Startseite Generation of superoxide and hydrogen peroxide by side reactions of mitochondrial 2-oxoacid dehydrogenase complexes in isolation and in cells
Artikel
Lizenziert
Nicht lizenziert Erfordert eine Authentifizierung

Generation of superoxide and hydrogen peroxide by side reactions of mitochondrial 2-oxoacid dehydrogenase complexes in isolation and in cells

  • Victoria I. Bunik

    Victoria I. Bunik, PhD in Biology, Dr of Sci. (habilitation) in Chemistry, leads a research group of metabolic engineering at Belozersky Institute of Physicochemical Biology of Moscow Lomonosov State University and is a Professor of the Faculty of Bioengineering and Bioinformatics of Moscow Lomonosov State University. Her work on the ROS producing activity of mammalian 2-oxo acid dehydrogenase complexes and their interaction with mitochondrial thioredoxin was performed during research stays at GhK Kassel (Germany) and Tuebingen University (Germany), supported by DFG, Volkswagen Foundation and Alexander von Humboldt Foundation (Germany).

         und Martin D. Brand

    Martin D. Brand BSc, MA, PhD, FMedSci is a Professor at the Buck Institute for Research on Aging, Novato, CA, USA. He was trained in Biochemistry in the UK at the University of Manchester Institute of Science and Technology (BSc) and the University of Bristol (PhD), followed by a postdoctoral position at Johns Hopkins University (Baltimore, USA) with Professor Albert Lehninger. He was a faculty member of the Biochemistry Department at the University of Cambridge (UK), then a group leader at the Medical Research Council in Cambridge. He moved to the Buck Institute in 2008. Dr Brand’s scientific research focuses on mitochondrial and cellular energy transformation and reactive oxygen species.

     EMAIL logo
Veröffentlicht/Copyright: 9. Januar 2018
Biological Chemistry
Aus der Zeitschrift Biological Chemistry Band 399 Heft 5

Abstract

Mitochondrial 2-oxoacid dehydrogenase complexes oxidize 2-oxoglutarate, pyruvate, branched-chain 2-oxoacids and 2-oxoadipate to the corresponding acyl-CoAs and reduce NAD+ to NADH. The isolated enzyme complexes generate superoxide anion radical or hydrogen peroxide in defined reactions by leaking electrons to oxygen. Studies using isolated mitochondria in media mimicking cytosol suggest that the 2-oxoacid dehydrogenase complexes contribute little to the production of superoxide or hydrogen peroxide relative to other mitochondrial sites at physiological steady states. However, the contributions may increase under pathological conditions, in accordance with the high maximum capacities of superoxide or hydrogen peroxide-generating reactions of the complexes, established in isolated mitochondria. We assess available data on the use of modulations of enzyme activity to infer superoxide or hydrogen peroxide production from particular 2-oxoacid dehydrogenase complexes in cells, and limitations of such methods to discriminate specific superoxide or hydrogen peroxide sources in vivo.

Keywords: α-ketoglutarate; muscle; 2-oxoglutarate; pyruvate; radical; ROS

About the authors

Victoria I. Bunik

Victoria I. Bunik, PhD in Biology, Dr of Sci. (habilitation) in Chemistry, leads a research group of metabolic engineering at Belozersky Institute of Physicochemical Biology of Moscow Lomonosov State University and is a Professor of the Faculty of Bioengineering and Bioinformatics of Moscow Lomonosov State University. Her work on the ROS producing activity of mammalian 2-oxo acid dehydrogenase complexes and their interaction with mitochondrial thioredoxin was performed during research stays at GhK Kassel (Germany) and Tuebingen University (Germany), supported by DFG, Volkswagen Foundation and Alexander von Humboldt Foundation (Germany).

Martin D. Brand

Martin D. Brand BSc, MA, PhD, FMedSci is a Professor at the Buck Institute for Research on Aging, Novato, CA, USA. He was trained in Biochemistry in the UK at the University of Manchester Institute of Science and Technology (BSc) and the University of Bristol (PhD), followed by a postdoctoral position at Johns Hopkins University (Baltimore, USA) with Professor Albert Lehninger. He was a faculty member of the Biochemistry Department at the University of Cambridge (UK), then a group leader at the Medical Research Council in Cambridge. He moved to the Buck Institute in 2008. Dr Brand’s scientific research focuses on mitochondrial and cellular energy transformation and reactive oxygen species.

Acknowledgment

V.I.B. acknowledges the work of her PhD student, Mr. A. Artiukhov, preparing the reaction equations using ACDChemSketch (ACD Labs).

References

Aleshin, V.A., Artiukhov, A.V., Oppermann, H., Kazantsev, A.V., Lukashev, N.V., and Bunik, V.I. (2015). Mitochondrial impairment may increase cellular NAD(P)H: resazurin oxidoreductase activity, perturbing the NAD(P)H-based viability assays. Cells 4, 427–451.10.3390/cells4030427Suche in Google Scholar

Allen, E.L., Ulanet, D.B., Pirman, D., Mahoney, C.E., Coco, J., Si, Y., Chen, Y., Huang, L., Ren, J., Choe, S., et al. (2016). Differential aspartate usage identifies a subset of cancer cells particularly dependent on OGDH. Cell Rep. 17, 876–890.10.1016/j.celrep.2016.09.052Suche in Google Scholar

Ambrus, A., Nemeria, N.S., Torocsik, B., Tretter, L., Nilsson, M., Jordan, F., and Adam-Vizi, V. (2015). Formation of reactive oxygen species by human and bacterial pyruvate and 2-oxoglutarate dehydrogenase multienzyme complexes reconstituted from recombinant components. Free Radic. Biol. Med. 89, 642–650.10.1016/j.freeradbiomed.2015.10.001Suche in Google Scholar

Arrieta-Cruz, I. and Gutierrez-Juarez, R. (2016). The role of circulating amino acids in the hypothalamic regulation of liver glucose metabolism. Adv. Nutr. 7, 790S–797S.10.3945/an.115.011171Suche in Google Scholar

Artiukhov, A.V., Graf, A.V., and Bunik, V.I. (2016). Directed regulation of multienzyme complexes of 2-oxo acid dehydrogenases using phosphonate and phosphinate analogs of 2-oxo acids. Biochem. Biokhimiia 81, 1498–1521.10.1134/S0006297916120129Suche in Google Scholar

Barja, G. and Herrero, A. (1998). Localization at complex I and mechanism of the higher free radical production of brain nonsynaptic mitochondria in the short-lived rat than in the longevous pigeon. J. Bioenerg. Biomemb. 30, 235–243.10.1111/j.1749-6632.1998.tb09961.xSuche in Google Scholar

Brand, M.D. (2016). Mitochondrial generation of superoxide and hydrogen peroxide as the source of mitochondrial redox signaling. Free Radic. Biol. Med. 100, 14–31.10.1016/j.freeradbiomed.2016.04.001Suche in Google Scholar

Brand, M.D., Goncalves, R.L., Orr, A.L., Vargas, L., Gerencser, A.A., Borch Jensen, M., Wang, Y.T., Melov, S., Turk, C.N., Matzen, J.T., et al. (2016). Suppressors of superoxide-H2O2 production at site IQ of mitochondrial complex I protect against stem cell hyperplasia and ischemia-reperfusion injury. Cell Metab. 24, 582–592.10.1016/j.cmet.2016.08.012Suche in Google Scholar

Bryk, R., Lima, C.D., Erdjument-Bromage, H., Tempst, P., and Nathan, C. (2002). Metabolic enzymes of mycobacteria linked to antioxidant defense by a thioredoxin-like protein. Science 295, 1073–1077.10.1126/science.1067798Suche in Google Scholar

Bunik, V. (2000). Increased catalytic performance of the 2-oxoacid dehydrogenase complexes in the presence of thioredoxin, a thiol-disulfide oxidoreductase. J. Mol. Catal. B Enzym. 8, 165–174.10.1016/S1381-1177(99)00054-5Suche in Google Scholar

Bunik, V.I. (2003). 2-Oxo acid dehydrogenase complexes in redox regulation. Eur. J. Biochem. 270, 1036–1042.10.1046/j.1432-1033.2003.03470.xSuche in Google Scholar

Bunik, V. (2017). Vitamin-dependent multienzyme complexes of 2-oxo acid dehydrogenases: structure, function, regulation and medical implications (New York, USA: Nova Science Publisher).Suche in Google Scholar

Bunik, V.I. and Degtyarev, D. (2008). Structure-function relationships in the 2-oxo acid dehydrogenase family: substrate-specific signatures and functional predictions for the 2-oxoglutarate dehydrogenase-like proteins. Proteins 71, 874–890.10.1002/prot.21766Suche in Google Scholar

Bunik, V.I. and Fernie, A.R. (2009). Metabolic control exerted by the 2-oxoglutarate dehydrogenase reaction: a cross-kingdom comparison of the crossroad between energy production and nitrogen assimilation. Biochem. J. 422, 405–421.10.1042/BJ20090722Suche in Google Scholar

Bunik, V. and Follmann, H. (1993). Thioredoxin reduction dependent on alpha-ketoacid oxidation by alpha-ketoacid dehydrogenase complexes. FEBS Lett. 336, 197–200.10.1016/0014-5793(93)80801-ZSuche in Google Scholar

Bunik, V.I. and Sievers, C. (2002). Inactivation of the 2-oxo acid dehydrogenase complexes upon generation of intrinsic radical species. Eur. J. Biochem. 269, 5004–5015.10.1046/j.1432-1033.2002.03204.xSuche in Google Scholar

Bunik, V.I., Buneeva, O.A., and Gomazkova, V.S. (1991a). Regulation of cooperative properties of α-ketoglutarate dehydrogenase by means of thiol-disulfide exchange. Biochemistry (Moscow) 56, 470–479 (English translation).Suche in Google Scholar

Bunik, V.I., Romash, O.G., and Gomazkova, V.S. (1991b). Effect of alpha-ketoglutarate and its structural analogues on hysteretic properties of α-ketoglutarate dehydrogenase. FEBS Lett. 278, 147–150.10.1016/0014-5793(91)80104-BSuche in Google Scholar

Bunik, V., Shoubnikova, A., Loeffelhardt, S., Bisswanger, H., Borbe, H.O., and Follmann, H. (1995). Using lipoate enantiomers and thioredoxin to study the mechanism of the 2-oxoacid-dependent dihydrolipoate production by the 2-oxoacid dehydrogenase complexes. FEBS Lett. 371, 167–170.10.1016/0014-5793(95)00904-NSuche in Google Scholar

Bunik, V., Raddatz, G., Lemaire, S., Meyer, Y., Jacquot, J.P., and Bisswanger, H. (1999). Interaction of thioredoxins with target proteins: role of particular structural elements and electrostatic properties of thioredoxins in their interplay with 2-oxoacid dehydrogenase complexes. Prot. Sci. 8, 65–74.10.1110/ps.8.1.65Suche in Google Scholar PubMed PubMed Central

Bunik, V.I., Schloss, J.V., Pinto, J.T., Dudareva, N., and Cooper, A.J. (2011). A survey of oxidative paracatalytic reactions catalyzed by enzymes that generate carbanionic intermediates: implications for ROS production, cancer etiology, and neurodegenerative diseases. Adv. Enzymol. 77, 307–360.10.1002/9780470920541.ch7Suche in Google Scholar PubMed PubMed Central

Bunik, V.I., Raddatz, G., and Strumilo, S. (2013). Translating enzymology into metabolic regulation: the case of 2-oxoglutarate dehydrogenase multienzyme complex. Curr. Chem. Biol. 7, 74–93.10.2174/2212796811307010008Suche in Google Scholar

Bunik, V.I., Artiukhov, A., Kazantsev, A., Goncalves, R., Daloso, D., Oppermann, H., Kulakovskaya, E., Lukashev, N., Fernie, A., Brand, M., et al. (2015). Specific inhibition by synthetic analogs of pyruvate reveals that the pyruvate dehydrogenase reaction is essential for metabolism and viability of glioblastoma cells. Oncotarget 6, 40036–40052.10.18632/oncotarget.5486Suche in Google Scholar PubMed PubMed Central

Bunik, V., Mkrtchyan, G., Grabarska, A., Oppermann, H., Daloso, D., Araujo, W.L., Juszczak, M., Rzeski, W., Bettendorff, L., Fernie, A.R., et al. (2016). Inhibition of mitochondrial 2-oxoglutarate dehydrogenase impairs viability of cancer cells in a cell-specific metabolism-dependent manner. Oncotarget 7, 26400–26421.10.18632/oncotarget.8387Suche in Google Scholar PubMed PubMed Central

Denton, R.M., Pullen, T.J., Armstrong, C.T., Heesom, K.J., and Rutter, G.A. (2016). Calcium-insensitive splice variants of mammalian E1 subunit of 2-oxoglutarate dehydrogenase complex with tissue-specific patterns of expression. Biochem. J. 473, 1165–1178.10.1042/BCJ20160135Suche in Google Scholar PubMed PubMed Central

Diaz-Munoz, M.D., Bell, S.E., Fairfax, K., Monzon-Casanova, E., Cunningham, A.F., Gonzalez-Porta, M., Andrews, S.R., Bunik, V.I., Zarnack, K., Curk, T., et al. (2015). The RNA-binding protein HuR is essential for the B cell antibody response. Nat. Immunol. 16, 415–425.10.1038/ni.3115Suche in Google Scholar PubMed PubMed Central

Fisher-Wellman, K.H., Gilliam, L.A., Lin, C.T., Cathey, B.L., Lark, D.S., and Neufer, P.D. (2013). Mitochondrial glutathione depletion reveals a novel role for the pyruvate dehydrogenase complex as a key H2O2-emitting source under conditions of nutrient overload. Free Radic. Biol. Med. 65, 1201–1208.10.1016/j.freeradbiomed.2013.09.008Suche in Google Scholar PubMed PubMed Central

Frank, R.A., Kay, C.W., Hirst, J., and Luisi, B.F. (2008). Off-pathway, oxygen-dependent thiamine radical in the Krebs cycle. J. Am. Chem. Soc. 130, 1662–1668.10.1021/ja076468kSuche in Google Scholar PubMed PubMed Central

Gallogly, M.M., Starke, D.W., Leonberg, A.K., English Ospina, S.M., and Mieyal, J.J. (2008). Kinetic and mechanistic characterization and versatile catalytic properties of mammalian glutaredoxin 2: implications for intracellular roles. Biochemistry 47, 11144–11157.10.1021/bi800966vSuche in Google Scholar PubMed PubMed Central

Gazaryan, I.G., Krasnikov, B.F., Ashby, G.A., Thorneley, R.N., Kristal, B.S. and Brown, A.M. (2002). Zinc is a potent inhibitor of thiol oxidoreductase activity and stimulates reactive oxygen species production by lipoamide dehydrogenase. J. Biol. Chem. 277, 10064–10072.10.1074/jbc.M108264200Suche in Google Scholar PubMed

Goncalves, R.L.S., Rothschild, D.E., Quinlan, C.L., Scott, G.K., Benz, C.C., and Brand, M.D. (2014). Sources of superoxide/H2O2 during mitochondrial proline oxidation. Redox Biol. 2, 901–909.10.1016/j.redox.2014.07.003Suche in Google Scholar PubMed PubMed Central

Goncalves, R.L.S., Quinlan, C.L., Perevoshchikova, I.V., Hey-Mogensen, M., and Brand, M.D. (2015). Sites of superoxide and hydrogen peroxide production by muscle mitochondria assessed ex vivo under conditions mimicking rest and exercise. J. Biol. Chem. 290, 209–227.10.1074/jbc.M114.619072Suche in Google Scholar PubMed PubMed Central

Goncalves, R.L.S., Bunik, V.I., and Brand, M.D. (2016). Production of superoxide/hydrogen peroxide by the mitochondrial 2-oxoadipate dehydrogenase complex. Free Radic. Biol. Med. 91, 247–255.10.1016/j.freeradbiomed.2015.12.020Suche in Google Scholar PubMed

Hagen, J., te Brinke, H., Wanders, R.J., Knegt, A.C., Oussoren, E., Hoogeboom, A.J., Ruijter, G.J., Becker, D., Schwab, K.O., Franke, I., et al. (2015). Genetic basis of alpha-aminoadipic and α-ketoadipic aciduria. J. Inherit. Metab. Dis. 38, 873–879.10.1007/s10545-015-9841-9Suche in Google Scholar PubMed

Hansford, R.G., Hogue, B.A., and Mildaziene, V. (1997). Dependence of H2O2 formation by rat heart mitochondria on substrate availability and donor age. J. Bioenerg. Biomembr. 29, 89–95.10.1023/A:1022420007908Suche in Google Scholar

Heublein, M., Burguillos, M.A., Vogtle, F.N., Teixeira, P.F., Imhof, A., Meisinger, C., and Ott, M. (2014). The novel component Kgd4 recruits the E3 subunit to the mitochondrial α-ketoglutarate dehydrogenase. Mol. Biol. Cell 25, 3342–3349.10.1091/mbc.e14-07-1178Suche in Google Scholar PubMed PubMed Central

Kalyanaraman, B., Darley-Usmar, V., Davies, K.J., Dennery, P.A., Forman, H.J., Grisham, M.B., Mann, G.E., Moore, K., Roberts, L.J., and Ischiropoulos, H. (2012). Measuring reactive oxygen and nitrogen species with fluorescent probes: challenges and limitations. Free Radic. Biol. Med. 52, 1–6.10.1016/j.freeradbiomed.2011.09.030Suche in Google Scholar PubMed PubMed Central

Kareyeva, A.V., Grivennikova, V.G., Cecchini, G., and Vinogradov, A.D. (2011). Molecular identification of the enzyme responsible for the mitochondrial NADH-supported ammonium-dependent hydrogen peroxide production. FEBS Lett. 585, 385–389.10.1016/j.febslet.2010.12.019Suche in Google Scholar PubMed PubMed Central

Klivenyi, P., Starkov, A.A., Calingasan, N.Y., Gardian, G., Browne, S.E., Yang, L., Bubber, P., Gibson, G.E., Patel, M.S., and Beal, M.F. (2004). Mice deficient in dihydrolipoamide dehydrogenase show increased vulnerability to MPTP, malonate and 3-nitropropionic acid neurotoxicity. J. Neurochem. 88, 1352–1360.10.1046/j.1471-4159.2003.02263.xSuche in Google Scholar PubMed

Kumar, M.J., Nicholls, D.G., and Andersen, J.K. (2003). Oxidative alpha-ketoglutarate dehydrogenase inhibition via subtle elevations in monoamine oxidase B levels results in loss of spare respiratory capacity: implications for Parkinson’s disease. J. Biol. Chem. 278, 46432–46439.10.1074/jbc.M306378200Suche in Google Scholar PubMed

Liu, S., Miriyala, S., Keaton, M.A., Jordan, C.T., Wiedl, C., Clair, D.K., and Moscow, J.A. (2014). Metabolic effects of acute thiamine depletion are reversed by rapamycin in breast and leukemia cells. PLoS One 9, e85702.10.1371/journal.pone.0085702Suche in Google Scholar PubMed PubMed Central

Mailloux, R.J., Craig Ayre, D., and Christian, S.L. (2016a). Induction of mitochondrial reactive oxygen species production by GSH mediated S-glutathionylation of 2-oxoglutarate dehydrogenase. Redox Biol. 8, 285–297.10.1016/j.redox.2016.02.002Suche in Google Scholar PubMed PubMed Central

Mailloux, R.J., Gardiner, D., and O’Brien, M. (2016b). 2-Oxoglutarate dehydrogenase is a more significant source of O2˙−/H2O2 than pyruvate dehydrogenase in cardiac and liver tissue. Free Radic. Biol. Med. 97, 501–512.10.1016/j.freeradbiomed.2016.06.014Suche in Google Scholar PubMed

Maksymiuk, C., Balakrishnan, A., Bryk, R., Rhee, K.Y., and Nathan, C.F. (2015). E1 of alpha-ketoglutarate dehydrogenase defends Mycobacterium tuberculosis against glutamate anaplerosis and nitroxidative stress. Proc. Nat. Acad. Sci. USA 112, E5834–E5843.10.1073/pnas.1510932112Suche in Google Scholar PubMed PubMed Central

Marrott, N.L., Marshall, J.J., Svergun, D.I., Crennell, S.J., Hough, D.W., van den Elsen, J.M., and Danson, M.J. (2014). Why are the 2-oxoacid dehydrogenase complexes so large? Generation of an active trimeric complex. Biochem. J. 463, 405–412.10.1042/BJ20140359Suche in Google Scholar PubMed

McCartney, R.G., Rice, J.E., Sanderson, S.J., Bunik, V., Lindsay, H., and Lindsay, J.G. (1998). Subunit interactions in the mammalian α-ketoglutarate dehydrogenase complex. Evidence for direct association of the α-ketoglutarate dehydrogenase and dihydrolipoamide dehydrogenase components. J. Biol. Chem. 273, 24158–24164.10.1074/jbc.273.37.24158Suche in Google Scholar PubMed

Nemeria, N.S., Ambrus, A., Patel, H., Gerfen, G., Adam-Vizi, V., Tretter, L., Zhou, J., Wang, J., and Jordan, F. (2014). Human 2-oxoglutarate dehydrogenase complex E1 component forms a thiamin-derived radical by aerobic oxidation of the enamine intermediate. J. Biol. Chem. 289, 29859–29873.10.1074/jbc.M114.591073Suche in Google Scholar PubMed PubMed Central

Nemeria, N.S., Gerfen, G., Guevara, E., Nareddy, P.R., Szostak, M., and Jordan, F. (2017). The human Krebs cycle 2-oxoglutarate dehydrogenase complex creates an additional source of superoxide/hydrogen peroxide from 2-oxoadipate as alternative substrate. Free Radic. Biol. Med. 108, 644–654.10.1016/j.freeradbiomed.2017.04.017Suche in Google Scholar PubMed

Nulton-Persson, A.C., Starke, D.W., Mieyal, J.J., and Szweda, L.I. (2003). Reversible inactivation of α-ketoglutarate dehydrogenase in response to alterations in the mitochondrial glutathione status. Biochemistry 42, 4235–4242.10.1021/bi027370fSuche in Google Scholar PubMed

O’Brien, M., Chalker, J., Slade, L., Gardiner, D., and Mailloux, R.J. (2017). Protein S-glutathionylation alters superoxide/hydrogen peroxide emission from pyruvate dehydrogenase complex. Free Radic. Biol. Med. 106, 302–314.10.1016/j.freeradbiomed.2017.02.046Suche in Google Scholar PubMed

Orr, A.L., Vargas, L., Turk, C.N., Baaten, J.E., Matzen, J.T., Dardov, V.J., Attle, S.J., Li, J., Quackenbush, D.C., Goncalves, R.L.S., et al. (2015). Suppressors of superoxide production from mitochondrial complex III. Nat. Chem. Biol. 11, 834–836.10.1038/nchembio.1910Suche in Google Scholar PubMed PubMed Central

Perevoshchikova, I.V., Quinlan, C.L., Orr, A.L., Gerencser, A.A., and Brand, M.D. (2013). Sites of superoxide and hydrogen peroxide production during fatty acid oxidation in rat skeletal muscle mitochondria. Free Radic. Biol. Med. 61, 298–309.10.1016/j.freeradbiomed.2013.04.006Suche in Google Scholar PubMed PubMed Central

Quinlan, C.L., Treberg, J.R., Perevoshchikova, I.V., Orr, A.L., and Brand, M.D. (2012). Native rates of superoxide production from multiple sites in isolated mitochondria measured using endogenous reporters. Free Radic. Biol. Med. 53, 1807–1817.10.1016/j.freeradbiomed.2012.08.015Suche in Google Scholar PubMed PubMed Central

Quinlan, C.L., Perevoshchikova, I.V., Hey-Mogensen, M., Orr, A.L., and Brand, M.D. (2013). Sites of reactive oxygen species generation by mitochondria oxidizing different substrates. Redox Biol. 1, 304–312.10.1016/j.redox.2013.04.005Suche in Google Scholar PubMed PubMed Central

Quinlan, C.L., Goncalves, R.L., Hey-Mogensen, M., Yadava, N., Bunik, V.I., and Brand, M.D. (2014). The 2-oxoacid dehydrogenase complexes in mitochondria can produce superoxide/hydrogen peroxide at much higher rates than complex I. J. Biol. Chem. 289, 8312–8325.10.1074/jbc.M113.545301Suche in Google Scholar PubMed PubMed Central

Schultz, C., Niebisch, A., Schwaiger, A., Viets, U., Metzger, S., Bramkamp, M., and Bott, M. (2009). Genetic and biochemical analysis of the serine/threonine protein kinases PknA, PknB, PknG and PknL of Corynebacterium glutamicum: evidence for non-essentiality and for phosphorylation of OdhI and FtsZ by multiple kinases. Mol. Microbiol. 74, 724–741.10.1111/j.1365-2958.2009.06897.xSuche in Google Scholar PubMed PubMed Central

Sen, T., Sen, N., Noordhuis, M.G., Ravi, R., Wu, T.C., Ha, P.K., Sidransky, D., and Hoque, M.O. (2012). OGDHL is a modifier of AKT-dependent signaling and NF-κB function. PLoS One 7, e48770.10.1371/journal.pone.0048770Suche in Google Scholar PubMed PubMed Central

Shi, Q., Chen, H.L., Xu, H., and Gibson, G.E. (2005). Reduction in the E2k subunit of the α-ketoglutarate dehydrogenase complex has effects independent of complex activity. J. Biol. Chem. 280, 10888–10896.10.1074/jbc.M409064200Suche in Google Scholar PubMed

Srinivasan, U., Mieyal, P.A., and Mieyal, J.J. (1997). pH profiles indicative of rate-limiting nucleophilic displacement in thioltransferase catalysis. Biochemistry 36, 3199–3206.10.1021/bi962017tSuche in Google Scholar PubMed

St-Pierre, J., Buckingham, J.A., Roebuck, S.J., and Brand, M.D. (2002). Topology of superoxide production from different sites in the mitochondrial electron transport chain. J. Biol. Chem. 277, 44784–44790.10.1074/jbc.M207217200Suche in Google Scholar PubMed

Starke, D.W., Chock, P.B., and Mieyal, J.J. (2003). Glutathione-thiyl radical scavenging and transferase properties of human glutaredoxin (thioltransferase). Potential role in redox signal transduction. J. Biol. Chem. 278, 14607–14613.10.1074/jbc.M210434200Suche in Google Scholar PubMed

Starkov, A.A., Fiskum, G., Chinopoulos, C., Lorenzo, B.J., Browne, S.E., Patel, M.S., and Beal, M.F. (2004). Mitochondrial α-ketoglutarate dehydrogenase complex generates reactive oxygen species. J. Neurosci. 24, 7779–7788.10.1523/JNEUROSCI.1899-04.2004Suche in Google Scholar PubMed PubMed Central

Tretter, L. and Adam-Vizi, V. (2004). Generation of reactive oxygen species in the reaction catalyzed by α-ketoglutarate dehydrogenase. J. Neurosci. 24, 7771–7778.10.1523/JNEUROSCI.1842-04.2004Suche in Google Scholar PubMed PubMed Central

Valsecchi, F., Monge, C., Forkink, M., de Groof, A.J., Benard, G., Rossignol, R., Swarts, H.G., van Emst-de Vries, S.E., Rodenburg, R.J., Calvaruso, M.A., et al. (2012). Metabolic consequences of NDUFS4 gene deletion in immortalized mouse embryonic fibroblasts. Biochim. Biophys. Acta 1817, 1925–1936.10.1016/j.bbabio.2012.03.006Suche in Google Scholar PubMed

Vaubel, R.A., Rustin, P., and Isaya, G. (2011). Mutations in the dimer interface of dihydrolipoamide dehydrogenase promote site-specific oxidative damages in yeast and human cells. J. Biol. Chem. 286, 40232–40245.10.1074/jbc.M111.274415Suche in Google Scholar PubMed PubMed Central

Wong, C.F., Shin, J., Subramanian Manimekalai, M.S., Saw, W.G., Yin, Z., Bhushan, S., Kumar, A., Ragunathan, P., and Gruber, G. (2017). AhpC of the mycobacterial antioxidant defense system and its interaction with its reducing partner Thioredoxin-C. Sci. Rep. 7, 5159.10.1038/s41598-017-05354-5Suche in Google Scholar PubMed PubMed Central

Yoon, W.H., Sandoval, H., Nagarkar-Jaiswal, S., Jaiswal, M., Yamamoto, S., Haelterman, N.A., Putluri, N., Putluri, V., Sreekumar, A., Tos, T., et al. (2017). Loss of nardilysin, a mitochondrial co-chaperone for α-ketoglutarate dehydrogenase, promotes mTORC1 activation and neurodegeneration. Neuron 93, 115–131.10.1016/j.neuron.2016.11.038Suche in Google Scholar PubMed PubMed Central

Yudkoff, M. (2017). Interactions in the metabolism of glutamate and the branched-chain amino acids and ketoacids in the CNS. Neurochem. Res. 42, 10–18.10.1007/s11064-016-2057-zSuche in Google Scholar PubMed PubMed Central

Zhenyukh, O., Civantos, E., Ruiz-Ortega, M., Sanchez, M.S., Vazquez, C., Peiro, C., Egido, J., and Mas, S. (2017). High concentration of branched-chain amino acids promotes oxidative stress, inflammation and migration of human peripheral blood mononuclear cells via mTORC1 activation. Free Radic. Biol. Med. 104, 165–177.10.1016/j.freeradbiomed.2017.01.009Suche in Google Scholar PubMed

Zhou, J., Damdimopoulos, A.E., Spyrou, G., and Brune, B. (2007). Thioredoxin 1 and thioredoxin 2 have opposed regulatory functions on hypoxia-inducible factor-1α. J. Biol. Chem. 282, 7482–7490.10.1074/jbc.M608289200Suche in Google Scholar PubMed

Zundorf, G., Kahlert, S., Bunik, V.I., and Reiser, G. (2009). α-Ketoglutarate dehydrogenase contributes to production of reactive oxygen species in glutamate-stimulated hippocampal neurons in situ. Neuroscience 158, 610–616.10.1016/j.neuroscience.2008.10.015Suche in Google Scholar PubMed

Received: 2017-11-14
Accepted: 2018-01-03
Published Online: 2018-01-09
Published in Print: 2018-04-25

©2018 Walter de Gruyter GmbH, Berlin/Boston

Artikel in diesem Heft

  1. Frontmatter
  2. Reviews
  3. Generation of superoxide and hydrogen peroxide by side reactions of mitochondrial 2-oxoacid dehydrogenase complexes in isolation and in cells
  4. Update on mitochondria and muscle aging: all wrong roads lead to sarcopenia
  5. Research Articles/Short Communications
  6. Protein Structure and Function
  7. CRISPR/Cas9-mediated modification of the extreme C-terminus impairs PDGF-stimulated activity of Duox2
  8. Membranes, Lipids, Glycobiology
  9. Changes of the peripheral blood mononuclear cells membrane fluidity from type 1 Gaucher disease patients: an electron paramagnetic resonance study
  10. Molecular Medicine
  11. Aβ42 oligomers impair the bioenergetic activity in hippocampal synaptosomes derived from APP-KO mice
  12. Cell Biology and Signaling
  13. Molecular determinants of Drosophila immunophilin FKBP39 nuclear localization
  14. The effect of lncRNA HOTAIR on chemoresistance of ovarian cancer through regulation of HOXA7
  15. Novel Techniques
  16. Determination of selenium during pathogenesis of hepatic fibrosis employing hydride generation and inductively coupled plasma mass spectrometry
https://doi.org/10.1515/hsz-2017-0284
Schlagwörter für diesen Artikel
α-ketoglutarate; muscle; 2-oxoglutarate; pyruvate; radical; ROS

Artikel in diesem Heft

  1. Frontmatter
  2. Reviews
  3. Generation of superoxide and hydrogen peroxide by side reactions of mitochondrial 2-oxoacid dehydrogenase complexes in isolation and in cells
  4. Update on mitochondria and muscle aging: all wrong roads lead to sarcopenia
  5. Research Articles/Short Communications
  6. Protein Structure and Function
  7. CRISPR/Cas9-mediated modification of the extreme C-terminus impairs PDGF-stimulated activity of Duox2
  8. Membranes, Lipids, Glycobiology
  9. Changes of the peripheral blood mononuclear cells membrane fluidity from type 1 Gaucher disease patients: an electron paramagnetic resonance study
  10. Molecular Medicine
  11. Aβ42 oligomers impair the bioenergetic activity in hippocampal synaptosomes derived from APP-KO mice
  12. Cell Biology and Signaling
  13. Molecular determinants of Drosophila immunophilin FKBP39 nuclear localization
  14. The effect of lncRNA HOTAIR on chemoresistance of ovarian cancer through regulation of HOXA7
  15. Novel Techniques
  16. Determination of selenium during pathogenesis of hepatic fibrosis employing hydride generation and inductively coupled plasma mass spectrometry
Jetzt anmelden und 20% sparen
Institutioneller Zugang
Wie funktioniert Authentifizierung?
Haben Sie eine Idee, wie wir unsere Website verbessern können?
Bitte schreiben Sie uns.
© 2025 De Gruyter Brill
Heruntergeladen am 6.9.2025 von https://www.degruyterbrill.com/document/doi/10.1515/hsz-2017-0284/pdf
Button zum nach oben scrollen