Ferritin accumulation under iron scarcity in Drosophila iron cells

Mehta, Anuja; Deshpande, Abhyuday; Bettedi, Lucia; Missirlis, Fanis

doi:10.1016/j.biochi.2009.05.003

Cited by 45 publications

(75 citation statements)

References 28 publications

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“…Drosophila ferritin is predominantly found in the haemolymph, but it is also stored in the iron region of the intestine (Mehta et al, 2009;Poulson and Bowen, 1952). We examined the iron region of wandering third instar larvae to determine tissue iron loading of ferritin in situ (Fig.2).…”

Section: Resultsmentioning

confidence: 99%

“…The iron staining and microscopy procedures have been described previously in detail (Mehta et al, 2009). Briefly, intestines from third instar larvae were dissected in phosphate-buffered saline (PBS), fixed in 4% formaldehyde in PBS for 30 min and permeabilised with 1% Tween 20 in PBS for 15 min.…”

Section: Iron Staining and Microscopymentioning

confidence: 99%

“…As a rule we dissected five larvae per genotype per condition and repeated experiments a minimum of three times; variations in staining were small and, overall, the images presented are highly representative. Larvae were used as they have been studied more extensively in the past (Mehta et al, 2009;Poulson and Bowen, 1952) and because mutants that do not survive to adulthood can be studied (Gutierrez et al, 2010).…”

Section: Iron Staining and Microscopymentioning

confidence: 99%

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Iron depletion in the intestines ofMalvoliomutant flies does not occur in the absence of a multicopper oxidase

Bettedi

Aslam

Szular

et al. 2011

Journal of Experimental Biology

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SUMMARYMalvolio (Mvl) encodes the sole Drosophila melanogaster homologue of divalent metal transporter-1 (DMT1). The Drosophila transporter has been implicated in iron, manganese and copper cellular import. Indeed, the extent of metal specificity for this family of transporters is still under investigation in many eukaryotic species. Here, we revisit metal accumulation in Mvl mutants raised under normal and metal-supplemented diets. We found iron deficiency in Mvl mutant flies, whereas whole body copper and manganese concentrations remained unaltered. Iron supplementation restored total body iron concentrations in Mvl mutants, but without replenishing iron stores in the middle midgut, suggesting a role for Mvl in systemic iron trafficking, in addition to a role in intestinal iron absorption. Interestingly, dietary copper sulphate supplementation further exacerbated the iron deficiency. We investigated whether dietary copper affected iron storage through the function of an insect multicopper oxidase (MCO), because the mammalian MCO ceruloplasmin is known to regulate iron storage in the liver. We identified a Drosophila MCO mutant that suppressed aspects of the Mvl mutant phenotype and most notably Mvl, MCO3 double mutants showed normal intestinal iron storage. Therefore, MCO3 may encode an insect ferroxidase. Intriguingly, MCO3 mutants had a mild accumulation of copper, which was suppressed in Mvl mutants, revealing a reciprocal genetic interaction between the two genes. Supplementary material available online at

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Section: Resultsmentioning

confidence: 99%

Section: Iron Staining and Microscopymentioning

confidence: 99%

Section: Iron Staining and Microscopymentioning

confidence: 99%

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Iron depletion in the intestines ofMalvoliomutant flies does not occur in the absence of a multicopper oxidase

Bettedi

Aslam

Szular

et al. 2011

Journal of Experimental Biology

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“…For detecting iron in the ironstoring cells of the midgut (35), a Prussian blue staining method was used (29). Midguts from wandering larvae or female adults were dissected and fixed in 4% (wt/vol) formaldehyde, permeabilized with 1% Tween-20, incubated with 2% (wt/vol) K 4 Fe(CN) 6 in 0.24 N HCl, and rinsed with water.…”

Section: Methodsmentioning

confidence: 99%

Multicopper oxidase-1 is a ferroxidase essential for iron homeostasis in Drosophila melanogaster

Lang

Braun

Kanost

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Multicopper ferroxidases catalyze the oxidation of ferrous iron to ferric iron. In yeast and algae, they participate in cellular uptake of iron; in mammals, they facilitate cellular efflux. The mechanisms of iron metabolism in insects are still poorly understood, and insect multicopper ferroxidases have not been identified. In this paper, we present evidence that Drosophila melanogaster multicopper oxidase-1 (MCO1) is a functional ferroxidase. We identified candidate iron-binding residues in the MCO1 sequence and found that purified recombinant MCO1 oxidizes ferrous iron. An association between MCO1 function and iron homeostasis was confirmed by two observations: RNAi-mediated knockdown of MCO1 resulted in decreased iron accumulation in midguts and whole insects, and weak knockdown increased the longevity of flies fed a toxic concentration of iron. Strong knockdown of MCO1 resulted in pupal lethality, indicating that MCO1 is an essential gene. Immunohistochemistry experiments demonstrated that MCO1 is located on the basal surfaces of the digestive system and Malpighian tubules. We propose that MCO1 oxidizes ferrous iron in the hemolymph and that the resulting ferric iron is bound by transferrin or melanotransferrin, leading to iron storage, iron withholding from pathogens, regulation of oxidative stress, and/or epithelial maturation. These proposed functions are distinct from those of other known ferroxidases. Given that MCO1 orthologues are present in all insect genomes analyzed to date, this discovery is an important step toward understanding iron metabolism in insects.

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“…However, similar observations of a slight systemic iron overload in mice and flies with a BTBD9 mutant background suggest that homeostatic and feedback mechanisms that ultimately control iron supply, availability and uptake in specific tissues require further investigation in these models. Since flies lack a genuine IRP2, but express ferritin heavy and light chains in an iron-responsive manner, 39,46,47 it is also conceivable that BTBD9 influences IRP-1A in a similar fashion or that its molecular substrate is different in flies and mammals. Whatever the case, it seems reasonable to conclude in patients), then it would be consistent with our observations in HEK cells where increased expression of BTBD9 elevates ferritin levels.…”

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confidence: 99%

An emerging role for Cullin-3 mediated ubiquitination in sleep and circadian rhythm

Freeman

Mandilaras

Missirlis

et al. 2013

Fly

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Ferritin accumulation under iron scarcity in Drosophila iron cells

Cited by 45 publications

References 28 publications

Iron depletion in the intestines ofMalvoliomutant flies does not occur in the absence of a multicopper oxidase

Iron depletion in the intestines ofMalvoliomutant flies does not occur in the absence of a multicopper oxidase

Multicopper oxidase-1 is a ferroxidase essential for iron homeostasis in Drosophila melanogaster

An emerging role for Cullin-3 mediated ubiquitination in sleep and circadian rhythm

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