Abstract
Mammalian NADH:ubiquinone oxidoreductase (Complex I) in the mitochondrial inner membrane catalyzes the oxidation of NADH in the matrix. Excess NADH reduces nine of the ten prosthetic groups of the enzyme in bovine-heart submitochondrial particles with a rate of at least 3,300 s−1. This results in an overall NADH→O2 rate of ca. 150 s−1. It has long been known that the bovine enzyme also has a specific reaction site for NADPH. At neutral pH excess NADPH reduces only three to four of the prosthetic groups in Complex I with a rate of 40 s−1 at 22 °C. The reducing equivalents remain essentially locked in the enzyme because the overall NADPH→O2 rate (1.4 s−1) is negligible. The physiological significance of the reaction with NADPH is still unclear. A number of recent developments has revived our thinking about this enigma. We hypothesize that Complex I and the Δp-driven nicotinamide nucleotide transhydrogenase (Nnt) co-operate in an energy-dependent attenuation of the hydrogen-peroxide generation by Complex I. This co-operation is thought to be mediated by the NADPH/NADP+ ratio in the vicinity of the NADPH site of Complex I. It is proposed that the specific H2O2 production by Complex I, and the attenuation of it, is of importance for apoptosis, autophagy and the survival mechanism of a number of cancers. Verification of this hypothesis may contribute to a better understanding of the regulation of these processes.
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Ackrell BAC, Kearney EB, Singer TP (1977) Effect of membrane environment on succinate dehydrogenase activity. J Biol Chem 252:1582–1588
Albracht SPJ (2010a) The reaction of NADPH with bovine mitochondrial NADH:ubiquinone oxidoreductase revisited: II. Comparison of the proposed working hypothesis with literature data. J Bioenerg Biomembr 42:279–292
Albracht SPJ (2010b) The reaction of NADPH with bovine mitochondrial NADH: ubiquinone oxidoreductase revisited: I. Proposed consequences for electron transfer in the enzyme. J Bioenerg Biomembr 42:261–278
Albracht SPJ, Heidrich HG (1975) Beef-heart submitochondrial particles: a mixture of mitochondrial inner and outer membranes. Biochim Biophys Acta 376:231–236
Albracht SPJ, Hedderich R (2000) Learning from hydrogenases: location of a proton pump and of a second FMN in bovine NADH-ubiquinone oxidoreductase (Complex I). FEBS Lett 485:1–6
Albracht SPJ, Dooijewaard G, Leeuwerik FJ, Swol BV (1977) EPR signals of NADH: Q oxidoreductase. Shape and intensity. Biochim Biophys Acta 459:300–317
Albracht SPJ, Van der Linden E, Faber BW (2003) Quantitative amino acid analysis of bovine NADH: ubiquinone oxidoreductase (Complex I) and related enzymes. Consequences for the number of prosthetic groups. Biochim Biophys Acta 1557:41–49
Anderson RF (1982) In: Massey V, Williams CH (eds) Flavins and flavoproteins: flavin-oxygen complex formed on the reaction of superoxide ions with flavosemiquinone radicals. Elsevier North-Holland, Inc., New York, pp 278–283
Andreyev AY, Kushnareva YE, Starkov AA (2005) Mitochondrial metabolism of reactive oxygen species. Biochemistry (Moscow) 70:200–214
Aon MA, Cortassa S, Maack C, O’Rourke B (2007) Sequential opening of mitochondrial ion channels as a function of glutathione redox thiol status. J Biol Chem 282:21889–21900
Arkblad EL, Tuck S, Pestov NB, Dmitriev RI, Kostina MB, Stenvall J, Tranberg M, Rydström J (2005) A Caenorhabditis elegans mutant lacking functional nicotinamide nucleotide transhydrogenase displays increased sensitivity to oxidative stress. Free Radic Biol Med 38:1518–1525
Armstrong FA, Albracht SPJ (2005) [NiFe]-hydrogenases: spectroscopic and electrochemical definition of reactions and intermediates. Phil Trans R Soc A 363:937–954
Aston-Mourney K, Wong N, Kebede M, Zraika S, Balmer L, McMahon JM, Fam BC, Favaloro J, Proietto J, Morahan G, Andrikopoulos S (2007) Increased nicotinamide nucleotide transhydrogenase levels predispose to insulin hypersecretion in a mouse strain susceptible to diabetes. Diabetologia 50:2467–2485
Bakker PT, Albracht SPJ (1986) Evidence for two independent pathways of electron transfer in mitochondrial NADH:Q oxidoreductase. I. Pre-steady-state kinetics with NADPH. Biochim Biophys Acta 850:413–422
Beinert H, Albracht SPJ (1982) New insights, ideas and unanswered questions concerning iron-sulfur clusters in mitochondria. Biochim Biophys Acta 683:245–277
Beinert H, Palmer G, Cremona T, Singer TP (1963) Correlation of enzymatic activity and the appearance of the EPR signal at g = 1.94 in NADH dehydrogenase and its thermal breakdown products. Biochem Biophys Res Commun 12:432–438
Beinert H, Kennedy MC, Stout CD (1996) Aconitase as iron-sulfur protein, enzyme, and iron-regulatory protein. Chem Rev 96:2335–2373
Belevich G, Euro L, Wikström M, Verkhovskaya M (2007) Role of the conserved Arginine 274 and Histidine 224 and 228 residues in the NuoCD subunit of complex I from Escherichia coli. Biochemistry 46:526–533
Berrisford JM, Sazanov LA (2009) Structural basis for the mechanism of respiratory complex I. J Biol Chem 284:29773–29783
Berrisford JM, Thompson CJ, Sazanov LA (2008) Chemical and NADH-induced, ROS-dependent, cross-linking between subunits of complex I from Escherichia coli and Thermus thermophilus. Biochemistry 47:10262–10270
Bizouarn T, Meuller J, Axelsson M, Rydström J (2000) The transmembrane domain and the proton channel in proton-pumping transhydrogenases. Biochim Biophys Acta 1459:284–290
Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED (2007) A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11:37–51
Borst P, Rottenberg S (2004) Cancer cell death by programmed necrosis? Drug Resist Update 7:321–324
Brand MD (2010) The sites and topology of mitochondrial superoxide production. Exp Gerontol 45:466–472
Bruice TC (1982) In: Massey V, Williams CH (eds) Flavins and flavoproteins: a progress report on studies of the activation of molecular oxygen by dihydroflavins. Elsevier North-Holland, Inc., New York, pp 265–277
Bursch W, Chabicovsky M, Wastl U, Grasl-Kraupp B, Bukowska K, Taper H, Schulte-Hermann R (2005) Apoptosis in stages of mouse hepatocarcinogenesis: failure to counterbalance cell proliferation and to account for strain differences in tumor susceptibility. Toxicol Sci 65:515–529
Cadenas E (2004) Mitochondrial free radical production and cell signaling. Mol Aspects Med 25:17–26
Cao W, Yacoub S, Shiverick KT, Namiki K, Sakai Y, Porvasnik S, Urbanek C, Rosser CJ (2008) Dichloroacetate (DCA) sensitizes both wild-type and over expressing Bcl-2 prostate cancer cells in vitro to radiation. Prostate 68:1223–1231
Carroll J, Fearnley IM, Skehel JM, Shannon RJ, Hirst J, Walker JE (2006) Bovine complex I is a complex of 45 different subunits. J Biol Chem 281:32724–32727
Chen LB (1988) Mitochondrial membrane potential in living cells. Annu Rev Cell Biol 4:155–181
Chen Y, Gibson SB (2008) Is mitochondrial generation of reactive oxygen species a trigger for autophagy? Autophagy 4:246–248
Chen Y, Azad MB, Gibson SB (2009) Superoxide is the major reactive oxygen species regulating autophagy. Cell Death Differ 16:1040–1052
Chin L, Gray JW (2008) Translating insights from the cancer genome into clinical practice. Nature 452:553–563
Cittadini A, Galeotti T, Terranova T (1971) The effect of pyruvate on cyanide-inhibited respiration in intact ascites tumor cells. Experientia 27:633–635
Cotton NPJ, White SA, Peake SJ, McSweeney S, Jackson JB (2001) The crystal structure of an asymmetric complex of the two nucleotide binding components of proton-translocating transhydrogenase. Structure 9:165–176
Cremona T, Kearney EB (1964) Studies on the respiratory chain-linked NADH dehydrogenase. VI. Further purification and properties of the enzyme from beef heart. J Biol Chem 239:2328–2334
De Jong L, Kemp A (1984) Stoicheiometry and kinetics of the prolyl 4-hydroxylase partial reaction. Biochim Biophys Acta 787:105–111
De Jong L, Albracht SPJ, Kemp A (1982) Prolyl 4-hydroxylase activity in relation to the oxidation state of enzyme-bound iron. The role of ascorbate in peptidyl proline hydroxylation. Biochim Biophys Acta 704:326–332
Diwan BA, Blackman KE (1980) Differential susceptibility of 3 sublines of C57BL/6 mice to the induction of colorectal tumors by 1,2-dimethylhydrazine. Cancer Lett 9:111–115
Djafarzadeh R, Kerscher S, Zwicker K, Radermacher M, Lindahl M, Schägger H, Brandt U (2000) Biophysical and structural characterization of proton-translocating NADH-dehydrogenase (complex I) from the strictly aerobic yeast Yarrowia lipolytica. Biochim Biophys Acta 1459:230–238
Dooijewaard G, Slater EC (1976) Steady-state kinetics of high molecular weight (type-I) NADH dehydrogenase. Biochim Biophys Acta 440:1–15
Dudkina NV, Kouril R, Peters K, Braun H-P, Boekema EJ (2010) Structure and function of mitochondrial supercomplexes. Biochim Biophys Acta 1797:664–670
Efremov RG, Baradaran R, Sazanov LA (2010) The architecture of respiratory complex I. Nature 465:441–445
Ellyard PW, San Pietro A (1969) The Warburg effect in a chloroplast-free preparation from Euglena gracilis. Plant Physiol 44:1679–1683
Ernster L, Dallner G, Azzone GF (1963) Differential effects of rotenone and amytal on mitochondrial electron and energy transfer. J Biol Chem 238:1124–1131
Estabrook RW, Holowinsky A (1961) Studies on the content and organization of the respiratory enzymes of mitochondria. J Biophys Biochem Cytol 9:19–28
Eytan GD, Carlenor E, Rydström J (1990) Energy-linked transhydrogenase. Effects of valinomycin and nigericn on the ATP-driven transhydrogenase reaction catalyzed by reconstituted transhydrogenase-ATPase vesicles. J Biol Chem 265:12949–12954
Fantin VR, St-Pierre J, Leder P (2006) Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9:425–434
Fearnley IM, Walker JE (1992) Conservation of sequences of subunits of mitochondrial complex I and their relationships with other proteins. Biochim Biophys Acta 1140:105–134
Finel M, Skehel JM, Albracht SPJ, Fearnley IM, Walker JE (1992) Resolution of NADH: ubiquinone oxidoreductase from bovine heart mitochondria into two subcomplexes, one of which contains the redox centers of the enzyme. Biochemistry 31:11425–11434
Finel M, Majander AS, Tyynelä J, De Jong AMP, Albracht SPJ, Wikström M (1994) Isolation and characterisation of subcomplexes of the mitochondrial NADH: ubiquinone oxidoreductase (complex I). Eur J Biochem 226:237–242
Flint DH, Tuminello JF, Emptage MH (1993) The inactivation of Fe-S cluster containing hydro-lyases by superoxide. J Biol Chem 268:22369–22376
Fontecilla-Camps JC, Volbeda A, Cavazza C, Nicolet Y (2007) Structure/function relationships of [NiFe]- and [FeFe]-hydrogenases. Chem Rev 107:4273–4303
Forkink M, Smeitink JAM, Brock R, Willems PHGM, Koopman WJH (2010) Detection and manipulation of mitochondrial reactive oxygen species in mammalian cells. Biochim Biophys Acta 1797:1034–1044
Freeman H, Shimomura K, Cox RD, Ashcroft FM (2006a) Nicotinamide nucleotide transhydrogenase: a link between insulin secretion, glucose metabolism and oxidative stress. Biochem Soc Trans 34:806–810
Freeman H, Shimomura K, Horner E, Cox RD, Ashcroft FM (2006b) Nicotinamide nucleotide transhydrogenase: a key role in insulin secretion. Cell Metab 3:35–45
Freeman HC, Hugill A, Dear NT, Ashcroft FM, Cox RD (2006c) Deletion of nicotinamide nucleotide transhydrogenase. A new quantitive trait locus accounting for glucose intolerance in C57BL/6J mice. Diabetes 55:2153–2156
Galkin AS, Grivennikova VG, Vinogradov AD (1999) H+/2e- stoichiometry in NADH-quinone reductase reactions catalyzed by bovine heart submitochondrial particles. FEBS Lett 451:157–161
George SJ, Kurkin S, Thorneley RNF, Albracht SPJ (2004) Reactions of H2, CO, and O2 with active [NiFe]-hydrogenase from Allochromatium vinosum. A stopped-flow infrared study. Biochemistry 43:6808–6819
Gostimskaya IS, Grivennikova VG, Cecchini G, Vinogradov AD (2007) Reversible dissociation of flavin mononucleotide from the mammalian membrane-bound NADH:ubiquinone oxidoreductase (Complex I). FEBS Lett 581:5803–5806
Grgic L, Zwicker K, Kashani-Poor N, Kerscher S, Brandt U (2004) Functional significance of conserved histidines and arginines in the 49-kDa subunit of mitochondrial complex I. J Biol Chem 279:21193–21199
Grigorieff N (1998) Three-dimensional structure of bovine NADH: ubiquinone oxidoreductase (complex I) at 22 Å in ice. J Mol Biol 277:1033–1046
Guénebaut V, Vincentelli R, Mills D, Weiss H, Leonard KR (1997) Three-dimensional structure of NADH-dehydrogenase from Neurospora crassa by electron microscopy and conical tilt reconstruction. J Mol Biol 265:409–418
Guénebaut V, Schlitt A, Weiss H, Leonard K, Friedrich T (1998) Consistent structure between bacterial and mitochondrial NADH: ubiquinone oxidoreductase (Complex I). J Mol Biol 276:105–112
Gutman M, Singer TP, Casida JE (1970) Studies on the respiratory chain-linked reduced nicotinamide adenine dinucleotide dehydrogenase. XVII. Reaction sites of piericidin A and rotenone. J Biol Chem 245:1992–1997
Happe RP, Roseboom W, Pierik AJ, Albracht SPJ, Bagley KA (1997) Biological activation of hydrogen. Nature 385:126
Hatefi Y, Hanstein WG (1973) Interactions of reduced and oxidized triphosphopyridine nucleotides with the electron-transport system of bovine heart mitochondria. Biochemistry 12:3515–3522
Hatefi Y, Bearden AJ (1976) Electron paramagnetic resonance studies on the reduction of the components of complex I and transhydrogenase-inhibited complex I by NADH and NADPH. Biochem Biophys Res Commun 69:1032–1038
Hatefi Y, Yamaguchi M (1996) Nicotinamide nucleotide transhydrogenase: a model for utilization of substrate binding energy for proton translocation. FASEB J 10:444–452
Hatefi Y, Haavik AG, Griffiths DE (1962) Studies on the electron transfer system; XL. Preparation and properties of mitochondrial DPNH-Coenzyme Q reductase. J Biol Chem 237:1667–1680
Heerdt BG, Houston MA, Augenlicht LH (2006) Growth properties of colonic tumor cells are a function of the intrinsic mitochondrial membrane potential. Cancer Res 66:1591–1596
Heidrich HG, Albracht SPJ, Bäckström D (1978) Two iron-sulfur centers in mitochondrial outer membranes from beef heart as prepared by free-flow electrophoresis. FEBS Lett 95:314–318
Hinkle PC, Butow RA, Racker E, Chance B (1967) Partial resolution of the enzymes catalyzing oxidative phosphorylation. XV. Reverse electron transfer in the flavin-cytochrome b region of the respiratory chain of beef heart submitochondrial particles. J Biol Chem 242:5169–5173
Hirst J (2010) Towards the molecular mechanism of respiratory complex I. Biochem J 425:327–339
Hirst J, Carroll J, Fearnley IM, Shannon RJ, Walker JE (2003) The nuclear encoded subunits of complex I from bovine heart mitochondria. Biochim Biophys Acta 1604:135–150
Hoek JB, Rydström J (1988) Physiological roles of nicotinamide nucleotide transhydrogenase. Biochem J 254:1–10
Hofhaus G, Weiss H, Leonard K (1991) Electron microscopic analysis of the peripheral and membrane parts of mitochondrial NADH dehydrogenase (complex I). J Mol Biol 221:1027–1043
Huang T-T, Carlson EJ, Raineri I, Gillespie AM, Kozy H, Epstein CJ (1999) The use of transgenic and mutant mice to study oxygen free radical metabolism. Ann NY Acad Sci 893:95–112
Huang T-T, Naeemuddin M, Elchuri S, Yamaguchi M, Kozy HM, Carlson EJ, Epstein CJ (2006) Genetic modifiers of the phenotype of mice deficient in mitochondrial superoxide dismutase. Hum Mol Genet 15:1187–1194
Hunte C, Zickermann V, Brandt U (2010) Functional modules and structural basis of conformational coupling in mitochondrial complex I. Science 329:448–451
Ingledew WJ, Ohnishi T (1980) An analysis of some thermodynamic properties of iron-sulphur centres in site I of mitochondria. Biochem J 186:111–117
Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG Jr (2001) HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292:464–468
Jaakkola P, Mole DR, Tian Y-M, Wilson MI, Gielbert J, Gaskell SJ, Von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Targeting of HIF-α to the von Hippel- Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 468–472.
Jackson JB (2003) Proton translocation by transhydrogenase. FEBS Lett 545:18–24
Jensen PK (1966) Antimycin-insensitive oxidation of succinate and reduced nicotinamide-adenine dinucleotide in electron-transport particles. I. pH dependency and hydrogen peroxide formation. Biochim Biophys Acta 122:157–166
Jiang P, Du W, Wang X, Mancuso A, Gao X, Wu M, Yang X (2011) p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nat Cell Biol 13:310–316
Jitrapakdee S, Wutthisathapornchai A, Wallace JC, MacDonald MJ (2010) Regulation of insulin secretion: role of mitochondrial signalling. Diabetologia 53:1019–1032
Jo S-H, Son M-K, Koh H-J, Lee S-M, Song I-H, Kim Y-O, Lee Y-S, Jeong K-S, Kim WB, Park J-W, Song BJ, Huh T-L (2001) Control of mitochondrial redox balance and cellular defense against oxidative damage by mitochondrial NADP+-dependent isocitrate dehydrogenase. J Biol Chem 276:16168–16176
Jones S, Zhang X, Parsons DW, Lin JC-H, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong S-M, Fu B, Lin M-T, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321:1801–1806
Kaelin WG Jr, Ratcliffe PJ (2008) Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 30:393–402
Kashani-Poor N, Zwicker K, Kerscher S, Brandt U (2001) A central functional role for the 49-kDa subunit within the catalytic core of mitochondrial complex I. J Biol Chem 276:24082–24087
Kato M, Li J, Chuang JL, Chuang DT (2007) Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by AZD7545, dichloroacetate, and radicicol. Structure 15:992–1004
Kawakita M, Ogura Y (1969) Spectrophotometric and electron spin resonance studies of NADH2-cytochrome c reductase complex. J Biochem (Japan) 66:203–211
Kim K, Rodriguez-Enriquez S, Lemasters JL (2007) Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys 462:245–253
Kim A, Chen C-H, Ursell P, Huang T-T (2010) Genetic modifier of mitochondrial superoxide dismutase-deficient mice delays heart failure and prolongs survival. Mamm Genome 21:534–542
Knowles HJ, Raval RR, Harris AL, Ratcliffe PJ (2003) Effect of ascorbate on the activity of hypoxia-inducible factor in cancer cells. Cancer Res 63:1764–1768
Koppenol W, Stanbury DM, Bounds PL (2010) Electrode potentials of partially reduced oxygen species, from dioxygen to water. Free Radic Biol Med 49:317–322
Kowal AT, Morningstar JE, Johnson MK, Ramsay RR, Singer TP (1986) Spectroscopic characterization of the number and type of iron-sulfur clusters in NADH: ubiquinone oxidoreductase. J Biol Chem 261:9239–9245
Krishnamoorthy G, Hinkle PC (1988) Studies on the electron transfer pathway, topography of iron-sulfur centers, and site of coupling in NADH-Q oxidoreductase. J Biol Chem 263:17566–17575
Kuiper C, Molenaar IGM, Dachs GU, Currie MJ, Sykes PH, Vissers MCM (2010) Low ascorbate levels are associated with increased hypoxia-inducible factor-1 activity and an aggressive tumor phenotype in endometrial cancer. Cancer Res 70:5749–5758
Kurkin S, George SJ, Thorneley RNF, Albracht SPJ (2004) Hydrogen-induced activation of the [NiFe]-hydrogenase from Allochromatium vinosum as studied by stopped-flow infrared spectroscopy. Biochemistry 43:6820–6831
Kussmaul L, Hirst J (2006) The mechanism of superoxide production by NADH: ubiquinone oxidoreductase (complex I) from bovine heart mitochondria. Proc Natl Acad Sci (USA) 103:7607–7612
Lambert AJ, Brand MD (2004a) Superoxide production by NADH:ubiquinone oxidoreductase (complex I) depends on the pH gradient across the mitochondrial inner membrane. Biochem J 382:511–517
Lambert AJ, Brand MD (2004b) Inhibitors of the quinone-binding site allow rapid superoxide production from mitochondrial NADH:ubiquinone oxidoreductase (complex I). J Biol Chem 279:39414–39420
Lambert AJ, Buckingham JA, Boysen HM, Brand MD (2008a) Diphenyleneiodonium acutely inhibits reactive oxygen species production by mitochondrial complex I during reverse, but not forward electron transport. Biochim Biophys Acta 1777:397–403
Lambert AJ, Buckingham JA, Brand MD (2008b) Dissociation of superoxide production by mitochondrial complex I from NAD(P)H redox state. FEBS Lett 592:1711–1714
Le A, Cooper CR, Gouw AM, Dinavahi R, Maitra A, Deck LM, Royer RE, Vander Jagt DL, Semenza GL, Dang CV (2010) Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci (USA) 107:2037–2042
Leonard K, Haiker H, Weiss H (1987) Three-dimensional structure of NADH: ubiquinone reductase (complex I) from Neurospora mitochondria determined by electron microscopy of membrane crystals. J Mol Biol 194:277–286
Li J, Kato M, Chuang DT (2009) Pivotal role of the C-terminal DW-motif in mediating inhibition of pyruvate dehydrogenase kinase 2 by dichloroacetate. J Biol Chem 284:34458–34467
Lind J, Merenyi G (1990) Kinetics and thermodynamics of the autoxidation of reduced flavin mononucleotide (FMN). Photochem Photobiol 51:21–27
Lippitt B, McCord JM, Fridovich I (1972) The sonochemical reduction of cytochrome c and its iInhibition by superoxide dismutase. J Biol Chem 247:4668–4690
Lu C-W, Lin S-C, Chen K-F, Lai Y-Y, Tsai S-J (2008) Induction of pyruvate dehydrogenase kinase-3 by hypoxia-inducible factor-1 promotes metabolic switch and drug resistance. J Biol Chem 283:28106–28114
Luciaková K, Kuzela S (1992) Increased steady-state levels of several mitochondrial and nuclear gene transcripts in rat hepatoma with a low content of mitochondria. Eur J Biochem 205:1187–1193
Lusty CJ, Machinist JM, Singer TP (1965) Studies on the respiratory chain-linked NADH dehydrogenase. VII. Labile sulfide groups in the dehydrogenase and in related proteins. J Biol Chem 240:1804–1810
Madhok BM, Yeluri S, Perry SL, Hughes TA, Jayne DG (2010) Dichloroacetate induces apoptosis and cell-cycle arrest in colorectal cancer cells. Br J Canc 102:1746–1752
Mathupala SP, Ko YH, Pedersen PL (2009) Hexokinase-2 bound to mitochondria: cancer’s stygian link to the “Warburg effect”and a pivotal target for effective therapy. Semin Cancer Biol 19:17–24
Mathupala SP, Ko YH, Pedersen PL (2010) The pivotal roles of mitochondria in cancer: Warburg and beyond and encouraging prospects for effective therapies. Biochim Biophys Acta 1797:1225–1230
McCord JM, Fridovich I (1969) Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J Biol Chem 244:6049–6055
McCord JM, Fridovich I (1978) The biology and pathology of oxygen radicals. Ann Intern Med 89:122–127
Meijer AJ, Codogno P (2009) Autophagy: regulation and role in disease. Crit Rev Clin Lab Sci 46:210–240
Michelakis ED, Webster L, Mackey JR (2008) Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br J Canc 99:989–994
Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E, Maguire C, Gammer T-L, Mackey JR, Fulton D, Abdulkarim B, McMurtry MS, Petruk KC (2010) Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med 2:31ra34
Miller DM, Buettner GR, Aust SD (1990) Transition metals as catalysts of “ autoxidation” reactions. Free Radic Biol Med 8:95–108
Miller EW, Dickinson BC, Chang CJ (2010) Aquaporin-3 mediates hydrogen peroxide uptake to regulate downstream intracellular signaling. Proc Natl Acad Sci (USA) 107:15681–15686
Mitchell PD (2004) Foundations of vectorial metabolism and osmochemistry. Biosci Rep 24:386–434
Mole DR, Blancher C, Copley RR, Pollard PJ, Gleadle JM, Ragoussis J, Ratcliffe PJ (2009) Genome-wide association of hypoxia-inducible factor (HIF)-1α and HIF-2α DNA binding with expression profiling of hypoxia-inducible transcripts. J Biol Chem 284:16767–16775
Morgan DJ, Sazanov LA (2008) Three-dimensional structure of respiratory complex I from Escherichia coli in ice in the presence of nucleotides. Biochim Biophys Acta 1777:711–718
Muller FL, Lustgarten MS, Jang Y, Richardson A, Van Remmen H (2007) Trends in oxidative aging theorie. Free Radic Biol Med 43:477–503
Murai M, Ishihara A, Nishioka T, Yagi T, Miyoshi H (2007) The ND1 subunit constructs the inhibitor binding domain in bovine heart mitochondrial complex I. Biochemistry 46:6409–6416
Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417:1–13
Murphy MP, Holmgren A, Larsson N-G, Halliwell B, Chang CJ, Kalyanaraman B, Rhee SG, Thornalley PJ, Partridge L, Gems D, Nyström T, Belousov V, Schumacker PT, Winterbourn CC (2011) Unraveling the biological roles of reactive oxygen species. Cell Metab 13:361–366
Nakashima Y, Shinzawa-Itoh K, Watanabe K, Naoki K, Hano N, Yoshikawa S (2002) Steady-state kinetics of NADH:coenzyme Q oxidoreductase isolated from bovine heart mitochondria. J Bioenerg Bioemembr 34:11–19
Nulton-Persson AC, Szweda LI (2001) Modulation of mitochondrial function by hydrogen peroxide. J Biol Chem 267:23357–23361
Ohnishi ST, Shinzawa-Itoh K, Ohta K, Yoshikawa S, Ohnishi T (2010) New insights into the superoxide generation sites in bovine heart NADH-ubiquinone oxidoreductase (Complex I): the significance of protein-associated ubiquinone and the dynamic shifting of generation sites between semiflavin and semiquinone radicals. Biochim Biophys Acta 1797:1901–1909
Ohnishi T, Leigh JS, Ragan CI, Racker E (1974) Low temperature electron paramagnetic resonance studies on iron-sulfur centers in cardiac NADH dehydrogenase. Biochem Biophys Res Commun 56:775–782
Ohnishi T, Blum H, Galante YM, Hatefi Y (1981) Iron-sulfur N-1 clusters studied in NADH-ubiquinone oxidoreductase and in soluble NADH dehydrogenase. J Biol Chem 256:9216–9220
Okado-Matsumoto A, Fridovich I (2001) Subcellular distribution of superoxide dismutases (SOD) in rat liver: Cu, Zn-SOD in mitochondria. J Biol Chem 276:38388–38393
Orme-Johnson NR, Hansen RE, Beinert H (1974) Electron paramagnetic resonance-detectable electron acceptors in beef heart mitochondria. Reduced diphosphopyridine nucleotide ubiquinone reductase segment of the electron transfer system. J Biol Chem 249:1922–1927
Paech C, Reynolds JR, Singer TP, Holm RH (1981) Structural identification of the iron-sulfur clusters of the respiratory chain-linked NADH dehydrogenase. J Biol Chem 256:3167–3170
Papa S (1969) In: Papa S, Tager JM, Quagliariello E, Slater EC (eds) The energy level and metabolic control in mitochondria: control of the utilization of mitochondrial reducing equivalents. Adriatica Editrice, Bari, Italy, pp 402–409
Papandreou I, Goliasova T, Denko NC (2010) Anticancer drugs that target metabolism: is dichloroacetate the new paradigm? Int J Cancer 128:1001–1008
Parker N, Vidal-Puig AJ, Azzu V, Brand MD (2009) Dysregulation of glucose homeostasis in nicotinamide nucleotide transhydrogenase knockout mice is independent of uncoupling protein 2. Biochim Biophys Acta 1787:1451–1457
Parsons DW, Jones S, Zhang X, Lin JC-H, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu I-M, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SKN, Shinjo SMO, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812
Pastorino JG, Hoek JB (2008) Regulation of hexokinase binding to VDAC. J Bioenerg Biomembr 40:171–182
Pedersen A, Karlsson GB, Rydström J (2008) Proton-translocating transhydrogenase: an update of unsolved and controversial issues. J Bioenerg Biomembr 40:463–473
Pedersen A, Karlsson J, Althage M, Rydström J (2003) Properties of the apo-form of the NADP(H)-binding domain III of proton-pumping Escherichia coli transhydrogenase: implications for the reaction mechanism of the intact enzyme. Biochim Biophys Acta 1604:55–59
Pedersen PL (1978) Tumor mitochondria and the bioenergetics of cancer cells. Progr Exp Tumor Res 22:190–274
Peng G, Fritzsch G, Zickermann V, Schagger H, Mentele R, Lottspeich F, Bostina M, Radermacher M, Huber R, Stetter KO, Michel H (2003) Isolation, characterization and electron microscopic single particle analysis of the NADH:ubiquinone oxidoreductase (complex I) from the hyperthermophilic eubacterium Aquifex aeolicus. Biochemistry 42:3032–3039
Persson B, Enander K, Tang H-L, Rydstrom J (1984) Energy-linked nicotinamide nucleotide transhydrogenase. Properties of proton-translocating mitochondrial transhydrogenase from beef heart purified by fast protein liquid chromatography. J Biol Chem 259:8626–8632
Pollard PJ, Ratcliffe PJ (2009) Puzzling patterns of predisposition. Science 324:192–194
Pryde KR, Hirst J (2011) Superoxide is produced by the reduced flavin in mtiochondrial complex I: a single, unified mechanism that applies during both forward and reverse electron transfer. J Biol Chem 286:18056–18065
Ragan CI (1976) The effects of proteolytic digestion by trypsin on the structure and catalytic properties of reduced nicotinamide-adenine dinucleotide dehydrogenase from bovine heart mitochondria. Biochem J 156:367–374
Ragan CI, Racker E (1973) Resolution and reconstitution of the mitochondrial electron transport system. IV. The reconstitution of rotenone-sensitive reduced nicotinamide adenine dinucleotide-ubiquinone reductase from reduced nicotinamide adenine dinucleotide dehydrogenase and phospholipids. J Biol Chem 248:6876–6884
Ragan CI, Widger WR (1975) The reconstitution of the mitochondrial energy-linked transhydrogenase. Biochem Biophys Res Commun 62:744–749
Ringler RL, Minakami S, Singer TP (1960) Isolation and properties of the DPNH dehydrogenase of the respiratory chain from heart mitochondria. Biochem Biophys Res Commun 3:417–422
Ringler RL, Minakami S, Singer TP (1963) Studies on the respiratory chain-linked NADH dehydrogenase. II. Isolation and molecular properties of the enzyme from beef heart. J Biol Chem 238:801–810
Robinson JM, Smith MG, Gibbs M (1980) Influence of hydrogen peroxide upon carbon dioxide photoassimilation in the spinach chloroplast. I. Hydrogen peroxide generated by broken chloroplasts in an “intact” chloroplast preparation is a causal agent of the Warburg effect. Plant Physiol 65:755–759
Rossi C, Cremona T, Machinist JM, Singer TP (1965) Studies on the respiratory chain-linked reduced nicotinamide adenine dinucleotide dehydrogenase. VIII. Inactivation, fragmentation, and protection by substrates. J Biol Chem 240:2634–2643
Rydström J (1972) Site-specific inhibitors of mitochondrial nicotinamide-nucleotide transhydrogenase. Eur J Biochem 31:496–504
Rydström J (1977) Energy-linked nicotinamide nucleotide transhydrogenases. Biochim Biophys Acta 463:155–184
Rydström J (2006a) Mitochondrial transhydrogenase—a key enzyme in insulin secretion and, potentially, diabetes. Trends Biochem Sci 31:355–358
Rydström J (2006b) Mitochondrial NADPH, transhydrogenase and disease. Biochim Biophys Acta 1757:721–726
Rydström J, Montelius J, Bäckström D, Ernster L (1978) The mechanism of oxidation of reduced nicotinamide dinucleotide phosphate by submitochondrial particles from beef heart. Biochim Biophys Acta 501:370–380
Salerno JC, Ohnishi T, Lim J, Widger WR, King TE (1977) Spin coupling between electron carriers in the dehydrogenase segments of the respiratory chain. Biochem Biophys Res Commun 75:618–624
Sazanov LA, Hinchliffe P (2006) Structure of the hydrophilic domain of respiratory Complex I from Thermus thermophilus. Science 311:1430–1436
Scherz-Shouval R, Shvets E, Fass E, Shorer H, Gil L, Elazar Z (2007) Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J 26:1749–1760
Semenza GL (2008a) Mitochondrial autophagy. Autophagy 4:534–536
Semenza GL (2008b) Regulation of oxygen homeostasis by hypoxia-inducible factor 1. Physiology 24:97–106
Sharpley MS, Shannon RJ, Draghi F, Hirst J (2006) Interactions between phospholipids and NADH:ubiquinone oxidoreductase (complex I) from bovine mitochondria. Biochemistry 45:241–248
Shinzawa-Itoh K, Seiyama J, Terada H, Nakatsubo R, Naoki K, Nakashima Y, Yoshikawa S (2010) Bovine heart NADH-ubiquinone oxidoreductase contains one molecule of ubiquinone with ten isoprene units as one of the cofactors. Biochemistry 49:487–492
Sinegina L, Wikström M, Verkhovsky MI, Verkhovskaya ML (2005) Activation of isolated NADH:ubiquinone reductase I (Complex I) from Escherichia coli by detergent and phospholipids. Recovery of ubiquinone reductase activity and changes in EPR signals of iron-sulfur clusters. Biochemistry 44:8500–8505
Sled VD, Rudnitzky NI, Hatefi Y, Ohnishi T (1994) Thermodynamic analysis of flavin in mitochondrial NADH: ubiquinone oxidoreductase (complex I). Biochemistry 33:10069–10075
Stratton MR, Campbell PJ, Futreal PA (2009) The cancer genome. Nature 458:719–724
Sun RC, Fadia M, Dahlstrom JE, Parish CR, Board PG, Blackburn AC (2010) Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo. Breast Cancer Res Treat 120:253–260
Suslick KS (1990) Sonochemistry. Science 247:1439–1445
Suslick KS, Flannigan DJ (2008) Inside a collapsing bubble: sonoluminescence and the conditions during cavitation. Annu Rev Phys Chem 59:659–683
Taylor SI, Mukherjee C, Jungas RL (1975) Regulation of pyruvate dehydrogenase in isolated rat liver mitochondria. Effects of octanoate, oxidation-reduction state, and adenosine triphosphate to adenosine diphosphate ratio. J Biol Chem 250:2028–2035
Terman A, Kurz T, Navratil M, Arriaga EA, Brunk UT (2010) Mitochondrial turnover and aging of long-lived postmitotic cells. The mitochondrial-lysosomal axis theory of aging. Antioxid Redox Signal 12:503–535
Tocilescu MA, Fendel U, Zwicker K, Kerscher S, Brandt U (2007) Exploring the ubiquinone binding cavity of respiratory complex I. J Biol Chem 282:29514–29520
Tocilescu MA, Fendel U, Zwicker K, Dröse S, Kerscher S, Brandt U (2010) The role of a conserved tyrosine in the 49-kDa subunit of complex I for ubiquinone binding and reduction. Biochim Biophys Acta 1797:625–632
Toye AA, Lippiat JD, Proks P, Shimomura K, Bentley L, Hugill A, Mijat V, Goldsworthy M, Moir L, Haynes A, Quarterman J, Freeman HC, Ashcroft FM, Cox RD (2005) A genetic and physiological study of impaired glucose homeostasis control in C57BL/6J mice. Diabetologia 48:675–686
Van Belzen R, Albracht SPJ (1989) The pathway of electron transfer in NADH: Q oxidoreductase. Biochim Biophys Acta 974:311–320
Van Belzen R, Van Gaalen MC, Cuypers PA, Albracht SPJ (1990) New evidence for the dimeric nature of NADH: Q oxidoreductase in bovine-heart submitochondrial particles. Biochim Biophys Acta 1017:152–159
Van den Broeke C, Radu M, Chernoff J, Favoreel HW (2010) An emerging role for p21-activated kinases (Paks) in viral infections. Trends Cell Biol 20:160–169
Van der Linden E, Faber BW, Bleijlevens B, Burgdorf T, Bernhard M, Friedrich B, Albracht SPJ (2004) Selective release and function of one of the two FMN groups in the cytoplasmic NAD+-reducing [NiFe]-hydrogenase from Ralstonia eutropha. Eur J Biochem 271:801–808
Van der Linden E, Burgdorf T, De Lacey AL, Buhrke T, Scholte M, Fernandez VM, Friedrich B, Albracht SPJ (2006) An improved purification procedure for the soluble [NiFe]-hydrogenase of Ralstonia eutropha: new insights into its (in)stability and spectroscopic properties. J Biol Inorg Chem 11:247–260
Vásquez-Vivar J, Kalyanaraman B, Kennedy MC (2000) Mitochondrial aconitase is a source of hydroxyl radical—An electron spin resonance investigation. J Biol Chem 275:14064–14069
Vincent KA, Parkin A, Lenz O, Albracht SPJ, Fontecilla-Camps JC, Cammack R, Friedrich B, Armstrong FA (2005) Electrochemical definitions of O2 sensitivity and oxidative inactivation in hydrogenases. J Am Chem Soc 127:18179–18189
Vissers MCM, Wilkie RP (2007) Ascorbate deficiency results in impaired neutrophil apoptosis and clearance and is associated with up-regulation of hypoxia-inducible factor 1α. J Leukoc Biol 81:1236–1244
Vissers MCM, Gunningham SP, Morrison MJ, Dachs GU, Currie MJ (2007) Modulation of hypoxia-inducible factor-1 alpha in cultured primary cells by intracellular ascorbate. Free Radic Biol Med 42:765–772
Volbeda A, Garcia E, Piras C, De Lacey AL, Fernandez VM, Hatchikian EC, Frey M, Fontecilla-Camps JC (1996) Structure of the [NiFe] hydrogenase active site: evidence for biologically uncommon Fe ligands. J Am Chem Soc 118:12989–12996
Volbeda A, Martin L, Cavazza C, Matho M, Faber BW, Roseboom W, Albracht SPJ, Garcin E, Rousset M, Fontecilla-Camps JC (2005) Structural differences between the ready and unready oxidized states of [NiFe] hydrogenases. J Biol Inorg Chem 10:239–249
Walker JE (1992) The NADH: ubiquinone oxidoreductase (complex I) of respiratory chains. Q Rev Biophys 25:253–324
Warburg O (1927) Über den heutigen stand des carcinomproblems. Naturwissenschaften 15:1–4
Warburg O (1948) Schwermetalle als Wirkungsgruppen von Fermenten, Verlag Dr. W. Saenger, 2. Auflage, Berlin
Warburg O (1954) Krebsforschung. Naturwissenschaften 41:485–486
Warburg O, Krippahl G (1960) Glykolsäurebildung in Chlorella. Z Naturforsch 15b:197–199
Warburg O, Posener K, Negelein E (1924) Über den stoffwechsel der carcinomzelle. Biochem Z 152:309–344
Watt W, Tulinsky A, Swenson RP, Watenpaugh KD (1991) Comparison of the crystal structures of a flavodoxin in its three oxidation states at cryogenic temperatures. J Mol Biol 218:195–208
Westermann B (2010) Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol 11:872–884
Whitehouse S, Cooper RH, Randle PJ (1974) Mechanism of activation of pyruvate dehydrogenase by dichloroacetate and other halogenated carboxylic acids. Biochem J 141:761–774
Wikström M (1984) Two protons are pumped from the mitochondrial matrix per electron transferred between NADH and ubiquinone. FEBS Lett 169:300–304
Wong JYY, Huggins GS, Debidda M, Munshi NC, De Vivo I (2008) Dichloroacetate induces apoptosis in endometrial cancer cells. Gynecol Oncol 109:394–402
Yagi T (1987) Inhibition of NADH-ubiquinone reductase activity by N, N’- dicyclohexylcarbodiimide and correlation of this inhibition with the occurrence of energy-coupling site 1 in various organisms. Biochemistry 26:2822–2828
Yamamoto N, Ushijima N, Koga Y (2009) Immunotherapy of HIV-infected patients with Gc protein-derived macrophage activating factor (GcMAF). J Med Virol 81:16–26
Yamamoto N, Suyama H, Nakazato H, Yamamoto N, Koga Y (2008) Immunotherapy of metastatic colorectal cancer with vitamin D-binding protein-derived macrophage-activating factor, GcMAF. Canc Immunol Immunother 57:1007–1016
Yip C, Harbour ME, Jayawardena K, Fearnley IM, Sazanov LA (2011) Evolution of respiratory complex I. “Supernumerary” subunits are present in the α-proteobacterial enzyme. J Biol Chem 286:5023–5033
Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, Gonzalez FJ, Semenza GL (2008) Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 283:10892–10903
Zhang Y, Marcillat O, Giulivi C, Ernster L, Davies KJA (1990) The oxidative inactivation of mitochondrial electron transport chain components and ATPase. J Biol Chem 265:16330–16336
Zickermann V, Kerscher S, Zwicker K, Tocilescu MA, Radermacher M, Brandt U (2009) Architecture of complex I and its implications for electron transfer and proton pumping. Biochim Biophys Acta 1787:574–583
Zwicker K, Galkin A, Dröse S, Grgic L, Kerscher S, Brandt U (2006) The redox-Bohr group associated with iron-sulfur cluster N2 of complex I. J Biol Chem 281:23013–23017
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Albracht, S.P.J., Meijer, A.J. & Rydström, J. Mammalian NADH:ubiquinone oxidoreductase (Complex I) and nicotinamide nucleotide transhydrogenase (Nnt) together regulate the mitochondrial production of H2O2—Implications for their role in disease, especially cancer. J Bioenerg Biomembr 43, 541–564 (2011). https://doi.org/10.1007/s10863-011-9381-4
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DOI: https://doi.org/10.1007/s10863-011-9381-4