Domingo J. Piñero

Iron in the Brain: An Important Contributor in Normal and Diseased States

Iron is essential for normal neurological function because of its role in oxidative metabolism and because it is a cofactor in the synthesis of neurotransmitters and myelin. In the past several years, there has been increased attention to the importance of oxidative stress in the central nervous system. Iron is the most important inducer of reactive oxygen species, therefore, the relation of iron to neurodegenerative processes is more appreciated today than it was a few years ago. Nevertheless, despite this increased attention and awareness, our knowledge of iron metabolism in the brain at the cellular and molecular levels is still limited. Iron is distributed in a heterogeneous fashion among the different regions and cells of the brain. This regional and cellular heterogeneity is preserved across many species. Brain iron concentrations are not static; they increase with age and in many diseases and decrease when iron is deficient in the diet. In infants and children, insufficient iron in the diet is associated with decreased brain iron and with changes in behavior and cognitive functioning. Abnormal iron accumulation in the diseased brain areas and, in some cases, alterations in iron-related proteins have been reported in many neurodegenerative diseases, including Hallervorden-Spatz syndrome, Alzheimer’s disease, Parkinson’s disease, and Friedreich’s ataxia. There is strong evidence for iron-mediated oxidative damage as a primary contributor to cell death in these disorders. Demyelinating diseases, such as multiple sclerosis, especially warrant study in relation to iron availability. Myelin synthesis and maintenance have a high iron requirement, thus, oligodendrocytes must have a relatively high and constant supply of iron. However, the high oxygen utilization, high density of lipids, and high iron content of white matter all combine to increase the risk of oxidative damage. We review here the current knowledge of the normal metabolism of iron in the brain and the suspected role of iron in neuropathology.

Interleukin-1β increases binding of the iron regulatory protein and the synthesis of ferritin by increasing the labile iron pool

This study was undertaken to begin to elucidate the mechanisms by which cytokines influence intracellular iron homeostasis. Intracellular iron homeostasis is maintained by the coordinated regulation of ferritin and transferrin receptor synthesis. The synthesis of these proteins is coordinated by cytoplasmic iron regulatory proteins (IRP), which bind to iron responsive elements (IRE) on their mRNAs. We evaluated the effects of interleukin-1beta (IL-1beta) on iron metabolism in human astrocytoma cells (SW1088). Exposure to IL-1beta for 16 h increased binding of the IRPs to the IRE and also increased ferritin synthesis. Using the iron sensitive dye calcein, we determined that the intracellular labile iron pool increased within 4 h of IL-1beta exposure and continued to increase for 8 h, returning to normal by 16 h. We propose that the cytokine induced increase in the labile iron pool stimulates ferritin synthesis resulting in a subsequent decrease in the labile iron pool. The decrease in the labile iron pool is consistent with the increase in IRE/IRP interaction measured at 16 h. These results indicate that cytokines can influence the labile iron pool and the post-transcriptional regulatory mechanism for maintaining iron homeostasis. These results contribute to understanding the response of ferritin to inflammation by suggesting ferritin synthesis may reflect changes in the labile iron pool. The approach used in this study may provide a model system for studying relations between the labile iron pool and proteins responsible for maintaining intracellular homeostasis

Subcellular localization of iron regulatory proteins to Golgi and ER membranes.

Interaction between iron regulatory proteins and iron responsive elements on certain mRNAs is at the core of regulation of intracellular iron homeostasis. Previous results suggested that in cultured cells iron regulatory proteins (IRPs) exist in cytosolic and microsomal subcellular locations and that this distribution is affected by cellular iron status. In this study, we tested the hypothesis that the membrane-associated fractions of iron regulatory proteins are specifically in the endoplasmic reticulum and Golgi membranes. Confocal microscopy revealed that IRP1 could be co-localized to the endoplasmic reticulum and the Golgi apparatus. To examine the intracellular distribution of IRPs biochemically, we used rats fed normal or iron-deficient diets. As expected, the IRPs were found predominantly in the cytosolic fraction. However, subfractionation of crude microsomal preparations revealed IRP1 in the Golgi apparatus. In animals fed an iron-deficient diet, IRP1 was found in the Golgi apparatus and the endoplasmic reticulum. To identify the mechanisms and factors involved in the localization of iron regulatory proteins in the cytosol and membrane fractions, cells were treated with a phorbol ester, a protein kinase C inhibitor (chelerythrine), hydrogen peroxide, interleukin-1β, and 1,2-bis-(o-aminophenoxy)-ethane-N,N,-N′N′-tetraacetic acid tetraacetoxy-methyl ester. The results indicate that iron-regulatory-protein-binding activity in the membrane fraction can be altered by cell stress or iron status and that phosphorylation plays a role in the translocation. As a result of this study we propose a novel model for intracellular distribution of IRPs and identify differences between the two iron regulatory proteins.

An Assessment of Nutrition Education in Selected Counties in New York State Elementary Schools (Kindergarten through Fifth Grade).

OBJECTIVE To assess the extent to which nutrition education is implemented in selected counties in New York State elementary schools (kindergarten through fifth grade) and explore how nutrition knowledge is presented in the classroom and what factors support it. DESIGN Cross-sectional, self-administered survey. SETTING New York State elementary schools in selected counties. PARTICIPANTS New York State elementary school teachers (n = 137). MAIN OUTCOME MEASURES Hours spent teaching nutrition; nutrition topics, methods of teaching, education resources, and aspects of the school environment that may influence nutrition education. ANALYSIS Crosstabs with a chi-square statistic and ANOVA. RESULTS Eighty-three percent of teachers taught some nutrition (9.0 ± 10.5 hours) during the academic year. Teachers taught lessons about finding and choosing healthy food (61%), relationship between diet and health (54%), and MyPyramid (52%) most often. Suburban teachers (12.4 ± 12.5 hours) taught significantly (P = .006) more hours of nutrition than rural teachers (4.2 ± 3.9 hours). Teachers at schools with fewer than 80% nonwhite students taught significantly (P = .02) more (10.4 ± 11.4 hours) compared to schools with greater than 80% nonwhite students (5.6 ± 6.4 hours). CONCLUSIONS AND IMPLICATIONS Teachers reported that nutrition education is important and that they are willing to teach nutrition. Efforts should be made that support integrated nutrition topics, methods of instruction, and availability of resources.