Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0016719 (Friedreich's ataxia)
 2,098 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Friedreich ataxia (FA) is caused by decreased frataxin expression that results in mitochondrial iron (Fe) overload. However, the role of frataxin in mammalian Fe metabolism remains unclear. In this investigation we examined the function of frataxin in Fe metabolism by implementing a well-characterized model of erythroid differentiation, namely, Friend cells induced using dimethyl sulfoxide (DMSO). We have characterized the changes in frataxin expression compared to molecules that play key roles in Fe metabolism (the transferrin receptor [TfR] and the Fe transporter Nramp2) and hemoglobinization (beta-globin). DMSO induction of hemoglobinization results in a marked decrease in frataxin gene (Frda) expression and protein levels. To a lesser extent, Nramp2 messenger RNA (mRNA) levels were also decreased on erythroid differentiation, whereas TfR and beta-globin mRNA levels increased. Intracellular Fe depletion using desferrioxamine or pyridoxal isonicotinoyl hydrazone, which chelate cytoplasmic or cytoplasmic and mitochondrial Fe pools, respectively, have no effect on frataxin expression. Furthermore, cytoplasmic or mitochondrial Fe loading of induced Friend cells with ferric ammonium citrate, or the heme synthesis inhibitor, succinylacetone, respectively, also had no effect on frataxin expression. Although frataxin has been suggested by others to be a mitochondrial ferritin, the lack of effect of intracellular Fe levels on frataxin expression is not consistent with an Fe storage role. Significantly, protoporphyrin IX down-regulates frataxin protein levels, suggesting a regulatory role of frataxin in Fe or heme metabolism. Because decreased frataxin expression leads to mitochondrial Fe loading in FA, our data suggest that reduced frataxin expression during erythroid differentiation results in mitochondrial Fe sequestration for heme biosynthesis.
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PMID:Erythroid differentiation and protoporphyrin IX down-regulate frataxin expression in Friend cells: characterization of frataxin expression compared to molecules involved in iron metabolism and hemoglobinization. 1198 41

Hypertrophic cardiomyopathy is a common complication of Friedreich's ataxia (FRDA). Histological sections reveal abnormal cardiomyocytes, muscle fiber necrosis, reactive inflammation, and increased endomysial connective tissue. Scattered muscle fibers display perinuclear collections of minute iron-positive granules that lie in rows between myofibrils. Frataxin deficiency in FRDA causes mitochondrial iron dysmetabolism. We studied total iron and the iron-related proteins ferritin, mitochondrial ferritin, divalent metal transporter 1 (DMT1), and ferroportin in FRDA hearts by biochemical and histological techniques. Total iron in the left ventricular wall of FRDA patients (30.7+/-19.3 mg/100 g dry weight) was not significantly higher than normal (31.3+/-24.1 mg/100 g dry weight). Similarly, cytosolic holoferritin levels in FRDA hearts (230+/-172 microg/g wet weight) were not significantly elevated above normal (148+/-86 microg/g wet weight). The iron-positive granules exhibited immunoreactivity for cytosolic ferritin, mitochondrial ferritin, and ferroportin. Electron microscopy showed enhanced electron density of mitochondrial deposits after treatment with bismuth subnitrate supporting ferritin accumulation. The inflammatory cells in the endomysium were reactive for CD68, cytosolic ferritin, and the DMT1 isoform(s) translated from messenger ribonucleic acids containing iron-responsive elements (DMT1+). Progressive cardiomyopathy in FRDA is the likely result of iron-catalyzed mitochondrial damage followed by muscle fiber necrosis and a chronic reactive myocarditis.
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PMID:Iron and iron-responsive proteins in the cardiomyopathy of Friedreich's ataxia. 1713 88

Frataxin deficiency in Friedreich's ataxia (FRDA) causes cardiac, endocrine, and nervous system manifestations. Frataxin is a mitochondrial protein, and adequate amounts are essential for cellular iron homeostasis. The main histological lesion in the brain of FRDA patients is neuronal atrophy and a peculiar proliferation of synaptic terminals in the dentate nucleus termed grumose degeneration. This cerebellar nucleus may be especially susceptible to FRDA because it contains abundant iron. We examined total iron and selected iron-responsive proteins in the dentate nucleus of nine patients with FRDA and nine normal controls by biochemical and microscopic techniques. Total iron (1.53 +/- 0.53 mumol/g wet weight) and ferritin (206.9 +/- 46.6 mug/g wet weight) in FRDA did not significantly differ from normal controls (iron: 1.78 +/- 0.88 mumol/g; ferritin: 210.9 +/- 9.0 mug/g) but Western blots exhibited a shift to light ferritin subunits. Immunocytochemistry of the dentate nucleus revealed loss of juxtaneuronal ferritin-containing oligodendroglia and prominent ferritin immunoreactivity in microglia and astrocytes. Mitochondrial ferritin was not detectable by immunocytochemistry. Stains for the divalent metal transporter 1 confirmed neuronal loss while endothelial cells reacting with antibodies to transferrin receptor 1 protein showed crowding of blood vessels due to collapse of the normal neuropil. Regions of grumose degeneration were strongly reactive for ferroportin. Purkinje cell bodies, their dendrites and axons, were also ferroportin-positive, and it is likely that grumose degeneration is the morphological manifestation of mitochondrial iron dysmetabolism in the terminals of corticonuclear fibers. Neuronal loss in the dentate nucleus is the likely result of trans-synaptic degeneration.
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PMID:The dentate nucleus in Friedreich's ataxia: the role of iron-responsive proteins. 1744 34

A growing set of observations points to mitochondrial dysfunction, iron accumulation, oxidative damage and chronic inflammation as common pathognomonic signs of a number of neurodegenerative diseases that includes Alzheimer's disease, Huntington disease, amyotrophic lateral sclerosis, Friedrich's ataxia and Parkinson's disease. Particularly relevant for neurodegenerative processes is the relationship between mitochondria and iron. The mitochondrion upholds the synthesis of iron-sulfur clusters and heme, the most abundant iron-containing prosthetic groups in a large variety of proteins, so a fraction of incoming iron must go through this organelle before reaching its final destination. In turn, the mitochondrial respiratory chain is the source of reactive oxygen species (ROS) derived from leaks in the electron transport chain. The co-existence of both iron and ROS in the secluded space of the mitochondrion makes this organelle particularly prone to hydroxyl radical-mediated damage. In addition, a connection between the loss of iron homeostasis and inflammation is starting to emerge; thus, inflammatory cytokines like TNF-alpha and IL-6 induce the synthesis of the divalent metal transporter 1 and promote iron accumulation in neurons and microglia. Here, we review the recent literature on mitochondrial iron homeostasis and the role of inflammation on mitochondria dysfunction and iron accumulation on the neurodegenerative process that lead to cell death in Parkinson's disease. We also put forward the hypothesis that mitochondrial dysfunction, iron accumulation and inflammation are part of a synergistic self-feeding cycle that ends in apoptotic cell death, once the antioxidant cellular defense systems are finally overwhelmed.
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PMID:The interplay between iron accumulation, mitochondrial dysfunction, and inflammation during the execution step of neurodegenerative disorders. 2465