Proton-translocating transhydrogenase: an update of unsolved and controversial issues

Pedersen, Anders; Karlsson, Bengt; Rydström, Jan

doi:10.1007/s10863-008-9170-x

Cited by 60 publications

(54 citation statements)

References 86 publications

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“…Thus, the concentrations of the two enzymes in bovine-heart SMP are about the same. The structural information on Nnt (Bizouarn et al 2000;Cotton et al 2001;Jackson 2003;Pedersen et al 2008) shows that its NADPH-producing site is close to the membrane surface, as was already predicted from inhibitor studies in 1972 (Rydström 1972). An association between the two enzymes could rule the NADPH/NADP + ratio in the vicinity of the NADPH site of Complex I (Fig.…”

supporting

confidence: 70%

“…430 residues), which is hydrophobic and thought to contain 14 trans-membrane helices; and a Cterminal one (domain III, ca. 200 residues), which is hydrophilic and binds NADP(H) (Rydström 1972(Rydström , 1977Hatefi and Yamaguchi 1996;Bizouarn et al 2000;Cotton et al 2001;Jackson 2003;Pedersen et al 2008). Its reaction can be written as:…”

Section: Some General Properties Of the Enzymes Involvedmentioning

confidence: 99%

“…GSH is the main electron donor for the reduction of mitochondrial H 2 O 2 (by glutathione peroxidase); for overviews see (Cadenas 2004;Andreyev et al 2005;Rydström 2006a;Muller et al 2007;Murphy 2009). In mammalian heart and skeletal muscle the NADPH-producing capacity of the mitochondrial IDH2 is potentially greater than that of Nnt; therefore, the specific physiological role of Nnt in bovine heart has not been well understood (Hoek and Rydström 1988;Jo et al 2001;Pedersen et al 2008). It should be kept in mind, however, that the comparison between the activities, determined as maximal initial activities, did not take into account that Nnt, because of its linkage to the Δp, can drive the mitochondrial NADPH/NADP + ratio to much higher values than IDH2 can.…”

Section: Production Of Omentioning

confidence: 99%

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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

Albracht

Meijer

Rydström

2011

J Bioenerg Biomembr

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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→O 2 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→O 2 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 H 2 O 2 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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supporting

confidence: 70%

Section: Some General Properties Of the Enzymes Involvedmentioning

confidence: 99%

Section: Production Of Omentioning

confidence: 99%

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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

Albracht

Meijer

Rydström

2011

J Bioenerg Biomembr

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“…NNT is localized to the mitochondrial inner membrane, where it catalyzes the transfer of a hydride ion from NADH to NADP ϩ coupled to H ϩ transport into the matrix. NNT is considered to be a significant source of mitochondrial NADPH required for regeneration of GSH from its oxidized form (58). We hypothesized that NNT activity might be decreased, due either to the relatively low state of membrane energization during PCarn catabolism (Fig.…”

Section: Lowmentioning

confidence: 99%

Electron Transport Chain-dependent and -independent Mechanisms of Mitochondrial H2O2 Emission during Long-chain Fatty Acid Oxidation

Seifert

Estey

Xuan

et al. 2010

Journal of Biological Chemistry

224

175

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Oxidative stress in skeletal muscle is a hallmark of various pathophysiologic states that also feature increased reliance on long-chain fatty acid (LCFA) substrate, such as insulin resistance and exercise. However, little is known about the mechanistic basis of the LCFA-induced reactive oxygen species (ROS) burden in intact mitochondria, and elucidation of this mechanistic basis was the goal of this study. Specific aims were to determine the extent to which LCFA catabolism is associated with ROS production and to gain mechanistic insights into the associated ROS production. Because intermediates and byproducts of LCFA catabolism may interfere with antioxidant mechanisms, we predicted that ROS formation during LCFA catabolism reflects a complex process involving multiple sites of ROS production as well as modified mitochondrial function. Thus, we utilized several complementary approaches to probe the underlying mechanism(s). Using skeletal muscle mitochondria, our findings indicate that even a low supply of LCFA is associated with ROS formation in excess of that generated by NADH-linked substrates. Moreover, ROS production was evident across the physiologic range of membrane potential and was relatively insensitive to membrane potential changes. Determinations of topology and membrane potential as well as use of inhibitors revealed complex III and the electron transfer flavoprotein (ETF) and ETF-oxidoreductase, as likely sites of ROS production. Finally, ROS production was sensitive to matrix levels of LCFA catabolic intermediates, indicating that mitochondrial export of LCFA catabolic intermediates can play a role in determining ROS levels. Reactive oxygen species (ROS)2 are generated in mitochondria as a normal byproduct of aerobic metabolism; 0.2-2% of O 2 consumption is estimated to be lost as superoxide under normal conditions (1, 2). Within the mitochondrial matrix, a suite of enzymes manages the ROS load by converting ROS to less toxic species or by mitigating their formation. Nevertheless, mitochondria are significant sources of cellular ROS, and oxidative stress is a hallmark of various physiological and pathological states, including exercise, insulin resistance, and atherosclerosis (3-10).Inhibitor studies in mitochondria utilizing NADH-or FADH 2 -linked substrates suggest that complexes I and III of the electron transport chain (ETC) are predominant sites of superoxide production (11-13). Whether this is the case under physiologic conditions is not well appreciated. ROS generation by the ETC is critically dependent upon ETC redox state, such that ROS production is low until the inner membrane is significantly polarized and then rises steeply with small increments in membrane potential (14). However, a membrane potential-independent component of ROS production has been observed in brain mitochondria (15)(16)(17). Indeed, electrons may escape from sites other than the respiratory complexes, such as from the electron transfer flavoprotein (ETF) and ETF-ubiquinone oxidoreductase (ETF-QO) (18) or the ␣-ket...

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“…This innocuous pathway critically depends on the enzymatic reduction of r-no 2 to r-nH 2 , which hinges on the catalytic activity of the multifunctional mitochondrial flavoprotein of complex I. The energy coupled reduction of this flavoprotein by NADPH depends on the transhydrogenation of nadP + by NADH (8). Since we observed an as yet unspecified bioenergetic defect in cancer cells (9), we predicted that this defect may impede the oXPHoS-dependent reduction of r-no 2 to r-nH 2 in tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Enzymatic mechanism of the tumoricidal action of 4-iodo-3-nitrobenzamide

Kun（张坤）¹

2009

Mol Med Rep

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Abstract. activation of the prodrug 4-iodo-3-nitrobenzamide critically depends on the cellular reducing system specific to cancer cells. in non-malignant cells, reduction of this prodrug to the non-toxic amine occurs by the flavoprotein of complex I of mitochondria receiving Mg 2+ -aTP-dependent reducing equivalents from nadH to nadPH via pyridine nucleotide transhydrogenation. This hydride transfer is deficient in malignant cells; therefore, the lethal synthesis of 4-iodo-3-nitrosobenzamide takes place selectively. enzymatic evidence for this mechanism has been provided by cellular studies with lysolecithin-permeabilized cells and cell fractions, which have identified the defect in transhydrogenation in neoplastic cells to be located at the energy transfer site. Confirming previous results, the present study demonstrates the validity of the selective tumoricidal action of the prodrug in cell cultures.

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Proton-translocating transhydrogenase: an update of unsolved and controversial issues

Cited by 60 publications

References 86 publications

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

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

Electron Transport Chain-dependent and -independent Mechanisms of Mitochondrial H2O2 Emission during Long-chain Fatty Acid Oxidation

Enzymatic mechanism of the tumoricidal action of 4-iodo-3-nitrobenzamide

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