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.

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.

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.

I think on-off disorders are due to wide swings in ACO1/IRP1. Suddenly the citric acidĀ  cycle is functioning and then the citric acid 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 isĀ  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 may be a unitary explanation for cycling disorders.

Iron chelators

Iron chelators are being clinically tested in a number of neurodegenerative illnesses such as Alzheimer’s and Parkinson’s disease . I do not think iron chelation is going to work. In fact I think iron chelators will make Alzheimer’s and Parkinson’s worse. I very much hope I am mistaken. The difficulty isn’t iron per se but rather dysregulation of iron regulated biological processes. A sensible choice now is to stay away from iron supplements except for anemia.  My ideas are very sensible but sensible ideas are wrong all the time. Iron chelation is a very sensible approach to treatment of Alzheimer’s and Parkinson’s which I think is going to be disastrous.