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Nicotinamide Nucleotide transferase (NNT)

Discussion in 'Other Health News and Research' started by pattismith, Oct 18, 2017.

  1. pattismith

    pattismith Senior Member

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    WIKIPEDIA EXTRACT:

    Function

    NAD(P) transhydrogenase, mitochondrial is an integral protein of the inner mitochondrial membrane.
    The enzyme couples hydride transfer of reducing equivalent between NAD(H) and NADP(+) to proton translocation across the inner mitochondrial membrane.
    Under most physiological conditions, the enzyme uses energy from the mitochondrial proton gradient to produce high concentrations of NADPH. The resulting NADPH is used for biosynthesis as well as in reactions inside the mitochondria required to remove reactive oxygen species such as to retain a reduced glutathione pool (high GSH/GSSG ratio). The enzyme may be inactivated by oxidative modifications.[8]


    Reaction catalyzed:
    NADPH + NAD+ = NADP+ + NADH

    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.
    Ronchi JA1, Francisco A1, Passos LA2, Figueira TR3, Castilho RF4.

    Abstract
    The forward reaction of nicotinamide nucleotide transhydrogenase (NNT) reduces NADP(+) at the expense of NADH oxidation and H(+) movement down the electrochemical potential across the inner mitochondrial membrane, establishing an NADPH/NADP(+) ratio severalfold higher than the NADH/NAD(+) ratio in the matrix. In turn, NADPH drives processes, such as peroxide detoxification and reductive biosynthesis. In this study, we generated a congenic mouse model carrying a mutated Nnt(C57BL/6J) allele from the C57BL/6J substrain. Suspensions of isolated mitochondria from Nnt(+/+), Nnt(+/-), and Nnt(-/-) mouse liver were biochemically evaluated and challenged with exogenous peroxide under different respiratory states. The respiratory substrates were also varied, and the participation of concurrent NADPH sources (i.e. isocitrate dehydrogenase-2, malic enzymes, and glutamate dehydrogenase) was assessed. The principal findings include the following: Nnt(+/-) and Nnt(-/-) exhibit ∼50% and absent NNT activity, respectively, but the activities of concurrent NADPH sources are unchanged. The lack of NNT activity in Nnt(-/-) mice impairs peroxide metabolism in intact mitochondria. The contribution of NNT to peroxide metabolism is decreased during ADP phosphorylation compared with the non-phosphorylating state; however, it is accompanied by increased contributions of concurrent NADPH sources, especially glutamate dehydrogenase. NNT makes a major contribution to peroxide metabolism during the blockage of mitochondrial electron transport. Interestingly, peroxide metabolism in the Nnt(+/-) mitochondria matched that in the Nnt(+/+) mitochondria. Overall, this study demonstrates that the respiratory state and/or substrates that sustain energy metabolism markedly influence the relative contribution of NNT (i.e. varies between nearly 0 and 100%) to NADPH-dependent mitochondrial peroxide metabolism.

    Glutamate dehydrogenase (GLDH, GDH) is an enzyme, present in most microbes and the mitochondria of eukaryotes, as are some of the other enzymes required for urea synthesis, that converts glutamate to α-ketoglutarate. In animals, the produced ammonia is usually used as a substrate in the urea cycle

    L-glutamate + H2O + NAD(P)+ [​IMG] 2-oxoglutarate + NH3 + NAD(P)H + H+

    Clinical significance of NNT
    In failing hearts, a partial loss of NAD(P) transhydrogenase's mitochondrial activity negatively impacts the NADPH-dependent enzyme activities in the mitochondria and the capacity of mitochondria to maintain proton gradients, which may adversely impact energy production and oxidative stress defense in heart failure and exacerbate oxidative damage to cellular proteins.[9]


    Mutations in the NNT gene have been associated to familial glucocorticoid deficiency 1, a severe autosomal recessive disorder in human characterized by insensitivity to adrenocorticotropic hormone action on the adrenal cortex and an inability of the adrenal cortex to produce cortisol [10] Glucocorticoid deficiency 1 usually presents in neonatal to early childhood with episodes of hypoglycemia and other symptoms related to cortisol deficiency, including failure to thrive, recurrent illnesses or infections, convulsions, and shock. Diagnosis is confirmed with a low plasma cortisol measurement in the presence of an elevated adrenocorticotropic hormone level, and normal aldosterone and plasma renin measurements.
    [10]

    Mutation of the NNT can also produce mineralocorticoid deficiency

    https://www.ncbi.nlm.nih.gov/pubmed/26070314

    https://www.ncbi.nlm.nih.gov/pubmed/27474736


    https://en.wikipedia.org/wiki/NNT_(gene)#cite_note-Sheeran_FL_2010-9


    https://en.wikipedia.org/wiki/Glutamate_dehydrogenase


    Personnal comment: NNT makes a major contribution when OXPHOS is lowered (mito disorders either inborn or not)
    so in that case, Glutamate may be higher in plasma.
    My blood glutamate is in the high range, and healthrising gives it as a possible factor for ME/CFS, so I think NTT/Glutamate dhase is one more tiny piece of the puzzle...

    https://www.healthrising.org/blog/2...fs-puzzle-the-neuroinflammatory-series-pt-ii/
     
    Last edited: Oct 18, 2017
  2. Learner1

    Learner1 Professional Patient

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    Pacific Northwest
    Interesting read. Thanks for sharing. :) A few questions come to mind.

    The big one is in how to intervene. I suspect that we have different issues with the process of making ATP. For some of us its the quality if the membrane, for others it may be heavy metals interfering with the membrane function, for others its lack of some ingredient(s) in the process (NR, NADH, CoQ, etc.). And some of us have issues with superoxide dismutase and catalase which can allow damage to the membrane.

    I've been hoping for analysis of all of this somewhere.

    Do you find that taking NAC, GABA, or LDN, as mentioned in the link, helps?
     
    pattismith likes this.
  3. pattismith

    pattismith Senior Member

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    I made a mistake in the title, it is Transhydrogenase and not Transferase...sorry...:jaw-drop:

    I took NAC for years, I didn't see any difference, I tryed LDN without any effect, same for Glutathione even Liposomal one... I tryed a bit of SOD too, with no noteworthy effect.

    But since I started Nicotinamide Riboside, I feel very different: the impact on my brain is short but strong, so I need to understand what is going on and to investigate a bit...

    I received my blood amino acids test, but it seems that the samples were not perfectly preserved, so cystine is low with no conclusion to be drawn about it (degradation is quite quick by breaking of the disulfide bond).
    The only interesting thing is Arginine a bit high (also a bit high in urine), and Glutamate close to the maximum
    range.
    I was surprised that Lysine is not much higher because I take 1g every day...

    AAPLASMA.jpg
     
    ljimbo423 likes this.
  4. pattismith

    pattismith Senior Member

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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
    April 10, 2014.

    Abstract

    Mitochondrial reactive oxygen species (ROS) are implicated in the etiology of multiple neurodegenerative diseases including Parkinsons disease (PD). Mitochondria are known to be net producers of ROS but recently we have shown that brain mitochondria can consume mitochondrial hydrogen peroxide (H2O2) in a respiration-dependent manner predominantly by the thioredoxin/peroxiredoxin (Trx/Prx) system. Here we sought to determine the mechanism linking mitochondrial respiration with H2O2 catabolism in brain mitochondria and dopaminergic cells. We hypothesized that nicotinamide nucleotide transhydrogenase (Nnt), which utilizes the proton gradient to generate NADPH from NADH and NADP+, provides the link between mitochondrial respiration and H2O2 detoxification through the Trx/Prx system. Pharmacological inhibition of Nnt in isolated brain mitochondria significantly decreased their ability to consume H2O2 in the presence, but not absence, of respiration substrates. Nnt inhibition in liver mitochondria, which do not require substrates to detoxify H2O2, had no effect. Pharmacological inhibition or lentiviral knockdown of Nnt in N27 dopaminergic cells
    a) decreased H2O2 catabolism
    b) decreased NADPH and increased NADP+ levels and
    c) decreased basal, spare and maximal mitochondrial oxygen consumption rates. Nnt deficient cells possessed higher levels of oxidized mitochondrial Prx which rendered them more susceptible to steady-state increases in H2O2 and cell death following exposure to subtoxic levels of paraquat. This data implicates Nnt as the critical link between the metabolic and H2O2 antioxidant function in brain mitochondria and suggests Nnt as a potential therapeutic target to improve the redox balance in conditions of oxidative stress associated with neurodegenerative diseases.


    http://www.jbc.org/content/early/2014/04/10/jbc.M113.533653

    And an old article but interesting:

    1981 Aug 10;256(15):8217-21.
    Inhibition of the mitochondrial nicotinamide nucleotide transhydrogenase by dicyclohexylcarbodiimide and diethylpyrocarbonate.

    Phelps DC, Hatefi Y.
    Abstract
    The mitochondrial nicotinamide nucleotide transhydrogenase enzyme (EC 1.6.1.1) is inhibited by treatment with dicyclohexylcarbodiimide or diethylpyrocarbonate. Both inhibitions are pseudo first order with respect to incubation time, and both reaction orders with respect to inhibitor concentration are close to unit, indicating that in each case inhibition results from the binding of one inhibitor molecule per active unit of the transhydrogenase enzyme. In the presence of either inhibitor, both the energy-linked and the nonenergy-linked transhydrogenation reactions are inhibited at about the same rate. The water-soluble carbodiimide, N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide, showed no inhibition, however, NAD(H) and reduced or oxidized 3-acetylpyridine adenine dinucleotide protected the enzyme against inhibition by dicyclohexylcarbodiimide, while NADP (but not NADPH) appeared to increase the rate of inhibition. Substrates did not protect the enzyme against inhibition by diethylpyrocarbonate. [14C]dicyclohexylcarbodiimide labeled the transhydrogenase enzyme in submitochondrial particles. Treatment of labeled particles with trypsin resulted in fragmentation of the transhydrogenase enzyme and loss of a labeled polypeptide of Mr = approximately 100,000 as determined by polyacrylamide gel electrophoresis.

    https://www.ncbi.nlm.nih.gov/pubmed/7263646

    5. Diabetes: a disease potentially linked to a defective transhydrogenase gene

    http://www.sciencedirect.com/science/article/pii/S000527280600065X
     
  5. ljimbo423

    ljimbo423 Senior Member

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    United States, New Hampshire
    Hi Patti- Robert Naviaux seems to think lysine is important in opposing the CDR.

    LINK
    I started taking a couple grams a day about 2 weeks ago and now take 4.5 gms a day. I seem to feel a little more energy and a feeling of well-being. As a bonus I also feel less anxiety!:) Naviaux mentions above that lysine is anti-anxiety.

    Jim
     
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