Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02794 (ferritin)
 17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The nitroxide, Tempol, can protect tissue from oxidative damage by removing superoxide and by oxidizing Fe(II) to Fe(III), thus decreasing formation of the hydroxyl radical. However, long-term exposure to Tempol can damage cells. The oxidation of Fe could have profound effects on Fe metabolism in cells, yet this has not been previously studied. In the present investigation, the effects of Tempol on the synthesis of the Fe storage protein, ferritin, and its ability to store Fe were studied in cultured lens epithelial cells (LEC). In addition, the effects of short- and long-term Tempol treatment on the resistance of LEC to oxidative stress were determined. Tempol had a clear dose-dependent inhibitory effect on ferritin synthesis noted at 6 h. By 20 h, ferritin synthesis returned toward normal levels. However, Fe incorporation into ferritin was decreased by almost 90% by the highest dose of Tempol, even at the 20-h time point. The decrease in Fe incorporation into ferritin was accompanied by a significant increase in the LMW pool of Fe. After short-term (4 h) treatment with Tempol, LEC were protected against the toxic effects of tertiary butyl hydroperoxide. However, after longer term treatment (20 h), Tempol itself had a toxic effect and did not afford protection. Indeed, at the higher doses, Tempol significantly reduced the ability of the cells to withstand oxidative stress. The redistribution of Fe within the cell after 20 h of Tempol treatment appears to render the cells more vulnerable to oxidative stress. The deleterious effects of Tempol on LEC are likely due to its effects on Fe metabolism, perhaps by reducing the availability of Fe for incorporation into ferritin and Fe-dependent enzymes as well as enlarging a low molecular weight pool of Fe which may be capable of catalyzing damaging free radical reactions.
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PMID:The effects of Tempol on ferritin synthesis and Fe metabolism in lens epithelial cells. 1083 58

In mammals, two homologous cytosolic regulatory proteins, iron regulatory protein 1 (also known as IRP1 and Aco1) and iron regulatory protein 2 (also known as IRP2 and Ireb2), sense cytosolic iron levels and posttranscriptionally regulate iron metabolism genes, including transferrin receptor 1 (TfR1) and ferritin H and L subunits, by binding to iron-responsive elements (IREs) within target transcripts. Mice that lack IRP2 develop microcytic anemia and neurodegeneration associated with functional cellular iron depletion caused by low TfR1 and high ferritin expression. IRP1 knockout (IRP1(-/-)) animals do not significantly misregulate iron metabolism, partly because IRP1 is an iron-sulfur protein that functions mainly as a cytosolic aconitase in mammalian tissues and IRP2 activity increases to compensate for loss of the IRE binding form of IRP1. The neurodegenerative disease of IRP2(-/-) animals progresses slowly as the animals age. In this study, we fed IRP2(-/-) mice a diet supplemented with a stable nitroxide, Tempol, and showed that the progression of neuromuscular impairment was markedly attenuated. In cell lines derived from IRP2(-/-) animals, and in the cerebellum, brainstem, and forebrain of animals maintained on the Tempol diet, IRP1 was converted from a cytosolic aconitase to an IRE binding protein that stabilized the TfR1 transcript and repressed ferritin synthesis. We suggest that Tempol protected IRP2(-/-) mice by disassembling the cytosolic iron-sulfur cluster of IRP1 and activating IRE binding activity, which stabilized the TfR1 transcript, repressed ferritin synthesis, and partially restored normal cellular iron homeostasis in the brain.
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PMID:Tempol-mediated activation of latent iron regulatory protein activity prevents symptoms of neurodegenerative disease in IRP2 knockout mice. 1868 2

Genetic ablation of Iron Regulatory Protein 2 (Irp2, Ireb2), which post-transcriptionally regulates iron metabolism genes, causes a gait disorder in mice that progresses to hind-limb paralysis. Here we have demonstrated that misregulation of iron metabolism from loss of Irp2 causes lower motor neuronal degeneration with significant spinal cord axonopathy. Mitochondria in the lumbar spinal cord showed significantly decreased Complex I and II activities, and abnormal morphology. Lower motor neurons appeared to be the most adversely affected neurons, and we show that functional iron starvation due to misregulation of iron import and storage proteins, including transferrin receptor 1 and ferritin, may have a causal role in disease. We demonstrated that two therapeutic approaches were beneficial for motor neuron survival. First, we activated a homologous protein, IRP1, by oral Tempol treatment and found that axons were partially spared from degeneration. Secondly, we genetically decreased expression of the iron storage protein, ferritin, to diminish functional iron starvation. These data suggest that functional iron deficiency may constitute a previously unrecognized molecular basis for degeneration of motor neurons in mice.
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PMID:Iron insufficiency compromises motor neurons and their mitochondrial function in Irp2-null mice. 2200 90