhaszova M., Sollott S.J. 2014. Mitochondrial reactive oxygen species (ROS) and ROSinduced ROS release. Physiol. Rev. 94, 909–950. 3. Andreyev A.Y., Kushnareva Y.E., Murphy A.N., Starkov A.A. 2015. Mitochondrial ROS Metabolism: 10 Years Later. Biokhimia (Rus.). 80, 612–630. 4. Lee J., Giordano S., Zhang J. 2012. Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling. Biochem. J. 441, 523–540. 5. Antonenko Y.N., Khailova L.S., Knorre D.A., Markova O.V., Rokitskaya T.I., Ilyasova T.M., Severina I.I., Kotova E.A., Karavaeva Y.E., Prikhodko A.S., Severin F.F., Skulachev V.P. 2013. Penetrating cations enhance uncoupling activity of anionic protonophores in mitochondria. PLoS One. 8, e61902. doi 10.1371/ journal.pone.0061902 6. Schönfeld P, Wojtczak L. 2008. Fatty acids as modulators of the cellular production of reactive oxygen species. Free Rad. Biol. Med. 45, 231–341. 7. Severin F.F., Severina I.I., Antonenko Y.N., Rokitskaya T.I., Cherepanov D.A., Mokhova E.N., Vyssokikh M.Y., Pustovidko A.V., Markova O.V., Yaguzhinsky L.S., Korshunova G.A., Sumbatyan N.V., Skulachev M.V., Skulachev V.P. 2010. Penetrating cation/ fatty acid anion pair as a mitochondria-targeted protonophore. Proc. Natl. Acad. Sci. USA. 107, 663–668. 8. Samartsev V.N., Smirnov A.V., Zeldi I.P., Markova O.V., Mokhova E.N., Skulachev V.P. 1997. Involved of aspartate/glutamate antiporter in fatty acid-induced


194

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

SAMARTSEV, DUBININ uncoupling of liver mitochondria. Biochim. Biophys. Acta. 1339, 251–257. Samartsev V.N., Kozhina O.V. 2008. Oxidative stress as regulatory factor for fatty-acid-induced uncoupling involving liver mitochondrial ADP/ATP and aspartate/glutamate antiporters of old rats. Biokhimia (Rus.). 73, 972–980. Kozhina O.V., Samartsev V.N. 2010. Uncoupling activity of fatty acids in liver mitochondria in the presence of substrates of ADP/ATP and aspartate/glutamate antiporters is increased under oxidative stress. Biol. Membrany (Rus.). 27, 184–188. Wojtczak L., Nalecz M.J. 1979. Surface charge of biological membranes as a possible regulator of membrane-bound enzymes. Eur. J. Biochem. 94, 99–107. Mráček T., Drahota Z., Houštěk J. 2013. The function and the role of the mitochondrial glycerol-3-phosphate dehydrogenase in mammalian tissues. Biochim. Biophys. Acta. 1827, 401–410. Denton R.M. 2009. Regulation of mitochondrial dehydrogenases by calcium ions. Biochim. Biophys. Acta. 1787, 1309–1316. Nałecz M.J., Zborowski J., Famulski K.S., Wojtczak L. 1980. Effect of phospholipid composition on the surface potential of liposomes and the activity of enzymes incorporated. Eur. J. Biochem. 112, 75–80. Famulski K.S., Nałecz M.J., Wojtczak L. 1983. Phosphorylation of mitochondrial membrane proteins: Effect of the surface potential on monoamine oxidase. FEBS Lett. 157, 124–128. Girotti A.W. 1998. Lipid hydroperoxide generation, turnover, and effector action in biological systems. J. Lipid Res. 39, 1529–1542. Wojtczak L., Schönfeld P. 1993. Effect of fatty acids on energy coupling processes in mitochondria. Biochim. Biophys. Acta. 1183, 41–57. Samartsev V.N., Rybakova S.R., Dubinin M.V. 2013. Interaction of free fatty acids with mitochondria during uncoupling of oxidative phosphorylation. Biofizika (Rus.). 58, 481–487. Samartsev V.N., Dubinin M.V., Krasnoshchekova O.E. 2015. Features of inhibition of glycerol-3-phosphate oxidase activity of liver mitochondria by palmitic acid

20. 21.

22. 23.

24. 25.

26.

27.

28. 29.

30.

in the presence of ATP and tert-butylhydroperoxide. Biol. Membrany (Rus.). 32, 185–193. Gennis R. 1989. Biomembranes: Molecular structure and function. Springer Advanced Texts in Chemistry. Trendeleva T.A., Rogov A.G., Cherepanov D.A., Sukhanova E.I., Il’yasova T.M., Severina I.I., Zvyagilskaya R.A. 2012. Interaction of tetraphenylphosphonium and dodecyltriphenylphosphonium with lipid membranes and mitochondria. Biokhimia (Rus.). 77, 1230–1239. Chinopoulos C., Adam-Vizi V. 2010. Mitochondria as ATP consumers in cellular pathology. Biochim. Biophys. Acta. 1802, 221–227. Ježek J, Jabůrek M, Zelenka J, Ježek P. 2010. Mitochondrial phospholipase A2 activated by reactive oxygen species in heart mitochondria induces mild uncoupling. Physiol. Res. 59, 737–747. Liu H., Kehler J.P. 1996. The reduction of glutathione disulfide produced by t-butyl hydroperoxide in respiring mitochondria. Free Radic. Biol. Med. 20, 433–442. Kennedy C.H., Church D.F., Winston G.W., Pryor W.A. 1992. tert-Butyl hydroperoxide-induced radical production in rat liver mitochondria. Free Radic. Biol. Med. 12, 381–387. Kozhina O.V., Stepanova L.A., Samartsev V.N. 2007. Peculiarities of the uncoupling action of fatty acids in liver mitochondria under oxidative stress. Biol. Membrany (Rus.). 24, 421–429. Haynes R.C. Jr, Picking R.A. 1984. The interaction of glucagon treatment and uncoupler concentration on ATPase activity of rat liver mitochondria. J. Biol. Chem. 259, 13228–13234. Brdiczka D.G., Zorov D.B., Sheu S.S. 2006. Mitochondrial contact sites: Their role in energy metabolism and apoptosis. Biochim. Biophys. Acta. 1762, 148–163. Horvath S.E., Rampelt H., Oeljeklaus S., Warscheid B., van der Laan M., Pfanner N. 2015. Role of membrane contact sites in protein import into mitochondria. Protein Sci. 24, 277–297. Kaludercic N., Mialet-Perez J., Paolocci N., Parini A., Di Lisa F. 2014. Monoamine oxidases as sources of oxidants in the heart. J. Mol. Cell. Cardiol. 73, 34–42.

Translated by M. Dubinin


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