Iron positively regulates other enzymes in the citric acid cycle besides aconitase

Besides aconitase iron positively affects three other citric acid cycle enzymes, the enzymes being citrate synthase, isocitric dehydrogenase synthase and and succinate dehydrogenase.

Iron-dependent changes in cellular energy metabolism: influence on citric acid cycle and oxidative phosphorylation

Horst Oexle, Erich Gnaiger and Gunter Weiss Biochimica et Biophysica Acta (BBA) – Bioenergetics


Iron modulates the expression of the critical citric acid cycle enzyme aconitase via a translational mechanism involving iron regulatory proteins. Thus, the present study was undertaken to investigate the consequences of iron perturbation on citric acid cycle activity, oxidative phosphorylation and mitochondrial respiration in the human cell line K-562. In agreement with previous data iron increases the activity of mitochondrial aconitase while it is reduced upon addition of the iron chelator desferrioxamine (DFO). Interestingly, iron also positively affects three other citric acid cycle enzymes, namely citrate synthase, isocitric dehydrogenase, and succinate dehydrogenase, while DFO decreases the activity of these enzymes. Consequently, iron supplementation results in increased formation of reducing equivalents (NADH) by the citric acid cycle, and thus in increased mitochondrial oxygen consumption and ATP formation via oxidative phosphorylation as shown herein. This in turn leads to downregulation of glucose utilization. In contrast, all these metabolic pathways are reduced upon iron depletion, and thus glycolysis and lactate formation are significantly increased in order to compensate for the decrease in ATP production via oxidative phosphorylation in the presence of DFO. Our results point to a complex interaction between iron homeostasis, oxygen supply and cellular energy metabolism in human cells.

A proposed experiment

Tea very significantly decreases iron absorption as tannins in tea form insoluble complexes with iron. Iron in iron/tannin-complexes would also not be bioavailable in the gut. Still individuals who drink tea can have normal iron levels. The question is whether blood measures of iron status are a complete picture of iron status. In the proposed experiment rats would be given tea by gavage. Levels of tea given by gavage would not be levels that would cause anemia. What would be tested is the status of aconitase 1 in the gut and the effect of the tea on the citric acid cycle in the gut. Aconitase 1 is regulated by iron levels where with high levels of iron aconitase 1 acts as an aconitase but with low levels of iron aconitase 1 switches to IRP1 which regulates iron regulated proteins. Levels in the gut of citrate synthase, isocitric dehydrogenase and succinate dehydrogenase would would also be tested as iron positively affects these enzymes also. Blood levels of iron would also be tested. The hypothesis is that the effect of tea on the gut in terms of aconitase 1 and other enzymes in the citric acid cycle will be more pronounced than blood levels of iron would indicate.

Coffee and revolution

There was not an abundance of clear thinking during the French Revolution though there was lots and lots of agitation. Could coffee houses have played a role? ‘The Paris Cafe de Foy hosted the call to arms for the storming of the Bastille. During the Enlightenment, the Café Procope had been the place where men like Rousseau, Diderot and Voltaire gathered to hone their philosophies and art.’ The quote is from an article on on coffee and revolution.

Lithium blocks transport by the sodium-dependent multivitamin transporter

Lithium blocks the sodium-dependent multivitamin transporter. See Figure 2 E. The sodium-dependent multivitamin transporter (SMVT) transports pantothenate, biotin and lipoate. I have previously argued that pantothenate is involved in mania and negative symptoms. Lithium by blocking the SMVT would decrease transport of pantothenate and decrease mania. If this idea is correct treating bipolar disorder with lithium, which blocks other sodium-dependent transporters and has myriad other effects, would be equivalent to using a kilogram of plastique to kill a fly. Biotin via biotinylation decreases transcription of the the gene for the SMVT. Other supplements besides biotin are in all probability required to treat bipolar disorders. Biotin could be effective for the manic phase of bipolar disorder but would do zip and could even worsen the down phase of bipolar disorder.

The Major Histocompatibility Complex, HFE and schizophrenia

The Major Histocompatibility Complex (MHC) has been associated with schizophrenia. The hemochromatosis gene, HFE, which regulates iron levels is linked to the MHC on chromosome 6. In cells that express HFE IRP1 and IRP2 binding increases as the labile iron pool decreases with increased HFE expression. IRP1 and IRP2 are regulated by iron levels. Genetic studies that have associated the MHC region with schizophrenia frequently conclude that this is evidence for an infectious etiology to schizophrenia as the MHC is involved in immunity. What genetic associations of the MHC to schizophrenia could be picking up is associations of HFE with schizophrenia where such associations arise due to dysregulations in iron metabolism.

E-cigarettes and natural flavors

There is lots of controversy about flavorings for e-cigarettes. Here are some of the plant extract flavorings for e-cigarettes. Lung damage has been associated with vaping with e-cigarettes with flavorings found to be particularly harmful. Polyphenols bind iron. Polyphenols binding iron, which is needed for hemoglobin, in the lungs could adversely affect the ability to breathe. Mint flavorings are getting a pass in the FDA regulations on e-cigarette flavorings, however, mint has very high polyphenol contents.

Is Red Bull a safer alternative to sodas?

Red Bull contains taurine. In some formulations there are 800 mg. of taurine and in other formulations there are 400 milligrams of taurine. Taurine increases hydrogen sulfide levels. High levels of hydrogen sulfide are highly toxic. 1000 milligrams of taurine in supplement form taken three times a day is enough to increase brain fogginess noticeably. Red Bull is exactly the sort of drink that should never be drunk before the kinds of activities very frequently shown in Red Bull advertisements. 3000 milligrams of taurine a day will also lower blood pressure. Given there is a need to reduce blood pressure that should only be undertaken in a regulated way which would not be achieved by chugging Red Bulls. Glucuronolactone, which is a component of Red Bull, is hydrolyzed in the body to glucuronic acid. Increased glucuronic acid activity can result in a decrease of the concentration and metabolic half-life of glucuronic acid substrates, such as prescribed drugs, causing the plasma levels of glucuronidated drugs to fall below their therapeutic threshold. This Wikipedia page has list of some drugs affected by glucuronidation. The safety of glucuronic acid was tested on rats who were not on prescribed drugs. Red Bull also contains sucrose and glucose. In ruling on the safety of Red Bull the European Food and Safety Authority stated, “In the absence of new chronic and acute exposure data, the exposures used in this opinion are based on the data reported by the SCF in 2003, i.e. a daily mean chronic consumption of 0.5 cans per person and a high chronic exposure at the 95th percentile of 1.4 cans per regular consumer.” Red Bull is not a safer soft drink although a half a can a day of Red Bull drunk upon the conclusion of a sports activity could be safe. Formulation of soft drinks is one of the dark arts.

Inhibition of non-heme iron absorption in humans by drinks containing phenols

Phenol containing drinks are potent inhibitors of Fe absorption and reduce absorption of iron in a dose-dependent fashion depending on polyphenols contents of drinks.

The difficulty with phenol containing beverages is more severe than only decreased iron absorption as iron in the gut also regulates the citric acid cycle in the gut. Phenol compounds form complexes with iron whereby aconitase 1, which is regulated by iron, in the gut can become dysregulated when drinks with phenol compounds are drunk.

Histone acetylation and schizophrenia

Histone acetylation, which adds acetyl groups to lysine residues of histones, relaxes chromatin, which is composed of histones.  Histone acetylation increases transcription of genes. Acetyl groups are transferred to histones from acetyl-coenzyme A. Appropriate synthesis of coenzyme A and acetyl-coenzyme A are required for appropriate histone acetylation. With the pyruvate dehydrogenase complex, which synthesizes acetyl-coenzyme A,  dysregulated in schizophrenia there will not be appropriate histone acetylation in schizophrenia.   With histone acetylation dysregulated in schizophrenia epigenetic mechanisms are dysregulated in yet another way in schizophrenia.

Increasing histone acetylation by re-regulating the pyruvate dehydrogenase complex could have the same effect as  histone deacetylase inhibitors which improve learning. Improving abilities to learn in individuals with schizophrenia would clearly be going in the right direction.

Increasing histone acetylation could also improve learning in Alzheimer’s disease.  In Alzheimer’s disease synthesis of L-cysteine is decreased as evidenced by high homocysteine levels. See my paper A disease-modifying treatment for Alzheimer’s disease: focus on the trans-sulfuration pathway, which was published in Reviews in the Neurosciences.   With  synthesis of L-cysteine decreased synthesis of coenzyme A and acetyl-coenzyme A are decreased in Alzheimer’s disease which would lead to decreases in histone acetylation and difficulties in learning.

Nootropic effects of sulbutiamine could be do the ability of sulbutiamine to increase synthesis of acetyl-coenzyme A and thereby increase histone acetylaltion. Sublingual cocarboxylase seems to work better than sulbutiamine.

Wonderfully the treatment, presented on the Treatment page,  which would be effective for schizophrenia could also prevent and treat Alzheimer’s disease. Schizophrenia differs from Alzheimer’s disease as there are different epigenetic dysregulations, however, the headwaters of the schizophrenia and Alzheimer’s disease are the same which allows for identical treatments.

Physicists have a notion of symmetry breaking where at higher energy levels different particles are identical but upon symmetry breakings particles diverge from each other and become different particles.

Different epigenetic dysregulations are different symmetry breakings but at the headwaters of both illnesses schizophrenia and Alzheimer’s disease are identical.