Iron

links: Vitamins & Minerals reference: http://raypeat.com/articles/articles/iron-dangers.shtml 4-12-2021

Iron #

The RDI is a little too high according to Peat and the Root Cause guys.

• Interferes with Vitamin E uptake/absorption. Competes with Copper for absorption.
• http://raypeat.com/articles/articles/cholesterol-longevity.shtml
  • ““Especially when the lining of the blood vessel is too permeable, because of the influence of PUFA, Prostaglandins, Estrogen, etc., the heme and iron will enter the endothelial cells, where the iron will catalyze the formation of Free radicals, and the heme will be broken down by the enzyme heme oxygenase, into biliverdin, iron, and carbon monoxide, which can contribute to the oxidative stress of the cells. Carbon monoxide makes the blood vessel lining more permeable, allowing fats and fibrinogen to enter the cells (Allen, et al., 1988).
  • ““The hemolysis which is promoted by polyunsaturated fats and an imbalance of antioxidants and oxidants, releases iron and heme into the blood stream. The incidence of atherosclerosis is increased when the body iron stores are high (Kiechl, et al., 1997), probably because of its role in lipid peroxidation and lipofuscin formation.

Brain #

• The impact of brain iron accumulation on cognition: A systematic review
• Excess dietary iron is the root cause for increase in childhood autism and allergies
• Medication-naïve youth with ADHD have reduced brain iron compared to controls and psychostimulant-medicated patients, no differences were detected between the latter groups. R
• Mitochondria and Iron: Current Questions
  • Synthesze iron-sulfur clusters, which are exported via ABCB7, or something.
    • Fe-S cluster-containing proteins include ETC proteins, NADH:ubiquinone oxidoreductase, subunits of Succinate Dehydrogenase, Aconitase, Biotin synthase, Lipoic Acid synthase, et al
    • The iron atoms can exist in ferrous or ferric state, thus the whole complex participates in redox. They bond ionically to the apoproteins via iron and AA residues, mainly Cysteine. The paper goes into plenty of detail of the synthesis complex.
    • Any defects of the enymes in the Fe-S assembly pathway in yeast (“the best-studied eukaryotic model of Fe-S cluster synthesis”) results in mitochondrial iron accumulation: The essential role of mitochondria in the biogenesis of cellular iron-sulfur proteins
  • Synthesizes heme…
    • Heme-containing proteins: Cytochrome C, Cytochrome C Oxidase, Succinate Dehydrogenase, et al
    • Sideroblastic anemia (fucked up bone marrow erythrocyte synthesis stuff) results in disrupted heme synthesis and iron accumulation and increased MtFt (especially in erythroblasts? (mammalian nucleated erythrocyte)).
  • Or stores iron as mitochondrial ferritin, with the precursor peptide originally synthesized obviously outside: in cytoplasmic ribosomes. It contains a mitochondrial targeting sequence that is cleaved after arrival.
    • Lacks regulation IRP-IRE, unlike typical Ferritin. It is not expressed in Hepatocytes or splenoctes.
    • Most cells including erthyrocytes express extremely low levels of MtFt.
      • Overexpression of mitochondrial ferritin causes cytosolic iron depletion and changes cellular iron homeostasis
        • Naturally, overexpression depletes cytosolic iron, and increases the cellular iron uptake via Transferrin.
        • ROS generation is a natural result of Electron Transport Chain.
  • Entry:
    • Mitochondrial outer membrane is permeable to ions, but to enter the inner membrane, free Fe2+ in the LIP it is transported through Mfrn1/2.
    • Via metallochaperones/siderophones like frataxin
• Lysosomal iron modulates NMDA receptor-mediated excitation via small GTPase, Dexras1

Neurodegeneration #

• Mitochondrial Iron Metabolism and Its Role in Neurodegeneration
• Aberrant Cerebral Iron Trafficking Co-morbid With Chronic Inflammation: Molecular Mechanisms and Pharmacologic Intervention
  • Inflammation alters the trans- and para-cellular flux of iron at the BBB, resulting in a net accumulation of abluminal (the superficial layer, I guess) iron over time.
  • Healthy brains accumulate iron specifically within: Globus Pallidus, Caudate, Putamen, and Substantia Nigra. So all basal ganglionic structures. As well as the dentate nucleus, which is cerebella, but maybe it’s possible they meant gyrus.
  • Neuromelanin complexes with metals like iron. It is found in autolysosomes mostly in neurons of the Substantia Nigra and Locus Coeruleus.
• Iron Exposure and the Cellular Mechanisms Linked to Neuron Degeneration in Adult Mice
  • Exposure to high dietary iron (HDI) revealed no significant difference in the number of iron-positive cells and iron content in the cortex and hippocampal region between wild-type (WT) and APP/PS1 mice; however, compared with the control mice, the HDI-treated mice exhibited upregulated DMT1 and Ferroportin expression, and downregulated TfR1 receptor expression.
  • APP knockout mice reveal markedly increased hippocampal and cortical neuronal iron and oxidation
• Age-related iron accumulation and demyelination in the basal ganglia are closely related to verbal memory and executive functioning (Inversely, of course.)
• Iron accumulates in Huntington’s disease neurons: protection by deferoxamine
• Iron as the concert master in the pathogenic orchestra playing in sporadic Parkinson’s disease

Transport #

• Enterocytes take heme up via heme carrier protein 1 (HP1) and it is broken down by Heme Oxygenase. Many cells/organelles take free ferrous iron (and other 2+ metals) via DMT1.

• Free Fe2+ presumably binds to chaperones like PCBP-2 in the cytosol, whereby it may be used, or exported by Ferroportin or, or delivered to Ferritin.

  • Meanwhile, Hepcidin is a naughty boy inhibiting it and is inducd by stress.
  • Ferroportin also exports LIP back to the circulation.

• Ferroxidases like Hephaestin, colocalized with ferroportin, and Ceruloplasmin in the plasma, convert ferrous iron to ferric after leaving.

  • Steap4 is one such ferric reductase that reduces Fe3+ to Fe2.

• Ferritin enters lysosomes.

• Frataxin, a chaperone, carries iron to the mitochondria… and some other things

• Endosomes take up iron for some reason. Exported by DMT1/transferrin.