Regulation of iron metabolism by the transsulfuration pathway

top – ACO1; bottom – iron regulatory protein 1 bound to an mRNA

Iron metabolism is regulated by hepicidin, ferroportin and iron regulatory proteins. Aconitase 1 (ACO1) is a dual function protein that serves as an aconitase, which is an enzyme in the TCA cycle, when ACO1 has a 4Fe-4S iron sulfur cluster and as iron regulatory protein 1 when ACO1 looses a 4Fe-4S cluster. The sulfur for iron-sulfur clusters is derived from L-cysteine.

L-cysteine is synthesized from homocyteine via the transsulfuration pathway. Dysregulation of the transsufuration pathway by dysregulating L-cysteine synthesis could dysregulate iron-sulfur cluster formation thereby dyseregulating iron regulatory protein 1 and iron homestasis.

High homocysteine levels are present in a lot of illnesses, for example, schizophrenia, Parkinson’s disease, Alzheimer’s disease and bipolar disorder. A key part of the difficulties that arise from high homocysteine levels could be due to dysregulation of iron homeostasis.

Iron, aconitase 1, glutamate and schizophrenia

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Diminished glutamatergic neurotransmission is present in schizophrenia. N-methyl-D-aspartate receptor antagonists such as ketamine, can induce symptoms of acute schizophreniaIron.

Iron increases glutamate secretion by increasing cytosolic aconitase activity. The synthesis of isocitrate by cytosolic aconitase is the the first step in a three step synthesis of glutamate. Glutamate, arising from increases in cytosolic aconitase due to increases in iron, is secreted via the cystine/glutamate antiporter where at the same time cystine is imported into cells increasing glutathione levels in cells.

With iron supplementation in schizophrenia via iron carbonyl taken three times a day there could be increased glutamatergic neurotransmission via increases is secreted glutamate where at the same time there would be increases in cystine in cells and thereby increases in glutathione levels in cells. Supplementation with iron from iron carbonyl could be part the treatment of schizophrenia.

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

Abstract

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.

Mutations of genes for enzymes in the TCA cycle can inhibit TET enzymes

TET enzymes, which demethylate DNA, are 2-oxoglutarate dependent enzymes. 2-oxoglutarate is synthesized by the citric acid cycle. Mutation of genes for enzymes in the citric acid cycle can inhibit TET enzymes, thereby dysregulating epigenetic mechanisms.

Iron regulates enzymes is the TCA cycle. Dysregulation of iron metabolism could dysregulate the TCA cycle resulting in epigenetic dysregulations.

Measures to improve TCA cycle metabolism could benefit AD patients

Ann Neurol. 2005 May;57(5):695-703.
Bubber P, Haroutunian V, Fisch G, Blass JP, Gibson GE.

Abstract

Reductions in cerebral metabolism sufficient to impair cognition in normal individuals also occur in Alzheimer’s disease (AD). The degree of clinical disability in AD correlates closely to the magnitude of the reduction in brain metabolism. Therefore, we tested whether impairments in tricarboxylic acid (TCA) cycle enzymes of mitochondria correlate with disability. Brains were from patients with autopsy-confirmed AD and clinical dementia ratings (CDRs) before death. Significant (p < 0.01) decreases occurred in the activities of the pyruvate dehydrogenase complex (-41%), isocitrate dehydrogenase (-27%), and the alpha-ketoglutarate dehydrogenase complex (-57%). Activities of succinate dehydrogenase (complex II) (+44%) and malate dehydrogenase (+54%) were increased (p < 0.01). Activities of the other four TCA cycle enzymes were unchanged. All of the changes in TCA cycle activities correlated with the clinical state (p < 0.01), suggesting a coordinated mitochondrial alteration. The highest correlation was with pyruvate dehydrogenase complex (r = 0.77, r2= 0.59). Measures to improve TCA cycle metabolism might benefit AD patients.

Bill Gates is looking for new ideas on the etiology of Alzheimer’s disease. A heightened focus on the TCA citric acid cycle in Alzheimer’s disease is a new approach to the etiology of Alzheimer’s disease for which there is experimental backing.

Given there was a helpful answer on the biological basis of schizophrenia what kind of answer would that answer have to be?

Given there was a helpful answer to what was the biological cause of schizophrenia what kind of answer would that answer have to be?

Holding that 1000’s of common alleles each of which have an only miniscule impact lead to schizophrenia is a kind of answer that has absolutely no treatment implications.  Focusing on an allele of this or that gene in isolation has absolutely no treatment implications. Epigenetic changes that affect a gene in isolation from other genes have no treatment implications. Focusing on this or that biological anomaly has absolutely no treatment implications. There are hundreds of biologically anomalies in schizophrenia apparently all disconnected from each other.

A helpful answer must point to the headwaters of genetic or epigenetic dysregulations. A transcription factor could affect translation of many genes and at times various researchers have pointed to various transcription factors as being implicated in schizophrenia. Funding research on transcription factors in connection to schizophrenia makes sense in terms of translational medicine.

Another answer that would be helpful in terms of treatment is an answer that pointed to a biological pathway  that could widely dysregulate epigenetic mechanisms. Dysregulation of the TCA cycle via dysregulation of aconitase 1 and the 2-oxogultarate dehydrogenase complex could  widely  dysregulate epigenetic mechanisms.

Aconitase 1 and on-off disorders

Aconitase 1 (ACO1) is an enzyme in the citric acid cycle. Aconitase 1 is a dual function protein. Upon loss of an iron-sulfur cluster ACO1  becomes iron regulatory protein 1 (IRP1).  IRP1 affects stability of mRNA transcripts of proteins involved in iron metabolism such as ferritin, DMT1, which is an iron transporter, and ferroportin, which is the only known iron exporter.   Increasing iron levels switches IRP1 to ACO1 as IRP1 gains an iron-sulfur cluster. With a 4Fe-4S iron-sulfur cluster ACO1 can participate in the citric acid cycle and generate ATP.

On-off disorders could be are due to wide swings in ACO1/IRP1 and the TCA cycle. Suddenly the TCA cycle is functioning and then the TCA cycle is not functioning while at the same time there are swings in the regulation of iron regulated proteins. Dietary iron could be associated with swings in on-off symptoms.An added wrinkle is  that high IRP1 levels adversely affects copper absorption, however, copper is needed for iron metabolism.

I very much like answers that answer everything. On-off symptoms are prominent in lots and lots of illnesses. There is, of course, bipolar disorder but a lot of depressions cycle rapidly and are some of the most difficult depressions to treat.  Parkinson’s disease has a very prominent on-off symptoms.  In Parkinson’s disease there are  indications that iron metabolism is  dysregulated. There could be a unitary explanation for cycling disorders.