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What treatments would a quantum clinician use to enhance glutathione production in the liver?

Discussion in 'Ask Jack' started by John Schumacher, Jul 7, 2022.

  1. Dr. @Jack Kruse - As you know from my recent posts on Ask Jack, my focus has been on our mitochondrial function within the liver. Please review https://forum.jackkruse.com/index.p...-enhance-lipid-metabolism-in-the-liver.27049/

    Mitochondria use charge variation to make them energy efficient.
    Every cell depends on healthy mitochondrial function. Let’s take a look at:

    https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c01013 OXPHOS is a fundamental mitochondrial process, linking the tricarboxylic acid (TCA) cycle to the production of adenosine triphosphate (ATP).

    https://sci-hub.se/10.1021/acs.jmedchem.0c01013 The mitochondrial oxidative phosphorylation (OXPHOS) system is the final biochemical pathway in the production of ATP and requires the orchestrated action of electron transport chain (ETC) complexes and ATP synthase located in the inner mitochondrial membrane.


    Structures of oxidative phosphorylation (OXPHOS) complexes.

    (A) Complex I consist of a peripheral arm and membrane arm. The 49 kDa (light yellow) and PSST (cyan) subunits forming the ubiquinone-binding pocket and ND1 subunit (gray) forming the entrance of the ubiquinone access channel are shown. The FMN and Fe−S clusters that form the electron transfer chain.​

    (B) Complex II comprises four subunits: SDHA (Fp, green), SDHB (Ip, cyan), SDHC (CybL, yellow), SDHD (CybS, blue), with two ubiquinone-binding sites (Qp and Qd site) and a succinate binding site. The Fe−S clusters and heme that are essential for electron transfer.​

    (C) Complex III is a symmetrical dimer with three core subunits: cytochrome b (cyt b, gray) with two b-type hemes (bL and bH), cytochrome c1 (cyt c1, yellow) and the iron−sulfur protein (ISP) with a Fe−S cluster.​

    (D) The structure of complex IV. Two heme molecules (heme a and heme a3) along with two binuclear copper centers (CuA and CuB) embedded in the structure are critical for the electron transfer.​

    (E) Complex V (ATP synthase) is composed of the Fo sector and F1 sector.​

    The potential for OXPHOS inhibitors shows significant profitability for medical science.

    OXPHOS respiratory-chain Complex 1 inhibitors - https://www.frontiersin.org/articles/10.3389/fendo.2019.00294/full

    The inhibition of complex 1 decreases NADH oxidation, proton pumping across the inner mitochondrial membrane and oxygen consumption rate, resulting in lower proton gradient (Δψ) and reduction of proton-driven ATP synthesis from ADP and inorganic phosphate (Pi).​

    Now isn’t that just wonderful…
    • A decrease in NADH efficiency
    • Destruction of the proton pump across the inner mitochondrial membrane
    • Oxygen consumption rate is disrupted
    • Overall reduction in ATP synthesis
    OXPHOS pentose phosphate Complex II inhibitors - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697178/

    These inhibitors like Ionidanine effect the central energy metabolism by suppressing succinate-induced respiration of the mitochondria. This inhibitor induces cellular reactive oxygen species through the complex II pentose phosphate pathway and inhibits glutathione production. This inhibitor successfully produces cellular death.​

    OXPHOS mitochondrial electron transport chain (mETC) Complex III inhibitors - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225892/

    Antimycin A inhibits autophagy through its inhibitory activity on mETC complex III. Antimycin A is known to bind to the Qi site of cytochrome c reductase in the mitochondrial complex III to inhibit the oxidation of ubiquinol in the electron transport chain which blocks the mitochondrial electron transfer between cytochrome b and c. The inhibition of electron transport causes a collapse of the proton gradient across the mitochondrial inner membrane, leading to the loss of the mitochondrial membrane potential (ΔΨm). The consequences of inhibiting complex III include an increase in the production of ROS and a reduction in the cellular levels of ATP.​

    OXPHOS Ca2+ release in Complex IV inhibitors – https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/1750-1326-6-53

    85-90% inhibition of complex IV activity was required before a major increase in the rate of Ca2+-independent glutamate release from depolarized synaptosomes is excitotoxic. Inhibition of complex IV activity by 0.1 and 1 mM KCN significantly reduced ATP levels to approximately 70% and 10%, respectively, in both polarized and depolarized synaptosomes.​

    OXPHOS adenosinetriphosphatase protein Complex V inhibitors - https://pubmed.ncbi.nlm.nih.gov/6462171/

    Methyl 4-azidobenzimidate derivative of the naturally occurring ATPase inhibitor protein (IF1) inhibits complex V. These type of inhibitors are: NBF-Cl, efrapeptin, aurovertin, FSBA, and phenylglyoxal. Complex V was first treated with the artificial inhibitor (ferrous bathophenanthroline or octylguanidine) and then with IF1. Also Gboxin associates with multiple OXPHOS proteins and inhibits complex V activity, causing cell death.​

    Imbalance between ATP synthesis and NADH reoxidation often is linked to an increase in ROS production. A lot of evidence shows that cells better adjust to a deficit in ATP synthesis than to a deficit in coenzymes reoxidation. A number of correlations between mitochondrial network and mitochondrial functions alterations are found in the literature. - https://sci-hub.se/10.1016/B978-0-12-811752-1.00001-8

    It is now clear that ROS—produced at the mitochondrial level or by other cellular alternative pathways—are involved both in cell signaling and deleterious redox alterations. One of the remaining issues is to identify in pathophysiological situations the localization of ROS production and the ROS species involved.

    But wait there’s more opportunities for medical science to disrupt...

    The efficiency with which dietary reducing equivalents are converted to ATP by oxidative phosphorylation (OXPHOS) is known as the coupling efficiency. This is determined by the efficiency with which protons are pumped out of the matrix by complexes I, III, and IV and by the efficiency with which proton flux through complex V is converted to ATP. The uncoupler drug 2,4-dinitrophenol and the nDNA-encoded uncoupler proteins 1, 2, and 3 render the mitochondrial inner membrane “leaky” for protons. This short-circuits the mitochondrial inner-membrane capacitor; uncouples electron transport from ATP synthesis; and causes the ETC to run at its maximum rate, thereby dissipating the energy as heat.

    Do you think our medical community would give up such an opportunity for non-profit? Just look at the following two examples, they are loaded with biochemical processes just waiting for disruption by medical science.


    AMPK, AMP-activated protein kinase;
    • APE-1, apurinic/apyrimidinic endonuclease factor 1;
    • HNF4α, hepatocyte nuclear factor 4 alpha; IR, insulin receptor; IRS, insulin receptor substrate;
    • MAPK, mitogen-activated protein kinase;
    • mCAT, mitochondrially targeted catalase;
    • MEF2, myocyte-enhancing factor 2;
    • mtTFA, mitochondrial transcription factor A;
    • NF-κB, nuclear factor kappa B;
    • NRF, nuclear regulatory factor;
    • PTEN, phosphatase and tensin homolog.
    Mitochondrial Energetics and Therapeutics

    The cellular redox system is coordinated by eight redox control nodes:
    • mitochondrial and cytosolic NADPH/NADP+,
    • mitochondrial and nucleus-cytosolic NADH/NAD+,
    • thioredoxins 1 and 2 (SH)2/SS [Trx1(SH)2/SS and Trx2(SH)2/SS, where SH stands for thiol and SS stands for disulfide], reduced glutathione/oxidized glutathione (GSH/GSSG),
    • and cysteine/cystine (CyS/CySS).
    However, our mitochondria do not exist in isolation, but constantly undergo cycles of fusion and fission, and are actively transported around the neuron to sites of high energy demand. Intriguingly, axonal and dendritic mitochondria exhibit different morphologies. In axons mitochondria are small and sparse whereas in dendrites they are larger and more densely packed.

    Mechanisms and roles of mitochondrial localization and dynamics in neuronal function

    Findings show that neuronal activity drives ATP generation [DOI: 10.1016/j.cell.2013.12.042 )], confirming previous reports that OXPHOS is the major source of energy during neuronal activity and synaptic transmission to support spine growth, cytoskeletal rearrangements and protein synthesis.

    Let’s get back to: Mitochondria uses charge variation to make them energy efficient.

    The redox status of the mitochondrial redox couples has been estimated to be
    (a) −405 mV for NADPH/NADP+,
    (b) −340 to −360 mV for Trx2(SH)2/SS,
    (c) −300 mV for GSH/GSSG, and
    (d) −250 mV for NADH/NAD+.

    Because the redox potential of NADH/NAD+ within the mitochondrion is −250 mV, most of the electrons from NADH flow down the ETC to O2 at +1200 mV to generate H2O.

    If these calculations are accurate, then mitochondrial water production is very costly -> +1200 mV. That’s very expensive DDW.

    Now to the subject of Metformin

    Biguanides work by preventing the liver from converting fats and amino-acids into glucose.

    The mechanisms of action of metformin

    Metformin has been shown to act via both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms; by inhibition of mitochondrial respiration but also perhaps by inhibition of mitochondrial glycerophosphate dehydrogenase, and a mechanism involving the lysosome.


    Ok so, Metformin prevents fats acid synthesis in the liver. The primary drug is 1-(diaminomethylidene)guanidine, so let's look at guanidine.
    Guanidine compounds inhibits the Voltage-Gated potassium (Kv) channels, disrupting the protein-lipid interfaces, direct interaction with the voltage sensors, and pore-binding.
    Now isn't that just wonderful - Medical intervention.​

    Let’s get back to: Mitochondria uses charge variation to make them energy efficient.

    GPD1 glycerol-3-phosphate dehydrogenase 1 pathway

    This gene encodes a member of the NAD-dependent glycerol-3-phosphate dehydrogenase family. The encoded protein plays a critical role in carbohydrate and lipid metabolism by catalyzing the reversible conversion of dihydroxyacetone phosphate (DHAP) and reduced nicotine adenine dinucleotide (NADH) to glycerol-3-phosphate (G3P) and NAD+. The encoded cytosolic protein and mitochondrial glycerol-3-phosphate dehydrogenase also form a glycerol phosphate shuttle that facilitates the transfer of reducing equivalents from the cytosol to mitochondria.​

    Mitochondria: Ultrastructure, Dynamics, Biogenesis and Main Functions

    Mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) is a flavin-linked respiratory chain dehydrogenase bound on the inter membrane space side of the inner mitochondrial membrane. The mGPDH oxidizes glycerol-3-phosphate (G3P) to dihydroxyacetone phosphate (DHAP) with concurrent reduction of flavin adenine dinucleotide (FAD) to FADH2 and transfers electrons to coenzyme Q (CoQ). The mGPDH is encoded by GPD2 gene, which is controlled by different promoters conferring a unique tissue-specific expression profile and placing the gene expression under the regulation of thyroid hormones. Despite their complete lack of homology, GPD2 often is co-expressed with the GPD1 enzyme encoding cytosolic glycerol-3-phosphate dehydrogenase, strongly supporting their mutual contribution in the glycerol phosphate redox shuttle. These two enzymes through the glycerol phosphate redox shuttle will regenerate NAD+ from the NADH formed during glycolysis.​


    The main enzymatic systems of detoxification of ROS generated by the OXPHOS system is:
    • NADH dehydrogenase (I),
    • glycerol-3-phosphate dehydrogenase (G3PDH) - the respiratory chain involved in superoxide formation is complex I.
    There is now general agreement that, in this large multisubunit complex, the electron transfer is working at near equilibrium and, therefore, superoxide production might be linked to both forward electron transport (FET) and reverse electron transport (RET). It is likely that different sites of superoxide production exist in complex I and that the sites involved are different for FET or in RET. Rotenone inhibits electron transfer right upstream the quinone binding site. Consequently, superoxides that are produced by complex I in the presence of NADH are most likely because of the electron carriers (flavin or Fe/S clusters). ROS generation flux, however, seems mainly linked to reverse electron flux, and the iQ site could be a major player in this flux. It should be stressed that, unlike ROS production for FET, ROS production from RET can originate either at the actual RET site or at the dehydrogenase level.

    One way to reoxidize the NADH produced during glycolysis is the glycerol-3-phosphate shuttle. This shuttle is made up of two isoforms of the enzyme called glycerol-3-phosphate dehydrogenase (G3PDH), which differ by their localization and cofactors. The mitochondrial isoform is on the external side of the mitochondrial inner membrane and is a FAD-linked enzyme that donates electrons to the respiratory chain via the ubiquinone pool. Its ROS production is supposed to be the consequence of the absence of a coenzyme Q binding site in the mitochondrial G3DPH, which would diminish the protection of ubisemiquinone produced during glycerol-3-phosphate oxidation.

    The redox level of the respiratory chain electron carriers, including ubisemiquinone, is thermokinetically controlled. Thus, the forces directly associated with respiratory chain activity, that are the redox potential of the NADH/NAD+ couple and the protonmotive force, are powerful regulators of the steady-state concentration of the free ubisemiquinone radical.

    When the respiratory chain is inhibited a decrease of the redox proton pump efficiency (such as slipping) are expected.

    Fatty acids decrease mitochondrial generation of reactive oxygen species at the reverse electron transport but increase it at the forward transport

    Long-chain nonesterified (“free”) fatty acids (FFA) can affect the mitochondrial generation of reactive oxygen species (ROS) in two ways: (i) by depolarisation of the inner membrane due to the uncoupling effect and (ii) by partly blocking the respiratory chain.

    This inhibition was partly abolished by the blocker of ATP/ADP transfer, carboxyatractyloside, thus indicating that this effect was related to uncoupling (protonophoric) action of fatty acids. However, unsaturated fatty acids and phytanic acid increase ROS generation by partly inhibiting the electron transport.

    FFA facilitate the access of O2 to electron-donating sites within the respiratory chain and, in addition, the release of O2[​IMG]−.​

    Nitric oxide inactivates glyoxalase I in cooperation with glutathione

    Glyoxalase I (Glo I) is inactivated upon exposure of human endothelial cells to extracellular nitric oxide (NO).

    NO can modulate Glo I activity in cooperation with cellular glutathione (GSH). A higher level of GSH is required for the formation of GSNO within cells. One of the major roles of the GS is believed to be the detoxification of 2-oxoaldehydes, such as methylglyoxal (MG), which appears primarily to be a byproduct of the metabolism of carbohydrates and lipids.

    Glutathione-dependent detoxification of alpha-oxoaldehydes by the glyoxalase system: involvement in disease mechanisms and antiproliferative activity of glyoxalase I inhibitors

    The glyoxalase system is a metabolic pathway that catalyses the detoxification of alpha-oxoaldehydes RCOCHO to corresponding aldonic acids RCH(OH)CO2H. It thereby protects cells from alpha-oxoaldehyde-mediated formation of advanced glycation endproducts (AGEs). It is comprised of two enzymes, glyoxalase I and glyoxalase II, and a catalytic amount of reduced glutathione (GSH) as cofactor. It is present in the cytosol of cells of mammals and most micro-organisms. Physiological substrates of the glyoxalase system are:
    • glyoxal--formed from lipid peroxidation and glycation reactions,
    • methylglyoxal--formed from triosephosphates,
    • ketone body metabolism and threonine catabolism, and
    • 4,5-dioxovalerate--formed from 5-aminolevulinate and alpha-ketoglutarate.
    Depletion of cellular thiol concentration may potentiate advanced glycation. a-Oxoaldehydes react rapidly but reversibly with cysteine and cysteine residues. The reaction of methylglyoxal and glyoxal with the cysteine residue in GSH forms the hemithioacetal adducts which are substrates of glyoxalase I en route to detoxification. The reversible binding of methylglyoxal, glyoxal and other aoxoaldehydes to cysteine residues in vivo has the effect of providing a depot site for a-oxoaldehyde storage during periods of a-oxoaldehyde excess, allowing glyoxalase I activity to catalyse their eventual detoxification and preventing the irreversible formation of AGE on lysine and arginine residues.​

    If you have followed the process of OXPHOS respiratory-chain complex 1, I tried to keep it brief,
    I believe it is "our job" to identify the pathways, if enhanced, which provide "appropriate therapies" for the client.

    So my question:
    What treatments would a quantum clinician use to enhance glutathione production in the liver?
    Last edited: Jul 17, 2022

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