Iron metabolism in the Drosophila mutants fumble and malvolio
Date
2007-07-31
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Type
Degree Level
Masters
Abstract
The Drosophila mutant fumble has a defect in mitochondrially targeted pantothenate kinase (PANK) and exhibits a movement disorder in the females. The human disease pantothenate kinase associated neurodegeneration (PKAN) has the same genetic defect and a neurodegenerative phenotype as well as iron accumulation in the brain. We have found that fumble females accumulate almost 2 fold more iron in the heads than wildtype. Dietary iron supplementation increases the iron accumulation in the heads further. The small isoform of malvolio (MVL), a homologue of mammalian NRAMP iron transporters, is expressed in the heads of flies. Its expression is upregulated in the fumble females, as well as in dietary iron supplemented wildtype flies. Unlike in the wildtype, dietary iron supplementation leads to a downregulation of MVL in the fumble flies. Although iron levels were elevated in fumble, ferritin expression was relatively unchanged and remained unchanged in the heads of fumble and wildtype with dietary iron supplementation. The Drosophila mutant malvolio was used to determine how iron metabolism is affected when the MVL gene is defective. Iron levels were unchanged in malvolio relative to its parental strain (w1118) with or without dietary iron supplementation. Despite similar iron levels, a small decrease in ferritin expression was found in malvolio relative to w1118, and dietary iron increased ferritin expression in malvolio. However ferritin expression decreased in the parental strain of malvolio after iron supplementation. Most of the iron in the Drosophila heads was in the form of goethite and ferrihydrite. The presence of iron oxides implies that this iron is in a mineralized storage form, likely ferritin. Dietary iron supplementation induced the appearance of ferric phosphates in fumble, malvolio, and wildtype. The subcellular location of this iron is unknown. It may be non-transferrin bound iron in the hemolymph, or a cytosolic intermediate in the labile iron pool. Also of note was the presence of transferrin-bound iron in wildtype heads on normal diet that was not seen after iron supplementation or in the heads of the fumble mutant. The presence in fumble of the kind of ferrihydrite characteristic of the mitochondrial protein frataxin may indicate that iron is accumulating in mitochondria.The upregulation of MVL in the fumble mutant is of significant interest because it is the first protein involved in iron metabolism found to be altered with mitochondrial PANK deficiency. A disruption in MVL could be relevant to the brain iron accumulation in fumble and could be a treatment target for human PKAN.
Description
Keywords
malvolio, PKAN, ferritin, x-ray absorption spectroscopy, iron, NRAMP, fumble
Citation
Degree
Master of Science (M.Sc.)
Department
Anatomy and Cell Biology
Program
Anatomy and Cell Biology