Difficulties in iron-sulfur cluster formation can lead to iron accumulation in mitochondria

In Friedreich ataxia iron-sulfur clusters are not formed, due to deficiencies in frataxin which results in iron accumulation in mitochondria. The relevant point is that problems in iron-sulfur cluster formation can be associated with iron accumulation in mitochondria and iron toxicity. The point I have been making is that there are difficulties in synthesizing iron-sulfur clusters in many neurological illnesses due to dysregulation of the transsulfuration pathway which synthesizes L-cysteine. L-cysteine supplies sulfur for iron-sulfur cluster formation.

Iron chelators are now being investigated as treatments for Alzheimer’s disease and Parkinson’s disease. If iron is being accumulated in cells in Alzheimer’s disease and Parkinson’s disease due to difficulties in iron-sulfur cluster formation then iron chelators would not be appropriate treatments. Iron-sulfur cluster formation is increased by supplemental iron. Iron chelators by decreasing iron would decrease iron–sulfur cluster formation leading to iron accumulation in mitochondria and iron toxicity.

Inflammation, alpha-linoleic acid and taurine in schizophrenia, Parkinson’s disease and Alzheimer’s disease

Inflammation is associated with schizophrenia, Parkinson’s disease and Alzheimer’s disease. A point I have strongly stressed is that the transsulfuration pathway is dysregulated in many neurological illnesses. With the transsulfuration pathway dysregulated there will de decreased levels of L-cysteine which is synthesized via the transsulfuration pathway. Decreased levels of l-cysteine will lead to decreased levels of taurine. Taurine is synthesized from L-cysteine. The bile acid, taurocholate, is synthesized from taurine. With low levels of taurocholate fatty acids will not be absorbed sufficiently. Alpha–linoleic acid is an essential fatty acid that must be obtained from diets. Diets high in alpha-linoleic acid are protective against inflammation. With low levels of taurocholate sufficient alpha-linoleic acid will not be absorbed which will lead to inflammation. . Inflammation in schizophrenia, Parkinson’s disease and Alsheimer’s disease could be due to low levels of taurine which leads to failures to absorb sufficient alpha-linoleic acid which is protective against inflammation.

A new disease class – Epigenetic Disorders

There are infectious diseases subdivided into bacterial and viral diseases, there is cancer where there are many sorts of cancer, there is heart disease, lung disorders  etc. There could be a new disease class. There could  be epigenetic disorders where there is common origin for a wide range of epigenetic disorders. With epigenetic mechanisms  dysregulated many different diseases can arise as there are many different ways genes and histones can become inappropriately methylated.  My idea is that a dysregulation of aconitase 1 can dysregulate iron metabolism and decrease 2-oxogularate synthesis which will in turn dysregulate TET enzymes, which demethylate DNA,  and dysregulate Jumonji domain-containing proteins, which demethylate histones.   Dysregulation of  TET enzymes and dysregulation of Jumonji domain-containing proteins  can play out many different ways in terms of inappropriate DNA methylation and inappropriate histone methylation whereby many different diseases can arise. Though many different diseases can arise from dysregulations of aconitase 1, iron metabolism and 2-oxoglutarate synthesis prevention of a range of illnesses could be achieved by the same treatment. For example, a treatment than prevents schizophrenia could also prevent Alzheimer’s disease and Parkinson’s disease. The Treatment presented in the Treatment section is not ready for home use, however, a Moon shot would not be necessary to get the treatment to a state where family doctors could prescribe a treatment which would prevent a range of chronic illnesses from schizophrenia, to Alzheimer’s disease, to Parkinson’s disease. What is needed is a launch ten weather balloons into the high atmosphere then collect and analyze data kind of effort.

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 acid  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 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 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.