Nicotinamide Nucleotide Transhydrogenase (Nnt) Links the Substrate Requirement in Brain Mitochondria for Hydrogen Peroxide Removal to the Thioredoxin/Peroxiredoxin (Trx/Prx) System

Lopert, Pamela; Patel, Manisha

doi:10.1074/jbc.m113.533653

Cited by 75 publications

(56 citation statements)

References 58 publications

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“…Brain mitochondria rapidly degrade H 2 O 2 at micromolar concentrations [35,47,48] in a mechanism partially dependent on respiration and on the activity of nicotinamide nucleotide transhydrogenase, which uses the membrane proton gradient to generate NADPH from NADH and NADP ? .…”

Section: Lack Of Inhibitory Effect Of Rotenone On Mitochondrial Elimimentioning

confidence: 99%

Effects of Partial Inhibition of Respiratory Complex I on H2O2 Production by Isolated Brain Mitochondria in Different Respiratory States

et al. 2014

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The aim of this work was to characterize the effects of partial inhibition of respiratory complex I by rotenone on H2O2 production by isolated rat brain mitochondria in different respiratory states. Flow cytometric analysis of membrane potential in isolated mitochondria indicated that rotenone leads to uniform respiratory inhibition when added to a suspension of mitochondria. When mitochondria were incubated in the presence of a low concentration of rotenone (10 nm) and NADH-linked substrates, oxygen consumption was reduced from 45.9 ± 1.0 to 26.4 ± 2.6 nmol O2 mg(-1) min(-1) and from 7.8 ± 0.3 to 6.3 ± 0.3 nmol O2 mg(-1) min(-1) in respiratory states 3 (ADP-stimulated respiration) and 4 (resting respiration), respectively. Under these conditions, mitochondrial H2O2 production was stimulated from 12.2 ± 1.1 to 21.0 ± 1.2 pmol H2O2 mg(-1) min(-1) and 56.5 ± 4.7 to 95.0 ± 11.1 pmol H2O2 mg(-1) min(-1) in respiratory states 3 and 4, respectively. Similar results were observed when comparing mitochondrial preparations enriched with synaptic or nonsynaptic mitochondria or when 1-methyl-4-phenylpyridinium ion (MPP(+)) was used as a respiratory complex I inhibitor. Rotenone-stimulated H2O2 production in respiratory states 3 and 4 was associated with a high reduction state of endogenous nicotinamide nucleotides. In succinate-supported mitochondrial respiration, where most of the mitochondrial H2O2 production relies on electron backflow from complex II to complex I, low rotenone concentrations inhibited H2O2 production. Rotenone had no effect on mitochondrial elimination of micromolar concentrations of H2O2. The present results support the conclusion that partial complex I inhibition may result in mitochondrial energy crisis and oxidative stress, the former being predominant under oxidative phosphorylation and the latter under resting respiration conditions.

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Section: Lack Of Inhibitory Effect Of Rotenone On Mitochondrial Elimimentioning

confidence: 99%

Effects of Partial Inhibition of Respiratory Complex I on H2O2 Production by Isolated Brain Mitochondria in Different Respiratory States

et al. 2014

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“…Nicotinamide nucleotide transhydrogenase, for which this gene codes, is an oxidoreductase in the inner mitochondrial membrane. The enzyme has a ubiquitous tissue distribution (Humphrey, 1957) and participates in maintaining mitochondrial redox homeostasis by providing a link between mitochondrial respiration and H 2 O 2 detoxification via the thioredoxin/peroxiredoxin system (Lopert et al, 2014). Mutations in this gene result in mitochondrial redox abnormalities in C57BL/6J mice (Ronchi et al, 2013) and have been implicated in disorders such as familial glucocorticoid deficiency (Meimaridou et al, 2012) and diabetes-like impaired glucose tolerance (Toye et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Disparities in auditory physiology and pathology between C57BL/6J and C57BL/6N substrains

Kendall

Schacht

2014

Hearing Research

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C57BL/6 inbred mice are frequently used as models in auditory research, mostly the C57BL/6J and C57BL/6N substrains. Genetic variation and phenotypic disparities between these two substrains have been extensively investigated, but conflicting information exists about differences in their auditory and vestibular phenotypes. Literature-based comparisons are rendered difficult or impossible because most auditory publications do not designate the substrain used. We therefore evaluated commercial C57BL/6N and C57BL/6J mice for their baseline auditory brainstem response (ABR) thresholds at 3 months of age as well as their susceptibility to noise exposure and aminoglycoside antibiotics. Both substrains have similar thresholds at 4 and 12 kHz, but C57BL/6N show significantly higher baseline thresholds at 24 and 32 kHz. Because of these elevated thresholds, the N substrain is unsuitable as a model for drug ototoxicity, which primarily affects high frequencies. Exposure to 2–20 kHz broadband noise for 2 h at 110 dB produced significantly higher threshold shifts in the J substrain. These results suggest caution in the selection of C57BL/6 substrains for auditory research and indicate the need to specify substrains, age and the breeding source in all publications.

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“…(iii) Because of this last property, NNT is a very high-capacity source of NADPH because it unites the reductive potentials of a variety of mitochondrial substrates (16,17). The ⌬p maintained across the IMM by the activity of the respiratory chain thermodynamically drives the forward NNT reaction to establish an NADPH/NADP ϩ ratio that is at least 500-fold higher than the NADH/NAD ϩ ratio under the conditions present in respiring mitochondria (2).…”

mentioning

confidence: 99%

“…the relative contribution of NNT to the total NADPH supply) has been experimentally challenging but could be overcome via the molecular ablation of NNT expression/function (3,16,22,23). However, few studies involving mammalian cells or isolated intact mitochondria have contributed to understanding NNT function in the context of integrated mitochondrial energy metabolism (17,24).…”

mentioning

confidence: 99%

The Contribution of Nicotinamide Nucleotide Transhydrogenase to Peroxide Detoxification Is Dependent on the Respiratory State and Counterbalanced by Other Sources of NADPH in Liver Mitochondria

Ronchi¹,

Francisco²,

Passos

et al. 2016

Journal of Biological Chemistry

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The forward reaction of nicotinamide nucleotide transhydrogenase (NNT) reduces NADP؉ at the expense of NADH oxida- The coenzymes nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP) are soluble electron carriers that are reduced in oxidative reactions during the catabolism of energy substrates in the cytosol and mitochondria. Despite their structural similarity, reduced NAD and NADP are used to drive rather different processes in the cells (1). Given their roles as specific electron donors in diverse metabolic pathways, it is interesting that the redox states of NAD and NADP are linked to each other in the mitochondria of many organisms because the enzyme nicotinamide nucleotide transhydrogenase (NNT) 4 catalyzes the transfer of redox potential between these two coenzymes, reducing one at the expense of the oxidation of the other (2).The academic and clinical interest in the understanding of the role of NNT in redox metabolism (3) has grown substantially because mutations in the gene (Nnt) encoding this protein are present in the most widely used experimental mouse substrain (i.e. C57BL/6J) (4) and in some humans (5). Homozygous mutations of Nnt that are linked to familiar glucocorticoid insufficiency have been documented in humans (5), whereas the C57BL/6J mouse substrains have been shown to exhibit metabolic abnormalities (6 -8) with major implications regarding their use as experimental models in basic research (9 -12). The phenotype of the Nnt mutation in heterozygotes is not clear in humans (13) or mice.NADP ϩ reduction at the expense of NADH oxidation in the mitochondrial matrix is the well known primary role of NNT. Although mitochondria possess three other enzymatic oxidative reactions linked to NADP ϩ reduction (i.e. the enzymes isocitrate dehydrogenase (IDH2), malic enzymes (MEs), and glutamate dehydrogenase (GDH)), as highlighted in Fig. 1

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Nicotinamide Nucleotide Transhydrogenase (Nnt) Links the Substrate Requirement in Brain Mitochondria for Hydrogen Peroxide Removal to the Thioredoxin/Peroxiredoxin (Trx/Prx) System

Cited by 75 publications

References 58 publications

Effects of Partial Inhibition of Respiratory Complex I on H2O2 Production by Isolated Brain Mitochondria in Different Respiratory States

Effects of Partial Inhibition of Respiratory Complex I on H2O2 Production by Isolated Brain Mitochondria in Different Respiratory States

Disparities in auditory physiology and pathology between C57BL/6J and C57BL/6N substrains

The Contribution of Nicotinamide Nucleotide Transhydrogenase to Peroxide Detoxification Is Dependent on the Respiratory State and Counterbalanced by Other Sources of NADPH in Liver Mitochondria

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