Evidence that reconstituted bovine heart mitochondrial transhydrogenase functions as a proton pump

Earle, Steven R.; Anderson, W.Marshall; Fisher, Ronald R.

doi:10.1016/0014-5793(78)80008-8

Cited by 29 publications

(11 citation statements)

References 16 publications

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“…NNT is located at the inner mitochondrial membrane of eukaryotes and in bacteria. Under physiological conditions, this transporter generates reduced nicotinamide adenine dinucleotide phosphate (NADPH) and NAD + from NADP + and NADH in the mitochondrial matrix fueled by the proton gradient [25] , [26] , [27] (Eq. (2) ).…”

Section: Introductionmentioning

confidence: 99%

Impact of a novel homozygous mutation in nicotinamide nucleotide transhydrogenase on mitochondrial DNA integrity in a case of familial glucocorticoid deficiency

et al. 2015

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BackgroundFamilial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder that is characterized by isolated glucocorticoid deficiency. Recently, mutations in the gene encoding for the mitochondrial nicotinamide nucleotide transhydrogenase (NNT) have been identified as a causative gene for FGD; however, no NNT activities have been reported in FGD patients carrying NNT mutations.MethodsClinical, biochemical and molecular analyses of lymphocytes from FDG homozygous and heterozygous carriers for the F215S NNT mutation were performed.ResultsIn this study, we described an FGD-affected Japanese patient carrying a novel NNT homozygous mutation (c.644T>C; F215S) with a significant loss-of-function (NNT activity = 31% of healthy controls) in peripheral blood cells' mitochondria. The NNT activities of the parents, heterozygous for the mutation, were 61% of the controls.ConclusionsOur results indicated that (i) mitochondrial biogenesis (citrate synthase activity) and/or mtDNA replication (mtDNA copy number) were affected at ≤ 60% NNT activity because these parameters were affected in individuals carrying either one or both mutated alleles; and (ii) other outcomes (mtDNA deletions, protein tyrosine nitration, OXPHOS capacity) were affected at ≤ 30% NNT activity as also observed in murine cerebellar mitochondria from C57BL/6J (NNT−/−) vs. C57BL/6JN (NNT+/+) substrains.General significanceBy studying a family affected with a novel point mutation in the NNT gene, a gene–dose response was found for various mitochondrial outcomes providing for novel insights into the role of NNT in the maintenance of mtDNA integrity beyond that described for preventing oxidative stress.

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Section: Introductionmentioning

confidence: 99%

Impact of a novel homozygous mutation in nicotinamide nucleotide transhydrogenase on mitochondrial DNA integrity in a case of familial glucocorticoid deficiency

et al. 2015

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“…It consists of a single polypeptide Forward reaction C nH+ -chain of Mr 120000 which forms a dimer both in the dispersed form and in reconstituted lipid vesicles. The reconstituted enzyme is a proton pump, acting in concert with the transfer of electrons from NADPH to NAD+ [8,9]. Similarly, in mitochondria the reduction of NADP+ by NADH is coupled to the translocation of protons from the C-(cytoplasmic) side to the M-(matrix) side of the mitochondrial inner membrane (see Fig.…”

Section: Nadh + Nadp+ = Nad + Nadphmentioning

confidence: 99%

Physiological roles of nicotinamide nucleotide transhydrogenase

Hoek

Rydström

1988

Biochemical Journal

327

210

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From the foregoing considerations, the energy-linked transhydrogenase reaction emerges as a powerful and flexible element in the network of redox and energy interrelationships that integrate mitochondrial and cytosolic metabolism. Its thermodynamic features make it possible for the reaction to respond readily to challenges, either on the side of NADPH utilization or on the side of energy depletion. Yet, the kinetic features are designed to prevent a wasteful input of energy when other sources of reducing equivalents to NADP are available, or to deplete the redox potential of NADPH in other than emergency conditions. By virtue of these characteristics, the energy-linked transhydrogenase can act as an effective buffer system, guarding against an excessive depletion of NADPH, preventing uncontrolled changes in key metabolites associated with NADP-dependent enzymes and calling on the supply of reducing equivalents from NAD-linked substrates only under conditions of high demand for NADPH. At the same time, it can provide an emergency protection against a depletion of energy, especially in situations of anoxia where a supply of reducing equivalents through NADP-linked substrates can be maintained. The flexibility of this design makes it possible that the functions of the energy-linked transhydrogenase vary from one tissue to another and are readily adjustable to different metabolic conditions.

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“…NNT is located in the inner mitochondrial membrane, where it functions as a redox-dependent proton pump that uses the proton gradient across the inner mitochondrial membrane to catalyze interconversion of nicotinamide adenine dinucleotide phosphate (NADPH) and NAD + from NADP + and NADH in the mitochondrial matrix ( Earle et al 1978 ; Pedersen et al 2008 ). NNT activity has been estimated to account for approximately 45% of total production of NADPH, with the remainder coming from the pentose phosphate pathway, mitochondrial NAD(P)-malic enzyme, and NADP-isocitrate dehydrogenase ( Sauer et al 2004 ; Vogel et al 1999 ).…”

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confidence: 99%

The C57BL/6J Mouse Strain Background Modifies the Effect of a Mutation in Bcl2l2

Navarro

Trinh

Lucas

et al. 2012

G3 Genes|Genomes|Genetics

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Bcl2l2 encodes BCL-W, an antiapoptotic member of the BCL-2 family of proteins. Intercross of Bcl2l2 +/− mice on a mixed C57BL/6J, 129S5 background produces Bcl2l2 −/− animals with the expected frequency. In contrast, intercross of Bcl2l2 +/− mice on a congenic C57BL/6J background produces relatively few live-born Bcl2l2 −/− animals. Genetic modifiers alter the effect of a mutation. C57BL/6J mice (Mus musculus) have a mutant allele of nicotinamide nucleotide transhydrogenase (Nnt) that can act as a modifier. Loss of NNT decreases the concentration of reduced nicotinamide adenine dinucleotide phosphate within the mitochondrial matrix. Nicotinamide adenine dinucleotide phosphate is a cofactor for glutathione reductase, which regenerates reduced glutathione, an important antioxidant. Thus, loss of NNT activity is associated with increased mitochondrial oxidative damage and cellular stress. To determine whether loss of Bcl2l2 −/− mice on the C57BL/6J background was mediated by the Nnt mutation, we outcrossed Bcl2l2 congenic C57BL/6J (Nnt −/−) mice with the closely related C57BL/6JEiJ (Nnt +/+) strain to produce Bcl2l2 +/− ; Nnt +/+ and Bcl2l2 +/− ; Nnt −/− animals. Intercross of Bcl2l2 +/− ; Nnt +/+ mice produced Bcl2l2 −/− with the expected frequency, whereas intercross of Bcl2l2 +/− ; Nnt −/− animals did not. This finding indicates the C57BL/6J strain background, and possibly the Nnt mutation, modifies the Bcl2l2 mutant phenotype. This and previous reports highlight the importance of knowing the genetic composition of mouse strains used in research studies as well as the accurate reporting of mouse strains in the scientific literature.

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Evidence that reconstituted bovine heart mitochondrial transhydrogenase functions as a proton pump

Cited by 29 publications

References 16 publications

Impact of a novel homozygous mutation in nicotinamide nucleotide transhydrogenase on mitochondrial DNA integrity in a case of familial glucocorticoid deficiency

Impact of a novel homozygous mutation in nicotinamide nucleotide transhydrogenase on mitochondrial DNA integrity in a case of familial glucocorticoid deficiency

Physiological roles of nicotinamide nucleotide transhydrogenase

The C57BL/6J Mouse Strain Background Modifies the Effect of a Mutation in Bcl2l2

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